Neuroscience

Mode-dependent effect of high-frequency electrical stimulation of the anterior thalamic nucleus on amygdala-kindled seizures in rats.

Publication Date: 2012 May 12 PMID: 22588003
Authors: Zhang, Q. - Wu, Z. C. - Yu, J. T. - Yu, N. N. - Zhong, X. L. - Tan, L.
Journal: Neuroscience

Deep brain stimulation (DBS) is an emerging treatment of epilepsy. Anterior nucleus of the thalamus (ANT) is considered to be an attractive target due to its close connection to the limbic structures and wide regions of neocortex. The present study aimed to investigate the effects of high frequency stimulation (HFS) targeting the ANT on amygdala-kindled seizures in Wistar rats in two different stimulation modes i.e. pre-treatment and post-treatment stimulation, mimicking the scheduled and responsive stimulation in clinic use respectively. When fully-kindled seizures were achieved by daily amygdala kindling (1 s train of 1 ms pulses at 60 Hz), HFS (15 min train of 100 mus pulses at 150 Hz and 450-800 muA) was applied in two modes for 10 days. Bilateral post-treatment with HFS reduced the incidence of generalized seizures and the mean behavioral seizure stage and shortened average afterdischarge duration (ADD) and generalized seizure duration (GSD), while bilateral pre-treatment with HFS resulted in a similar but much weaker inhibition of seizures. On the other hand, we also found the two stimulation modes all increased the afterdischarge threshold and the differences of current intensity between afterdischarge threshold and generalized seizure threshold i.e. big up tri, open(GST-ADT). However, big up tri, open (GST-ADT) increased by at least 20 muA in bilateral post-treatment group, while less in bilateral pre-treatment group. Additionally, unilateral post-treatment with HFS failed to inhibit seizures. Our data shown that anti-epileptic effect of bilateral post-treatment with HFS of ANT is much stronger than that of bilateral pre-treatment HFS, indicating bilateral responsive stimulation might be more appropriate for clinical anti-epileptic treatment of ANT HFS.

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Cajal's first steps in scientific research.

Publication Date: 2012 May 12 PMID: 22588002
Authors: Serrano-Castro, P. J. - Garcia-Torrecillas, J. M.
Journal: Neuroscience

More than 125 years ago, Santiago Ramon y Cajal was able to draft and prove the neuron doctrine, and later, to develop prophetic theories about neural function and plasticity, many of which have been proven by current neuroscience. It was chance that made Cajal, during his doctorate studies, have his first contact with histology and force him to study the then current theories about pathogenesis of inflammation. Thus, he gained knowledge of the vascular hypothesis, by Julius Cohnheim, a German pathologist who, opposing the opinion of his teacher and father of cellular pathology, Rudolf Virchow, made leukocytes the protagonists of inflammation, given their ability to develop amoeboid movements directed by chemical signals. Cohnheim's chemotactic theory deeply influenced Cajal's conception of biology. So, the basic postulates of chemotaxis can be identified at different moments in Cajal's research, from the description of the "growth cone" in embryonic neuroblasts, the origin of the neurotrophic theory, to the proposal of the pathophysiological mechanisms of neuronal plasticity. From Cajal's point of view, the neurons move during its development and also to adapt to different external circumstances. Chemical endogenous substances can stimulate this movement in a similar way to leukocytes during the process of inflammation.

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Characterization of a Population of Th-Containing Interneurons in the External Plexiform Layer of the Rat Olfactory Bulb.

Publication Date: 2012 May 11 PMID: 22583798
Authors: Liberia, T. - Blasco-Ibanez, J. M. - Nacher, J. - Varea, E. - Zwafink, V. - Crespo, C.
Journal: Neuroscience

The olfactory bulb of mammals contains the major endogenous dopamine-producing system in the forebrain. The vast majority of dopaminergic neurons consists of juxtaglomerular cells, which innervate the olfactory glomeruli and modulate the entrance of sensory information to the olfactory bulb. Although dopaminergic juxtaglomerular cells have been widely investigated, the presence of dopaminergic interneurons other than juxtaglomerular cells has been largely unexplored. In this study, we analyze a population of tyrosine hydroxylase (TH)-containing interneurons located in the external plexiform layer of the rat olfactory bulb. These interneurons are GABAergic and morphologically heterogeneous. They have an axon and two to four dendrites running throughout the external plexiform layer. Frequently, they have appendages similar to spines in the dendrites and, sometimes, the distal portions of the dendritic branches show enlargements or swellings similar to varicosities. Contrary to other interneurons of the external plexiform layer, the TH-containing ones do not form dendro-dendritic synapses on principal cells and do not receive dendro-dendritic synapses from them. In fact, no synapses were found from the dendrites of these interneurons. When their dendrites are involved in synaptic contacts, they are always the postsynaptic element. They receive symmetrical and asymmetrical synapses from GABAergic and non-GABAergic axons of unidentified origin. Our data indicate that the local circuits of the external plexiform layer are more complex than previously thought. Although most of the interneurons of this layer establish dendro-dendritic synaptic relationships with principal cells, the TH-containing interneurons constitute an exception to this rule, resembling interneurons from other cortical areas.

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The soma and proximal dendrites of sympathetic preganglionic neurons innervating the major pelvic ganglion in female rats receive predominantly inhibitory inputs.

Publication Date: 2012 May 11 PMID: 22583797
Authors: Wu, L. - Chang, H. H. - Havton, L. A.
Journal: Neuroscience

Sympathetic preganglionic neurons (SPNs) in the intermediolateral (IML) and dorsal commissural nucleus (DCN) of the thoracolumbar segments of the spinal cord contribute to the autonomic control of the pelvic visceral organs. We examined the morphology of these neurons at the light and electron microscopic level and quantified the boutons apposing the soma and proximal dendrites of the SPNs innervating the major pelvic ganglion in female rats. The majority of these cells resided in the DCN (61.6 +/- 6.2%) and IML (33.2 +/- 4.4%) nuclei. Measurements of cell volume and shape revealed no differences between SPNs sampled from the DCN and IML populations. Ultrastructural studies of DCN and IML SPNs revealed that coverage of SPNs by synaptic inputs is sparse, with an average of 11.60 +/- 2.41% of the soma membrane and 16.33 +/- 6.18% of proximal dendrites apposed by boutons, though some somata exhibited no synaptic coverage. Three distinct types of boutons were found to appose the SPN somata and dendrites. The putatively inhibitory F-type bouton covered a significantly greater percentage of membrane on the soma (8.48 +/- 2.12%) and dendrites (12.65 +/- 4.34%), than the S-type bouton, a putatively excitatory bouton, which only covered 2.94 +/- 0.70% of the somatic and 3.68 +/- 2.98% of the dendritic membranes. Boutons with dense-core vesicles were rare. Our results demonstrate that SPNs of the DCN and IML of female rats are similar morphologically, and that synaptic input on these cells, though sparse, is predominantly inhibitory.

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Reactive Gliosis and Neuroinflammation in Rats with Communicating Hydrocephalus.

Publication Date: 2012 May 11 PMID: 22583796
Authors: Xu, H. - Zhang, S. L. - Tan, G. W. - Zhu, H. W. - Huang, C. Q. - Zhang, F. F. - Wang, Z. X.
Journal: Neuroscience

Reactive gliosis has been implicated in injury and recovery patterns associated with hydrocephalus. The roles that these mechanisms play in the pathophysiology of hydrocephalus are still not clear in terms of cytopathology and gene expression. In this paper, we investigated the relationship between reactive gliosis and neuroinflammation of hydrocephalic rats of different severity at both cellular and molecular levels. Therefore thirty five adult SD rats were randomly divided into the normal group(n=5), the sham operation group(n=5) and the model group (n=25). Hydrocephalic rat models were induced by intraventricular injections of 3% kaolin, and the ventricular dilatation were examinated by MRI at 2-week postoperation. Then the model group were subdivided into the mild group(n=5), the moderate group(n=7) and the severe group (n=9) according to the degree of ventricular dilatation. While IL-18, GFAP, Iba-1 were detected by ELISA, RT-PCR, Immunohistochemistry and western blot and correlation analysis was conducted at the same time. According to the result comparison between the normal group and the sham operation group, the ventricle of model group were obviously enlarged (P < 0. 01). The expression of GFAP and Iba-1 were increased (P < 0. 05) in brain tissue of model group and IL-18 was also increased in CSF sample of model group. It was revealed by correlation analysis that the increase was positively correlated with the severity of ventricular dilatation. Conclusion: These results indicate that gliosis and inflammation continue to rise dramatically in experimental hydrocephalus and can be regarded as the main factors of hydrocephalus. Regulating the level of gliosis and alleviateing inflammation may provide new therapeutic methods of hydrocephalus.

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Loss of histaminergic modulation of thermoregulation and energy homeostasis in obese mice.

Publication Date: 2012 May 9 PMID: 22579982
Authors: Sethi, J. - Sanchez-Alavez, M. - Tabarean, I. V.
Journal: Neuroscience

Histamine acts centrally to increase energy expenditure and reduce body weight by mechanisms not fully understood. It has been suggested that in the obese state hypothalamic histamine signaling is altered. Previous studies have also shown that histamine acting in the preoptic area controls thermoregulation. We aimed to study the influence of preoptic histamine on body temperature and energy homeostasis in control and obese mice. Activating histamine receptors in the preoptic area by increasing the concentration of endogenous histamine or by local injection of specific agonists induced an elevation of core body temperature and decreased respiratory exchange ratio (RER). In addition, the food intake was significantly decreased. The hyperthermic effect was associated with a rapid increase in mRNA expression of uncoupling proteins in thermogenic tissues, the most pronounced being that of uncoupling protein (UCP) 1 in brown adipose tissue and of UCP2 in white adipose tissue. In diet induced obese mice histamine had much diminished hyperthermic effects as well as reduced effect on RER. Similarly, the ability of preoptic histamine signaling to increase the expression of uncoupling proteins was abolished. We also found that the expression of mRNA encoding the H1 receptor subtype in the preoptic area was significantly lower in obese animals. These results indicate that histamine signaling in the preoptic area modulates energy homeostasis by regulating body temperature, metabolic parameters and food intake and that the obese state is associated with a decrease in neurotransmitter's influence.

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Maternal omega 3 fatty acid supplementation during pregnancy to a micronutrient imbalanced diet protects postnatal reduction of brain neurotrophins in the rat offspring.

Publication Date: 2012 May 9 PMID: 22579981
Authors: Sable, P. S. - Dangat, K. D. - Joshi, A. A. - Joshi, S. R.
Journal: Neuroscience

An altered one carbon cycle (folic acid, vitamin B(12)) and omega 3 fatty acid metabolism during pregnancy can increase the risk for neurodevelopmental disorders in the offspring. Our earlier studies have shown that a maternal diet imbalanced with micronutrients like folic acid, vitamin B(12) reduces levels of brain docosahexaenoic acid (DHA) and neurotrophins in the offspring at birth. The present study examines whether these effects can be reversed by a postnatal diet. Pregnant female rats were divided into six treatment groups at two levels of folic acid both in the presence and absence of vitamin B(12). Omega 3 fatty acid supplementation was given to the vitamin B(12) deficient groups. Following delivery, 8 dams from each group were randomly shifted back to control and remaining 8 continued on the same treatment diet. Plasma homocysteine levels could be normalized by a postnatal control diet. Brain DHA levels were similar in all the groups irrespective of the diet consumed during lactation. Brain derived nerve growth factor (BDNF) and (nerve growth factor (NGF) levels were lower in both the vitamin B(12) deficient groups even after consuming a diet with normal levels of vitamin B(12) during lactation (p<0.05 for all) indicating that the effects of maternal programming with respect to neurotrophins cannot be reversed by a postnatal diet. Our findings for the first time suggest that omega 3 fatty acid supplementation to a micronutrient imbalanced diet, during pregnancy and lactation protects the levels of BDNF and NGF. This may have significant implications in the development of psychiatric disorders/cognitive deficits in later life.

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RIP-1 kinase inhibition attenuates mitochondrial dysfunction in neurons and astrocytes following neonatal hypoxia-ischemia.

Publication Date: 2012 May 10 PMID: 22579794
Authors: Chavez-Valdez, R. - Martin, L. J. - Flock, D. L. - Northington, F. J.
Journal: Neuroscience

Receptor interacting protein (RIP)-1 kinase activity mediates a novel pathway that signals for regulated necrosis, a form of cell death prominent in traumatic and ischemic brain injury. Recently, we showed that inhibition of RIP-1 kinase activity, using necrostatin-1, provides neuroprotection in the forebrain following neonatal hypoxia-ischemia (HI). Because necrostatin-1 also prevents early oxidative injury, we hypothesized that mechanisms involved in this neuroprotection may involve preservation of mitochondrial function and prevention of secondary energy failure. Therefore, our objective was to determine if inhibition of RIP-1 kinase activity attenuates oxidative stress and mitochondrial injury. Postnatal day (p) 7 mice exposed to HI were injected intracerebroventricularly with 0.1muL (80 mumol) of necrostatin-1 or vehicle. RIP-1 kinase inhibition prevented the NO*, iNOS and 3-nitrotyrosine increase, and attenuated the glutathione oxidation that was found in vehicle-treated mice at 3h following HI. Similarly, RIP-1 kinase inhibition following HI prevented: i) up-regulation of HIF-1alpha and BNIP3 expression, ii) decline in mitochondrial complex-I activity, iii) decrease in ATP levels, and iv) mitochondrial structural pathology in astrocytes and in neurons. Up-regulation of glial fibrillary acidic protein (GFAP) following HI was also prevented by necrostatin-1 treatment. No differences by gender were observed. We conclude that inhibition of RIP-1 kinase activity, using necrostatin-1 immediately after HI, is strongly mitoprotective and prevents secondary energy failure by blocking early NO* accumulation, glutathione oxidation and attenuating mitochondrial dysfunction.

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Neuroscience disease models.

Publication Date: 2012 Jun 1 PMID: 22578882
Authors: Bezard, E. - Pisani, A. - Berton, O.
Journal: Neuroscience

This article is part of a Special Issue entitled: Neuroscience Disease Models.

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DNA memories of early social life.

Publication Date: 2012 May 7 PMID: 22575695
Authors: Hoffmann, A. - Spengler, D.
Journal: Neuroscience

The foundations of brain architecture are established early in life through a continuous series of dynamic interactions in which environmental conditions and personal experiences have a significant impact on how genetic predispositions are expressed. New scientific research shows that early social experiences can actually influence how genes are expressed. Thus, the old-school concepts that genes are "chiseled in stone" or that they alone determine development have been disproven. The discovery of the epigenome provides an explanation, at the molecular level, for why and how early positive and negative social experiences give rise to a biological memory that can have lifelong impacts. Signatures associated with the epigenome can be temporary or permanent, affect multiple organ systems, and increase the risk not only for poor physical and mental health outcomes but also for impairments in future learning capacity and behavior. Here, we focus on recent evidence for a role of epigenetic DNA modifications as a potential mechanism that explains how early social life experiences become embedded in the circuitry of the developing brain and are associated with lifelong consequences. This article is part of a Special Issue entitled: Epigenetics in brain function and evolution.

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Projections of the Central Medial Nucleus of the Thalamus in the Rat: Node in Cortical, Striatal and Limbic Forebrain Circuitry.

Publication Date: 2012 May 7 PMID: 22575585
Authors: Vertes, R. P. - Hoover, W. B. - Rodriguez, J. J.
Journal: Neuroscience

The central medial nucleus (CM) of thalamus is a prominent cell group of the rostral intralaminar complex of the thalamus. No previous report in the rat has comprehensively described the projections of CM. Using the anterograde anatomical tracer, Phaseolus vulgaris leucoagglutinin, we examined the efferent projections of CM, comparing projections from rostral (CMr) and caudal (CMc) regions of CM. We showed that the central medial nucleus distributes substantially to several cortical sites and to a limited number of subcortical structures. The primary CM targets were anterior and posterior regions of cortex, the claustrum, the caudate-putamen, the nucleus accumbens, the olfactory tubercle, and the amygdala. CMr and CMc distribute to several of the same structures but essentially to different parts of these structures. By comparison, CMr more strongly targets limbic structures, CMc more heavily sensorimotor structures. Main CMr projection sites were the medial agranular, anterior cingulate, prelimbic, dorsolateral orbital and dorsal agranular insular cortices, the dorsal striatum, the nucleus accumbens, and the basolateral nucleus of the amygdala. Main CMc cortical projection sites were the ventrolateral, lateral and dorsolateral orbital cortices, dorsal, ventral and posterior agranular insular cortices, visceral cortex, primary somatosensory and motor cortices, and perirhinal cortex. Main CMc subcortical projection sites were the dorsal striatum and the lateral, central, anterior cortical, and basomedial nuclei of amygdala. The largely complementary output of CMr and CMc to diverse areas of cortex and to regions of the striatum and amygdala suggest a combined CM influence over a widespread area of the anterior cortex and throughout the dorsal and ventral striatum and the amygdala. CM projections to limbic and sensorimotor structures of the rostral forebrain suggest that CM may serve to integrate affective, cognitive and sensorimotor functions for goal-directed behavior.

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Enhancing non-noxious perception: behavioural and neurophysiological correlates of a placebo-like manipulation.

Publication Date: 2012 May 5 PMID: 22569155
Authors: Fiorio, M. - Recchia, S. - Corra, F. - Simonetto, S. - Garcia-Larrea, L. - Tinazzi, M.
Journal: Neuroscience

Sensory perception can be influenced by cognitive functions like attention and expectation. An emblematic case of this is the placebo effect, where a reduction in pain perception can be obtained by inducing expectation of benefit following a treatment. The current study assessed the behavioural and brain activity correlates of a placebo procedure inducing an enhancement of non-noxious somatic sensation. An experimental group was verbally suggested and surreptitiously conditioned about the effect of an inert cream in enhancing tactile perception, while a control group was informed about the actual inefficacy of the cream. Both groups received non-noxious electric shocks activating A-Beta fibres on the right index finger, before and after application of the cream in the same site. The behavioural and neurophysiological effects of this procedure were measured by a numerical rating scale of subjective perception and by recording cortical and subcortical somatosensory evoked potentials (SEPs). Although the intensity of stimulation was physically identical in the two sessions, the experimental group reported stronger tactile sensation after cream treatment than before. In parallel, the experimental group showed enhanced somatosensory cortical responses (N140, P200) after treatment, whereas subcortical and early-cortical SEP components did not change. We suggest that these findings reflect top-down modulation on tactile perception probably due to an interplay between expectation and attention and might rely on interactions between prefrontal and parietal brain regions.

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Selectivity and Persistent Firing Responses to Social Vocalizations in the Basolateral Amygdala.

Publication Date: 2012 May 5 PMID: 22569154
Authors: Peterson, D. C. - Wenstrup, J. J.
Journal: Neuroscience

This study examined responsiveness to acoustic stimuli among neurons of the basolateral amygdala. While recording from single neurons in awake mustached bats (Pteronotus parnellii), we presented a wide range of acoustic stimuli including tonal, noise, and vocal signals. While many neurons displayed phasic or sustained responses locked to effective auditory stimuli, the majority of neurons (n = 58) displayed a persistent excitatory discharge that lasted well beyond stimulus duration and filled the interval between successive stimuli. Persistent firing usually began seconds (median value, 5.4 s) after the initiation of a train of repeated stimuli and lasted, in the majority of neurons, for at least 2 minutes after the end of the stimulus train. Auditory-responsive amygdalar neurons were generally excited by one stimulus or very few stimuli. Most neurons did not respond well to synthetic stimuli including tones, noise bursts or frequency-modulated sweeps, but instead responded only to vocal stimuli (82 of 87 neurons). Furthermore, most neurons were highly selective among vocal stimuli. On average, neurons responded to 1.7 of 15 different syllables or syllable sequences. The largest percentage of neurons responded to a hiss-like rectangular broadband noise burst (rBNB) call associated with aggressive interactions. Responsiveness to effective vocal stimuli was reduced or eliminated when the spectrotemporal features of the stimuli were altered in a subset of neurons. Chemical activation of the medial geniculate body increased both background and evoked firing. Among 39 histologically localized recording sites, we saw no evidence of topographic organization in terms of temporal response pattern, habituation, or the affect of calls to which neurons responded. Overall, these studies demonstrate that amygdalar neurons in the mustached bat show high selectivity to vocal stimuli, and suggest that persistent firing may be an important feature of amygdalar responses to social vocalizations.

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Hypoxic preconditioning induces an AT2-R/VEGFR-2(Flk-1) interaction in the neonatal brain microvasculature for neuroprotection.

Publication Date: 2012 May 5 PMID: 22569153
Authors: Lopez-Aguilera, F. - Plateo-Pignatari, M. G. - Biaggio, V. - Ayala, C. - Seltzer, A. M.
Journal: Neuroscience

The angiotensin II receptor subtype 2 (AT2-R) has been proposed to mediate protective vascular actions after brain injury. In this study we investigated the participation of this peptide in the tolerance to cellular damage induced by preconditioning in a rat model of neonatal hypoxia-ischemia (HI). We found that injured animals present a decreased number of microvessels in the ipsilateral side of the brain while in the contralateral side the microvessel number increased. On the contrary, in the preconditioned animals the microvessels maintained the same number as in control animals. However these vessels show a remarkable increase of the fluorescent signal when they are labeled with antiFlk-1 (VEGFR2), while the Flt-1 (VEGFR1) signal faded in both the injured and the preconditioned animals. The pharmacological blockade of the AT2-R by the drug PD123319 (1.69mM in the lateral ventricle) diminished the resilience of the microvasculature to HI injury provided by preconditioning and also the Flk-1 increase that occurred in these animals. In conclusion these results suggest an interaction of the AT2-R with VEGFR2 in the neonatal brain microvasculature that produces protective effects which are associated with injury tolerance.

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Pubertal Stage and Brain Anatomy in Girls.

Publication Date: 2012 May 5 PMID: 22569152
Authors: Blanton, R. E. - Cooney, R. E. - Joormann, J. - Eugene, F. - Glover, G. H. - Gotlib, I. H.
Journal: Neuroscience

Studies of puberty have focused primarily on changes in hormones and on observable physical bodily characteristics. Little is known, however, about the nature of the relation between pubertal status and brain physiology. This is particularly important given findings that have linked the onset of puberty with both changes in cognitive functioning and increases in the incidence of depression and anxiety. The present study examined relations between pubertal stage, as assessed by Tanner Staging, and brain anatomy in a sample of 54 girls aged 9 - 15 years. Brain morphometric analysis was conducted using high-resolution magnetic resonance imaging (MRI). The hippocampus and amygdala were manually traced on MRI scans in all participants. Stepwise regression analyses were conducted with total intracranial volume (ICV), age, and pubertal status as the predictor variables and hippocampus and amygdala volumes as outcome variables. Pubertal status was significantly associated with left amygdala volume, after controlling for both age and intracranial volume (ICV). In addition, puberty was related to right hippocampus and amygdala volumes, after controlling for ICV. In contrast, no significant associations were found between age and hippocampal and amygdala volumes after controlling for pubertal status and ICV. These findings highlight the importance of the relation between pubertal status and morphometry of the hippocampus and amygdala, and of limbic and subcortical structures that have been implicated in emotional and social behavior.

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ERK activation in spinal astrocytes and microglia contributes to cancer-induced bone pain in rats.

Publication Date: 2012 May 4 PMID: 22564552
Authors: Wang, X. W. - Li, T. T. - Zhao, J. - Mao-Ying, Q. L. - Zhang, H. - Hu, S. - Li, Q. - Mi, W. L. - Wu, G. C. - Zhang, Y. Q. - Wang, Y. Q.
Journal: Neuroscience

Cancer pain, especially cancer-induced bone pain, affects the quality of life of cancer patients, and current treatments for this pain are limited. The present study demonstrates that spinal ERK activation in glial cells plays a crucial role in cancer-induced bone pain. From day 4 to day 21 after the intra-tibia inoculation with Walker 256 mammary gland carcinoma cells, significant mechanical allodynia was observed as indicated by the decrease of mechanical withdrawal thresholds in the von Frey hair test. Intra-tibia inoculation with carcinoma cells induced a vast and persistent (>21 D) activation of ERK in the bilateral L2-L3 and L4-L5 spinal dorsal horn. The increased pERK1/2-immunoreactivity was observed in both Iba-1-expressing microglia and GFAP-expressing astrocytes but not in NeuN-expressing neurons. A single intrathecal injection of the selective MEK (ERK kinase) inhibitors PD98059 (10 mug) on day 12 and U0126 (1.25 mug, 3 mug) on day 14, attenuated the bilateral mechanical allodynia in the von Frey hair test. Altogether, our results suggest that ERK activation in spinal microglia and astrocytes is correlated with the onset of allodynia and important for allodynia maintenance in the cancer pain model. This study indicated that Inhibition of the ERK pathway may provide a new therapy for cancer-induced bone pain.

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Beyond counts and shapes: Studying pathology of dendritic spines in the context of the surrounding neuropil through serial section electron microscopy.

Publication Date: 2012 May 1 PMID: 22561733
Authors: Kuwajima, M. - Spacek, J. - Harris, K. M.
Journal: Neuroscience

Because dendritic spines are the sites of excitatory synapses, pathological changes in spine morphology should be considered as part of pathological changes in neuronal circuitry in the forms of synaptic connections and connectivity strength. In the past, spine pathology has usually been measured by changes in their number or shape. A more complete understanding of spine pathology requires visualization at the nanometer level to analyze how the changes in number and size affect their presynaptic partners and associated astrocytic processes, as well as organelles and other intracellular structures. Currently, serial section electron microscopy (ssEM) offers the best approach to address this issue because of its ability to image the volume of brain tissue at the nanometer resolution. Renewed interest in ssEM has led to recent technological advances in imaging techniques and improvements in computational tools indispensable for three-dimensional analyses of brain tissue volumes. Here we consider the small but growing literature that has used ssEM analysis to unravel ultrastructural changes in neuropil including dendritic spines. These findings have implications in altered synaptic connectivity and cell biological processes involved in neuropathology, and serve as anatomical substrates for understanding changes in network activity that may underlie clinical symptoms. This article is part of a Special Issue entitled: Spine Plasticity and Pathology in Brain Disorders.

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Is It All in the Family? The Effects of Early Social Structure on Neural-Behavioral Systems of Prairie Voles (Microtus ochrogaster).

Publication Date: 2012 May 1 PMID: 22561732
Authors: Greenberg, G. D. - van Westerhuyzen, J. A. - Bales, K. L. - Trainor, B. C.
Journal: Neuroscience

The transition to parenthood is generally associated with a reduction in anxiety or anxiety-like behavior across a wide range of species. In some species, juveniles provide supplementary parental care for younger siblings, a behavior known as alloparenting. Although the fitness consequences of alloparenting behavior have been a focus of evolutionary research, less is known about how alloparenting behavior impacts affective states. In the socially monogamous prairie vole (Microtus ochrogaster), most juveniles exhibit alloparenting behavior, making the species an ideal model for examining the effects of alloparenting on future behavioral outcomes. We randomly assigned juvenile voles to alloparenting (AL) or no alloparenting (NoAL) groups and behaviorally phenotyped them for anxiety-like and social behaviors using the elevated plus maze (EPM), open field test (OFT), startle box, social interaction test, juvenile affiliation test, and partner preference test. AL voles displayed more anxiety-like and less exploratory behavior than NoAL voles, spending significantly less time in the open arms of the EPM and center of an open field. We dissected the CA1 region of the hippocampus and the bed nucleus of the stria terminalis (BNST) from brains of behaviorally phenotyped voles and nontested siblings as well. Decreased BDNF expression in CA1 has generally been associated with increased anxiety-like behavior in other rodents, while an anxiogenic role for BDNF in BNST is less established. Western blot analyses showed that alloparenting experience increased expression of brain derived neurotrophic factor (BDNF) in the bed nucleus of stria terminalis (BNST) but decreased BDNF expression in the CA1 region of hippocampus (CA1) of nontested voles. There were similar differences in BNST BDNF of behaviorally phenotyped voles, and BDNF levels within this region were negatively correlated with exploratory behavior (i.e. time in center of OFT). Our results suggest that BDNF signaling in BNST and CA1 fluctuate with alloparenting experience, and they contribute to an increasingly complex "BDNF hypothesis" in which behavioral effects of this molecule are region-specific.

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Cholinergic denervation attenuates phencyclidine-induced c-fos responses in rat cortical neurons.

Publication Date: 2012 May 1 PMID: 22561731
Authors: Savage, S. - Mattsson, A. - Olson, L.
Journal: Neuroscience

The cortical cholinergic innervation, which is important for memory and cognition, has been implicated in schizophrenia. To experimentally analyze such a possible role of the cholinergic system, we have used the dissociative drug phencyclidine (PCP), known to produce schizophrenia-like psychosis in humans, to model aspects of schizophrenia in rats. We previously showed that induced cortical cholinergic hypofunction leads to enhanced PCP induced locomotor activity and attenuated social interaction. After PCP, rats lacking cortical cholinergic innervation also show impaired declarative memory. To directly study the role of the basalocortical cholinergic projections for PCP-induced neural activation in different cortical areas, we have now monitored the rapid (30 and 60 min) effects of low doses of PCP (2 and 3 mg/kg) on neural activation as reflected by transcriptional activation of c-fos in cortical areas, using quantitative in situ hybridization. We find an almost pan-cortical neural induction of c-fos mRNA with doses of PCP low enough not to alter levels of either BDNF or Nogo receptor mRNA levels. Specific unilateral lesioning of the uncrossed cholinergic projections to the cortical mantle by 192-IgG-saporin immunotoxin delivery to nc basalis (NBM) caused a striking ipsilateral decrease of the PCP-induced cortical c-fos mRNA induction, restricted to areas which had become effectively denervated. Because PCP at low doses is unlikely to directly influence cortical neurons, we suggest that it acts by activation of the cholinergic input, which in turn leads to cortical c-fos mRNA increases. Our results are compatible with a role for the cholinergic system in symptoms of schizophrenia, by showing that the basalocortical cholinergic projections are needed in order for PCP to have full activating effects on cortical neurons.

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Interactions between two propagating waves in rat visual cortex.

Publication Date: 2012 May 1 PMID: 22561730
Authors: Gao, X. - Xu, W. - Wang, Z. - Takagaki, K. - Li, B. - Wu, J. Y.
Journal: Neuroscience

Sensory-evoked propagating waves are frequently observed in sensory cortex. However, it is largely unknown how an evoked propagating wave affects the activity evoked by subsequent sensory inputs, or how two propagating waves interact when evoked by simultaneous sensory inputs. Using voltage-sensitive dye imaging, we investigated the interactions between two evoked waves in rat visual cortex, and the spatiotemporal patterns of depolarization in the neuronal population due to wave-to-wave interactions. We have found that visually-evoked propagating waves have a refractory period of about 300 ms, within which the response to a subsequent visual stimulus is suppressed. Simultaneous presentation of two visual stimuli at different locations can evoke two waves propagating toward each other, and these two waves fuse. Fusion significantly shortens the latency and half-width of the response, leading to changes in the spatial profile of evoked population activity. The visually-evoked propagating wave may also be suppressed by a preceding spontaneous wave. The refractory period following a propagating wave and the fusion between two waves may contribute to visual sensory processing by modifying the spatiotemporal profile of population neuronal activity evoked by sensory events.

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Controlled movement processing: Evidence for a common inhibitory control of finger, wrist, and arm movements.

Publication Date: 2012 Apr 30 PMID: 22554783
Authors: Brunamonti, E. - Ferraina, S. - Pare, M.
Journal: Neuroscience

We used the behavioral task and theoretical construct of the countermanding paradigm to test whether there is any difference between the inhibitory control of the finger, wrist, and arm. Participants were instructed (primary task) to respond to a directional go signal presented at the fovea by pressing a button with either their index or middle fingers, moving a joystick with their wrists, or reaching to a stimulus on a touch screen with their arms. They were also instructed (secondary task) to withhold their responses when a stop signal was presented on 25% of trials. The participants' ability to inhibit each of the commanded movements was captured by their inhibition probability function, which describes how withholding is increasingly difficult as the delay between the go and stop signals increased. By modeling each participant's inhibition function, we estimated that the time needed to inhibit a commanded movement was about 240ms, a variable that did not differ significantly between the three limb segments. Moreover, we found that the best-fit model of each segment's inhibition function could fit equally well the inhibition functions obtained with the other two segments. These results provide evidence that the upper limb segments share a common inhibitory control, which may facilitate the regulation of neuronal activity within the distributed motor cortical representations and thus simplify the voluntary control of multi-segmental movements.

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The C-terminus of neuronal Kv2.1 channels is required for channel localization and targeting but not for NMDA-receptor-mediated regulation of channel function.

Publication Date: 2012 Apr 30 PMID: 22554782
Authors: Baver, S. B. - O'Connell, K. M.
Journal: Neuroscience

The delayed rectifier voltage-gated potassium channel Kv2.1 underlies a majority of the somatic K(+) current in neurons and is particularly important for regulating intrinsic neuronal excitability. Various stimuli alter Kv2.1 channel gating as well as localization of the channel to cell-surface cluster domains. It has been postulated that specific domains within the C-terminus of Kv2.1 are critical for channel gating and sub-cellular localization; however, the distinct regions that govern these processes remain elusive. Here we show that the soluble C-terminal fragment of the closely related channel Kv2.2 displaces Kv2.1 from clusters in both rat hippocampal neurons and HEK293 cells, however neither steady-state activity nor N-methyl-d-aspartate (NMDA)-dependent modulation is altered in spite of this non-clustered localization. Further, we demonstrate that the C-terminus of Kv2.1 is not necessary for steady-state gating, sensitivity to intracellular phosphatase or NMDA-dependent modulation, though this region is required for localization of Kv2.1 to clusters. Thus, the molecular determinants of Kv2.1 localization and modulation are distinct regions of the channel that function independently.

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SK2 and SK3 expression differentially affect firing frequency and precision in dopamine neurons.

Publication Date: 2012 Apr 30 PMID: 22554781
Authors: Deignan, J. - Lujan, R. - Bond, C. - Riegel, A. - Watanabe, M. - Williams, J. T. - Maylie, J. - Adelman, J. P.
Journal: Neuroscience

The firing properties of dopamine (DA) neurons in the substantia nigra (SN) pars compacta are strongly influenced by the activity of apamin-sensitive small conductance Ca(2+)-activated K(+) (SK) channels. Of the three SK channel genes expressed in central neurons, only SK3 expression has been identified in DA neurons. The present findings show that SK2 was also expressed in DA neurons. Immuno-electron microscopy (iEM) showed that SK2 was primarily expressed in the distal dendrites, while SK3 was heavily expressed in the soma and, to a lesser extent, throughout the dendritic arbor. Electrophysiological recordings of the effects of the SK channel blocker apamin on DA neurons from wild type and SK(-/-) mice show that SK2-containing channels contributed to the precision of action potential (AP) timing, while SK3-containing channels influenced AP frequency. The expression of SK2 in DA neurons may endow distinct signaling and subcellular localization to SK2-containing channels.

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Differential effects of acute and regular physical exercise on cognition and affect.

Publication Date: 2012 Apr 30 PMID: 22554780
Authors: Hopkins, M. E. - Davis, F. C. - Vantieghem, M. R. - Whalen, P. J. - Bucci, D. J.
Journal: Neuroscience

The effects of regular exercise versus a single bout of exercise on cognition, anxiety, and mood were systematically examined in healthy, sedentary young adults who were genotyped to determine brain-derived neurotrophic factor (BDNF) allelic status (i.e., Val-Val or Val66Met polymorphism). Participants were evaluated on novel object recognition (NOR) memory and a battery of mental health surveys before and after engaging in either (a) a 4-week exercise program, with exercise on the final test day, (b) a 4-week exercise program, without exercise on the final test day, (c) a single bout of exercise on the final test day, or (d) remaining sedentary between test days. Exercise enhanced object recognition memory and produced a beneficial decrease in perceived stress, but only in participants who exercised for 4 weeks including the final day of testing. In contrast, a single bout of exercise did not affect recognition memory and resulted in increased perceived stress levels. An additional novel finding was that the improvements on the NOR task were observed exclusively in participants who were homozygous for the BDNF Val allele, indicating that altered activity-dependent release of BDNF in Met allele carriers may attenuate the cognitive benefits of exercise. Importantly, exercise-induced changes in cognition were not correlated with changes in mood/anxiety, suggesting that separate neural systems mediate these effects. These data in humans mirror recent data from our group in rodents. Taken together, these current findings provide new insights into the behavioral and neural mechanisms that mediate the effects of physical exercise on memory and mental health in humans.

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Brief mitochondrial inhibition causes lasting changes in motor behavior and corticostriatal synaptic physiology in the Fischer 344 rat.

Publication Date: 2012 Apr 30 PMID: 22554779
Authors: Akopian, G. - Crawford, C. - Petzinger, G. - Jakowec, M. W. - Walsh, J. P.
Journal: Neuroscience

The striatum is particularly vulnerable to mitochondrial dysfunction and this problem is linked to pathology created by environmental neurotoxins, stimulants like amphetamine, and metabolic disease and ischemia. We studied the course of recovery following a single systemic injection of the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NP) and found 3-NP caused lasting changes in motor behavior that were associated with altered activity-dependent plasticity at corticostriatal synapses in Fischer 344 rats. The changes in synapse behavior varied with the time after exposure to the 3-NP injection. The earliest time point studied, 24h after 3-NP, revealed 3-NP-induced an exaggeration of D1 Dopamine (DA) receptor dependent long-term potentiation (LTP) that reversed to normal by 48h post-3-NP exposure. Thereafter, the likelihood and degree of inducing D2 DA receptor dependent long-term depression (LTD) gradually increased, relative to saline controls, peaking at 1month after the 3-NP exposure. NMDA receptor binding did not change over the same post 3-NP time points. These data indicate even brief exposure to 3-NP can have lasting behavioral effects mediated by changes in the way DA and glutamate synapses interact.

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Dissipation of sleep pressure is stable across adolescence.

Publication Date: 2012 Apr 30 PMID: 22554778
Authors: Tarokh, L. - Carskadon, M. A. - Achermann, P.
Journal: Neuroscience

The sleep EEG undergoes many changes during adolescence. We assessed whether sleep homeostasis is altered across adolescent development using two measures: the dissipation of slow-wave activity (SWA, 0.6-4.6Hz) across the night and the rate of build-up of SWA in the first NREM sleep episode. Furthermore, we examined the association between homeostatic and circadian measures, by correlating the build-up of SWA in the first NREM sleep episode with circadian phase. Finally, we compared the dissipation of SWA in individuals with (PH+) and without (PH-) a parental history of alcohol abuse/dependence. Twenty children (8 PH+) and 25 teens (10 PH+) underwent two consecutive polysomnographic recordings at ages 9/10 and 15/16years and again 1.5-3years later. Thirteen young adults (ages 20-23; no PH+) were assessed one time. The decay of Process S was modeled for each individual at each assessment using data from both recordings. Four parameters of Process S were derived for EEG derivation C3/A2: time constant of the decay, lower asymptote (LA), the level of S at sleep onset (S(SO)), and S(SO) minus LA. We found no change in these parameters between assessments for the children and teen cohorts. Between-subject analysis of the follow-up assessment for children (ages 11-13) and the initial assessment for teens (ages 15/16) showed no difference in these parameters, nor did follow-up assessment of teens (ages 17-19) compared to the single assessment of young adults (ages 20-23). Similarly, we observed no developmental changes in the rate of the build-up of SWA in the first NREM sleep episode for our within- and between-subject analyses, or a correlation between this measure and circadian phase for either cohort. With regard to parental alcohol history, we found no difference in the dissipation of sleep pressure between PH+ and PH- children and teens. These results indicate that the dissipation of sleep pressure does not change across adolescent development, is not correlated with circadian phase, and does not differ between PH+ and PH- children and teens.

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Involvement of the Akt/GSK-3beta/CRMP-2 pathway in axonal injury after hypoxic-ischemic brain damage in neonatal rat.

Publication Date: 2012 Apr 30 PMID: 22554777
Authors: Xiong, T. - Tang, J. - Zhao, J. - Chen, H. - Zhao, F. - Li, J. - Qu, Y. - Ferriero, D. - Mu, D.
Journal: Neuroscience

Akt has been demonstrated as a survival kinase in brain after hypoxia-ischemia (HI). Previous studies have shown that glycogen synthase kinase-3beta (GSK-3beta)/collapsin response mediator protein 2 (CRMP-2) signaling pathway could be regulated by Akt for axonal-dendritic polarity. CRMP-2 is associated also with microtubule-mediated trafficking. However, whether Akt could regulate GSK-3beta/CRMP-2 pathway and the possible effects of this regulation is unclear in developing brain after HI. In this study, we detected the expression of total and phosphorylated Akt, GSK-3beta, and CRMP-2, as well as the axonal injury marker amyloid precursor protein (APP) by utilizing an HI model in postnatal 10-day rats. Axonal loss was determined by Bielschowsky silver impregnation, and histological injury was evaluated by hematoxylin and eosin (H&E) staining. We found that the phosphorylation of Akt was accompanied by phosphorylation of GSK-3beta and dephosphorylation of CRMP-2 after HI. Furthermore, Akt inhibition significantly decreased the phosphorylation of GSK-3beta and dephosphorylation of CRMP-2. Moreover, the down-regulation of dephosphorylated CRMP-2 was associated with increased axonal injury (increased APP expression and axonal loss). Our findings suggest that the Akt/GSK-3beta/CRMP-2 pathway mediates axonal injury in neonatal rat brain after HI.

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Age-dependent neuroinflammatory responses and deficits in long-term potentiation in the hippocampus during systemic inflammation.

Publication Date: 2012 Apr 30 PMID: 22554776
Authors: Liu, X. - Wu, Z. - Hayashi, Y. - Nakanishi, H.
Journal: Neuroscience

Chronic systemic inflammation induces age-dependent differential phenotypic changes in microglia and astrocytes, yielding an anti-inflammatory cell phenotype in young rats and a proinflammatory cell phenotype in middle-aged rats. These observations prompted further investigation of the functional outcomes of the resultant differential microglial phenotypic changes. The present study examined the effects of age-dependent differential microglial phenotypic changes following chronic systemic inflammation on the formation of the post-tetanic potentiation (PTP) and long-term potentiation (LTP) in the hippocampus. Microglia formed a proinflammatory cell phenotype to express ED1 and interleukin-1beta (IL-1beta) in the hippocampal CA1 region of middle-aged rats, but not in young rats following the establishment of adjuvant arthritis (AA). Furthermore, AA induced deficits in the formation of LTP in the Schaffer collateral-CA1 synapses of middle-aged rats, but not in young rats. On the other hand, the formation of PTP was impaired in both young and middle-aged AA rats. Minocycline, a known inhibitor of microglial activation, was systemically administered to middle-aged AA rats significantly restoring the mean magnitudes of both PTP and LTP. The mean expression levels of ED1 and IL-1beta were significantly suppressed. These observations strongly suggest that chronic systemic inflammation induces deficits in the hippocampal LTP in middle-aged rats through neuroinflammation mainly induced by microglia.

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Histamine is required during neural stem cell proliferation to increase neuron differentiation.

Publication Date: 2012 Apr 28 PMID: 22548783
Authors: Rodriguez, G. - Velasco, I. - Garcia-Lopez, G. - Solis, K. H. - Flores-Herrera, H. - Diaz, N. F. - Molina-Hernandez, A.
Journal: Neuroscience

Histamine in the adult central nervous system (CNS) acts as a neurotransmitter. This amine is one of the first neurotransmitters to appear during development reaching its maximum concentration simultaneously with neuron differentiation peak. This suggests that HA plays an important role in neurogenesis. We have previously shown that HA is able to increase neuronal differentiation of neural stem cells (NSCs) in vitro, by activating the histamine type 1 receptor. However the mechanism(s) by which HA has a neurogenic effect on NSCs has not been explored. Here we explore how HA is able to increase neuron phenotype. Cortex neuroepithelium progenitors were cultured and at passage two treatments with 100muM HA were given during cell proliferation and differentiation or only during differentiation. Immunocytochemistry was performed on differentiated cultures to detect mature neurons. To explore the expression of certain important transcriptional factors involved on asymmetric cell division and commitment, RT-PCR and qRT-PCR were performed. Results indicate that HA is required during cell proliferation in order to increase neuron differentiation and suggest that this amine increases neuron commitment during the proliferative phase probably by rising prospero 1 and neurogenin 1 expression.

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Phase de-synchronization effects auditory gating in the ventral striatum but not auditory cortex.

Publication Date: 2012 Apr 28 PMID: 22548782
Authors: Woldeit, M. L. - Schulz, A. L. - Ohl, F. W.
Journal: Neuroscience

The underlying mechanisms and involved brain areas in sensory gating of repetitive auditory stimuli remain unclear. Especially, the influence of the auditory cortex and the role of temporal precision are under debate. Our first objective was to analyze gating dynamics of local field potentials in the primary auditory cortex and the ventral striatum in an animal experiment, particularly, assessing the influence of the cortex. The second aim was to follow the hypothesis that auditory gating results from phase de-synchronization of evoked potentials in response to the second auditory stimulus. Local field potentials were recorded simultaneously in the auditory cortex and ventral striatum of awake Mongolian gerbils (n=15) during stimulation with trains of frequency-modulated tones. Gating was analyzed by amplitude ratios of the auditory potentials evoked by the first two stimuli in a train, as well as by time-frequency analyses and between-area phase coupling. The strength of auditory gating in the striatum was found to exceed that in the primary auditory cortex by more than 50%. While total-signal-power was comparable between areas, energy in the striatum was primarily expressed in the non-phase-locked fraction. At the same time, energy in the auditory cortex remained phase-locked to the stimuli. Furthermore, we also observed a between-area phase unlocking during sound presentations. Phase de-synchronization appears to be the candidate mechanism behind attenuation of responses to identical repetitive stimuli in the ventral striatum. We conclude that a direct inhibitory response suppression by the auditory cortex plays a minor role in this process.

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Spinal segmental and supraspinal mechanisms underlying the pain-relieving effects of spinal cord stimulation: An experimental study in a rat model of neuropathy.

Publication Date: 2012 Apr 28 PMID: 22548781
Authors: Barchini, J. - Tchagchagian, S. - Shamaa, F. - Jabbur, S. J. - Meyerson, B. A. - Song, Z. - Linderoth, B. - Saade, N. E.
Journal: Neuroscience

Spinal cord stimulation (SCS) may alleviate certain forms of neuropathic pain; its mechanisms of action are, however, not fully understood. Previous studies have mainly been focused onto segmental spinal mechanisms, though there is evidence indicating a supraspinal involvement. This study aims to evaluate the relative importance of segmental and supraspinal mechanisms related to the activation of the dorsal columns (DCs). Rats were used to induce the spared nerve injury neuropathy and simultaneously subjected to chronic bilateral DC lesions at the C6-C8 level. Two pairs of miniature electrodes were implanted in each animal, with a monopolar system placed in the dorsal epidural space at a low thoracic level (below lesion) and a bipolar system placed onto the dorsal column nuclei (above lesion). Stimulation (50Hz, 0.2ms, 2-4V, 5min) was applied via either type of electrodes, and tests for sensitivity to tactile and thermal stimuli were used to assess its inhibitory effects. Various receptor antagonists {bicuculline (GABA(A)), saclofen (GABA(B)), ketanserine (5HT(2)), methysergide (5HT(1-2)), phentolamine (alpha-adrenergic), propranolol (beta-adrenergic), sulpiride (D(2)/D(3) dopamine) or saline were injected prior to the SCS. Rostral and caudal stimulations produced a comparable inhibition of neuropathic manifestations, and these effects were attenuated by about 50% after DC lesions. Pretreatment with the various receptor antagonists differentially influenced the effects of rostral and caudal stimulation. Our findings suggest that both supraspinal and segmental mechanisms are activated by SCS, and that in this model with DC lesions, rostral and caudal stimulations may activate different synaptic circuitries and transmitter systems.

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High frequency stimulation alters motor maps, impairs skilled reaching performance and is accompanied by an upregulation of specific GABA, glutamate and NMDA receptor subunits.

Publication Date: 2012 Apr 27 PMID: 22546338
Authors: Henderson, A. K. - Pittman, Q. J. - Teskey, G. C.
Journal: Neuroscience

High frequency stimulation (HFS) has the potential to interfere with learning and memory. HFS and motor skill training both lead to potentiation of the stimulated network and alter motor map expression. However, the extent to which HFS can interfere with the learning and performance of a skilled motor task and the resulting effect on the representation of movement has not been examined. Moreover, the molecular mechanisms associated with HFS and skilled motor training on the motor cortex are not known. We hypothesized that HFS would impair performance on a skilled reaching task, and would be associated with alterations in motor map expression and protein levels compared to non-stimulated and untrained controls. Long Evans Hooded rats were chronically implanted with stimulating and recording electrodes in the corpus callosum and frontal neocortex, respectively. High frequency theta burst stimulation or sham stimulation was applied once daily for 20 sessions. The rats were divided into five groups: control, HFS and assessed at 1week post stimulation, HFS and assessed 3weeks post stimulation, reach trained, and HFS and reach trained. A subset of rats from each group was assessed with either intracortical microstimulation (ICMS) to examine motor map expression or Western blot techniques to determine protein expression of several excitatory and inhibitory receptor subunits. Firstly, we found that HFS resulted in larger and reorganized motor maps, and lower movement thresholds compared to controls. This was associated with an up-regulation of the GABA(A)alpha1 and NR1 receptor subunits 3weeks after the last stimulation session only. Stimulation affected skilled reaching performance in a subset of all stimulated rats. Rats that were poor performers had larger rostral forelimb areas, higher proximal and lower distal movement thresholds compared to rats that were good performers after stimulation. Reach training alone was associated with an up-regulation of GABA(A)alpha1, alpha2, GluR2, NR1 and NR2A compared to controls. HFS and reach-trained rats showed an up-regulation of GABA(A)alpha2 compared to stimulated rats that were not reach-trained. Therefore, we have shown that HFS induces significant plasticity in the motor cortex, and has the potential to disrupt performance on a skilled motor task.

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Dendritic spine pathology in schizophrenia.

Publication Date: 2012 Apr 27 PMID: 22546337
Authors: Glausier, J. R. - Lewis, D. A.
Journal: Neuroscience

Schizophrenia is a neurodevelopmental disorder whose clinical features include impairments in perception, cognition and motivation. These impairments reflect alterations in neuronal circuitry within and across multiple brain regions that are due, at least in part, to deficits in dendritic spines, the site of most excitatory synaptic connections. Dendritic spine alterations have been identified in multiple brain regions in schizophrenia, but are best characterized in layer 3 of the neocortex, where pyramidal cell spine density is lower. These spine deficits appear to arise during development, and thus are likely the result of disturbances in the molecular mechanisms that underlie spine formation, pruning, and/or maintenance. Each of these mechanisms may provide insight into novel therapeutic targets for preventing or repairing the alterations in neural circuitry that mediate the debilitating symptoms of schizophrenia. This article is part of a Special Issue entitled: Spine Plasticity and Pathology in Brain Disorders.

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Early and late activity in somatosensory cortex reflects changes in bodily self-consciousness: An evoked potential study.

Publication Date: 2012 Apr 27 PMID: 22546336
Authors: Aspell, J. E. - Palluel, E. - Blanke, O.
Journal: Neuroscience

How can we investigate the brain mechanisms underlying self-consciousness? Recent behavioural studies on multisensory bodily perception have shown that multisensory conflicts can alter bodily self-consciousness such as in the "full body illusion" (FBI) in which changes in self-identification with a virtual body and tactile perception are induced. Here we investigated whether experimental changes in self-identification during the FBI are accompanied by activity changes in somatosensory cortex by recording somatosensory-evoked potentials (SEPs). To modulate self-identification, participants were filmed by a video camera from behind while their backs were stroked, either synchronously (illusion condition) or asynchronously (control condition) with respect to the stroking seen on their virtual body. Tibial nerve SEPs were recorded during the FBI and analysed using evoked potential (EP) mapping. Tactile mislocalisation was measured using the crossmodal congruency task. SEP mapping revealed five sequential periods of brain activation during the FBI, of which two differed between the illusion condition and the control condition. Activation at 30-50ms (corresponding to the P40 component) in primary somatosensory cortex was stronger in the illusion condition. A later activation at approximately 110-200ms, likely originating in higher-tier somatosensory regions in parietal cortex, was stronger and lasted longer in the control condition. These data show that changes in bodily self-consciousness modulate activity in primary and higher-tier somatosensory cortex at two distinct processing steps. We argue that early modulations of primary somatosensory cortex may be a consequence of (1) multisensory integration of synchronous vs. asynchronous visuo-tactile stimuli and/or (2) differences in spatial attention (to near or far space) between the conditions. The later activation in higher-tier parietal cortex (and potentially other regions in temporo-parietal and frontal cortex) likely reflects the detection of visuo-tactile conflicts in the asynchronous condition.

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Inwardly rectifying potassium channel Kir4.1 is localized at the calyx endings of vestibular afferents.

Publication Date: 2012 Apr 27 PMID: 22546335
Authors: Udagawa, T. - Tatsumi, N. - Tachibana, T. - Negishi, Y. - Saijo, H. - Kobayashi, T. - Yaguchi, Y. - Kojima, H. - Moriyama, H. - Okabe, M.
Journal: Neuroscience

Inwardly rectifying potassium (Kir) channel Kir4.1 (also called Kcnj10) is expressed in various cells such as satellite glial cells. It is suggested that these cells would absorb excess accumulated K(+) from intercellular space which is surrounded by these cell membranes expressing Kir4.1. In the vestibular system, loss of Kir4.1 results in selective degeneration of type I hair cells despite normal development of type II hair cells. The mechanisms underlying this developmental disorder have been unclear, because it was thought that Kir4.1 is only expressed in glial cells throughout the entire nervous system. Here, we show that Kir4.1 is expressed not only in glial cells but also in neurons of the mouse vestibular system. In the vestibular ganglion, Kir4.1 mRNA is transcribed in both satellite cells and neuronal somata, whereas Kir4.1 protein is expressed only in satellite cells. On the other hand, in the vestibular sensory epithelia, Kir4.1 protein is localized at the calyx endings of vestibular afferents, which surround type I hair cells. Kir4.1 protein expression in the vestibular sensory epithelia is detected beginning after birth, and its localization gradually adopts a calyceal shape until type I hair cells are mature. Kir4.1 localized at the calyx endings may play a role in the K(+)-buffering action of vestibular afferents surrounding type I hair cells.

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Long-lasting transcriptional refractoriness triggered by a single exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine.

Publication Date: 2012 Apr 24 PMID: 22542874
Authors: Pattarini, R. - Rong, Y. - Shepherd, K. R. - Jiao, Y. - Qu, C. - Smeyne, R. J. - Morgan, J. I.
Journal: Neuroscience

Parkinson's disease (PD) is a progressive neurodegenerative disorder whose etiology is thought to have environmental (toxin) and genetic contributions. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) induces pathological features of PD including loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and striatal dopamine (DA) depletion. We previously described the striatal transcriptional response following acute MPTP administration in MPTP-sensitive C57BL/6J mice. We identified three distinct phases: early (5h), intermediate (24h) and late (72h) and reported that the intermediate and late responses were absent in MPTP-resistant Swiss-Webster (SWR) mice. Here we show that C57BL/6J mice pre-treated with a single 40mg/kg dose of MPTP and treated 9days later with 4x20mg/kg MPTP, display a striatal transcriptional response similar to that of MPTP-resistant SWR mice, i.e. a robust acute response but no intermediate or late response. Transcriptional refractoriness is dependent upon the dose of the priming challenge with as little as 10mg/kg MPTP being effective and can persist for more than 28days. Priming of SWR mice has no effect on their response to subsequent challenge with MPTP. We also report that paraquat, another free radical producer, also elicits striatal transcriptional alterations but these are largely distinct from those triggered by MPTP. Paraquat-induced changes are also refractory to priming with paraquat. However neither paraquat nor MPTP elicits cross-attenuation. Thus exposure to specific toxins triggers distinct transcriptional responses in striatum that are influenced by prior exposure to the same toxin. The prolonged refractory period described here for MPTP could explain at the molecular level the reported discrepancies between different MPTP administration regimens and may have implications for our understanding of the relationship between environmental toxin exposure and PD.

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Activation of alpha1-adrenoceptors enhances glutamate release onto ventral tegmental area dopamine cells.

Publication Date: 2012 Apr 24 PMID: 22542873
Authors: Velasquez-Martinez, M. C. - Vazquez-Torres, R. - Jimenez-Rivera, C. A.
Journal: Neuroscience

The ventral tegmental area (VTA) plays an important role in reward and motivational processes that facilitate the development of drug addiction. Glutamatergic inputs into the VTA contribute to dopamine (DA) neuronal activation related to reward and response-initiating effects in drug abuse. Previous investigations indicate that alpha1-adrenoreceptors (alpha1-ARs) are primarily localized at presynaptic elements in the ventral midbrain. Studies from several brain regions have shown that presynaptic alpha1-AR activation enhances glutamate release. Therefore, we hypothesized that glutamate released onto VTA-DA neurons is modulated by pre-synaptic alpha1-AR. Recordings were obtained from putative VTA-DA cells of male Sprague-Dawley rats (28-50days postnatal) using voltage clamp techniques. Phenylephrine (10muM) and methoxamine (80muM), both alpha1-AR agonists, increased AMPA receptor-mediated excitatory postsynaptic currents' (EPSCs) amplitude evoked by electrical stimulation of afferent fibers (p<0.05). This effect was blocked by the alpha1-AR antagonist prazosin (1muM). Phenylephrine decreased the paired-pulse ratio (PPR) and increased spontaneous EPSCs' frequencies but not their amplitudes suggesting a presynaptic locus of action. No changes in miniature EPSCs (0.5muM, tetrodotoxin [TTX]) were observed after phenylephrine's application which suggests that alpha1-AR effect was action potential dependent. Normal extra- and intracellular Ca(2+) concentration seems necessary for the alpha1-AR effect since phenylephrine in low Ca(2+) artificial cerebrospinal fluid (ACSF) and depletion of intracellular Ca(2+) stores with thapsigargin (10muM) failed to increase the AMPA EPSCs' amplitude. Chelerythrine (1muM, protein kinase C (PKC) inhibitor) but not Rp-cAMPS (11muM, PKA inhibitor) blocked the alpha1-AR activation effect on AMPA EPSCs, indicating that a PKC intracellular pathway is required. These results demonstrated that presynaptic alpha1-AR activation modulates glutamatergic inputs that affect VTA-DA neuronal excitability. alpha1-AR action might be heterosynaptically localized at glutamatergic fibers terminating onto VTA-DA neurons. It is suggested that drug-induced changes in alpha1-AR could be part to the neuroadaptations occurring in the mesocorticolimbic circuitry during the addiction process.

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First trial reactions and habituation rates over successive balance perturbations in Parkinson's disease.

Publication Date: 2012 Apr 24 PMID: 22542872
Authors: Nanhoe-Mahabier, W. - Allum, J. H. - Overeem, S. - Borm, G. F. - Oude Nijhuis, L. B. - Bloem, B. R.
Journal: Neuroscience

BACKGROUND: Balance control in Parkinson's disease is often studied using dynamic posturography, typically with serial identical balance perturbations. Because subjects can learn from the first trial, the magnitude of balance reactions rapidly habituates during subsequent trials. Changes in this habituation rate might yield a clinically useful marker. We studied balance reactions in Parkinson's disease using posturography, specifically focusing on the responses to the first, fully unpractised balance disturbance, and on the subsequent habituation rates. METHODS: Eight Parkinson patients and eight age- and gender-matched controls received eight consecutive toe-up rotations of a support-surface. Balance reactions were measured with a motion analysis system and converted to centre of mass displacements (primary outcome). RESULTS: Mean centre of mass displacement during the first trial was 51% greater in patients than controls (P=0.019), due to excessive trunk flexion and greater ankle plantar-flexion. However, habituated trials were comparable in both groups. Patients also habituated slower: controls were fully habituated at trial 2, whereas habituation in patients required up to five trials (P=0.004). The number of near-falls during the first trial was significantly correlated with centre of mass displacement during the first trial and with habituation rate. CONCLUSIONS: Higher first trial reactions and a slow habituation rate discriminated Parkinson's patients from controls, but habituated trials did not. Further work should demonstrate whether this also applies to clinical balance tests, such as the pull test, and whether repeated delivery of such tests offers better diagnostic value for evaluating fall risks in parkinsonian patients.

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Effects of minocycline on endogenous neural stem cells after experimental stroke.

Publication Date: 2012 Apr 24 PMID: 22542871
Authors: Rueger, M. A. - Muesken, S. - Walberer, M. - Jantzen, S. U. - Schnakenburg, K. - Backes, H. - Graf, R. - Neumaier, B. - Hoehn, M. - Fink, G. R. - Schroeter, M.
Journal: Neuroscience

Minocycline has been reported to reduce infarct size after focal cerebral ischemia, due to an attenuation of microglia activation and prevention of secondary damage from stroke-induced neuroinflammation. We here investigated the effects of minocycline on endogenous neural stem cells (NSCs) in vitro and in a rat stroke model. Primary cultures of fetal rat NSCs were exposed to minocycline to characterize its effects on cell survival and proliferation. To assess these effects in vivo, permanent cerebral ischemia was induced in adult rats, treated systemically with minocycline or placebo. Imaging 7days after ischemia comprised (i) Magnetic Resonance Imaging (MRI), assessing the extent of infarcts, (ii) Positron Emission Tomography (PET) with [(11)C]PK11195, characterizing neuroinflammation, and (iii) PET with 3'-deoxy-3'-[(18)F]fluoro-L-thymidine ([(18)F]FLT), detecting proliferating endogenous NSCs. Immunohistochemistry was used to verify ischemic damage and characterize cellular inflammatory and repair processes in more detail. In vitro, specific concentrations of minocycline significantly increased NSC numbers without increasing their proliferation, indicating a positive effect of minocycline on NSC survival. In vivo, endogenous NSC activation in the subventricular zone (SVZ) measured by [(18)F]FLT PET correlated well with infarct volumes. Similar to in vitro findings, minocycline led to a specific increase in endogenous NSC activity in both the SVZ as well as the hippocampus. [(11)C]PK11195 PET detected neuroinflammation in the infarct core as well as in peri-infarct regions, with both its extent and location independent of the infarct size. The data did not reveal an effect of minocycline on stroke-induced neuroinflammation. We show that multimodal PET imaging can be used to characterize and quantify complex cellular processes occurring after stroke, as well as their modulation by therapeutic agents. We found minocycline, previously implied in attenuating microglial activation, to have positive effects on endogenous NSC survival. These findings hold promise for the development of novel treatments in stroke therapy.

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An age-related axon terminal pathology around the first olfactory relay that involves amyloidogenic protein overexpression without plaque formation.

Publication Date: 2012 Apr 25 PMID: 22542680
Authors: Cai, Y. - Xue, Z. Q. - Zhang, X. M. - Li, M. B. - Wang, H. - Luo, X. G. - Cai, H. - Yan, X. X.
Journal: Neuroscience

The glomeruli are the first synaptic relay on the olfactory pathway and play a basic role in smell perception. Glomerular degeneration occurs in humans with age and in Alzheimer's disease (AD). The glomeruli heavily express beta-amyloid precursor protein (APP), beta-secretase (BACE1) and gamma-secretase complex. However, extracellular Abeta deposition occurs fairly rarely at this location in postmortem pathological studies. We sought to explore age-related glomerular changes that might link to alteration in amyloidogenic proteins and/or plaque pathogenesis in transgenic models of AD and humans. Focally increased BACE1 immunoreactivity (IR) in the glomerular layer was identified in several transgenic models, and characterized systematically in transgenic mice harboring five familiar AD-related mutations (5XFAD). These elements were co-labeled with antibodies against APP N-terminal (22C11) and Abeta N-terminal (3D6, 6E10) and mid-sequence (4G8). They were not co-labeled with two Abeta C-terminal antibodies (Ter40, Ter42), nor associated with extracellular amyloidosis. These profiles were further characterized to be most likely abnormal olfactory nerve terminals. Reduced glomerular area was detected in 6-12-month-old 5XFAD mice relative to non-transgenic controls, and in aged humans relative to young/adult controls, more robust in AD than aged subjects without cerebral amyloid and tau pathologies. The results suggest that olfactory nerve terminals may undergo age-related dystrophic and degenerative changes in AD model mice and humans, which are associated with increased labeling for amyloidogenic proteins but not local extracellular Abeta deposition. The identified axon terminal pathology might affect neuronal signal transmission and integration at the first olfactory synaptic relay.

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Lesioning noradrenergic neurons of the locus coeruleus in C57Bl/6 mice with unilateral 6-hydroxydopamine injection, to assess molecular, electrophysiological and biochemical changes in noradrenergic signaling.

Publication Date: 2012 Apr 25 PMID: 22542679
Authors: Szot, P. - Knight, L. - Franklin, A. - Sikkema, C. - Foster, S. - Wilkinson, C. W. - White, S. S. - Raskind, M. A.
Journal: Neuroscience

The locus coeruleus (LC) is the major loci of noradrenergic innervation to the forebrain. Due to the extensive central nervous system innervation of the LC noradrenergic system, a reduction in the number of LC neurons could result in significant changes in noradrenergic function in many forebrain regions. LC noradrenergic neurons were lesioned in adult male C57Bl/6 mice with the unilateral administration of 6-hydroxydopamine (6OHDA) (vehicle on the alternate side). Noradrenergic markers were measured 3weeks later to determine the consequence of LC loss in the forebrain. Direct administration of 6OHDA into the LC results in the specific reduction of noradrenergic neurons in the LC (as measured by electrophysiology, immunoreactivity and in situ hybridization), the lateral tegmental neurons and dopaminergic neurons in the substantia nigra (SN) and ventral tegmental region were unaffected. The loss of LC noradrenergic neurons did not result in compensatory changes in the expression of mRNA for norepinephrine (NE)-synthesizing enzymes. The loss of LC noradrenergic neurons is associated with reduced NE tissue concentration and NE transporter (NET) binding sites in the frontal cortex and hippocampus, as well as other forebrain regions such as the amygdala and SN. Adrenoreceptor (AR) binding sites (alpha(1)- and alpha(2)-AR) were not significantly affected on the 6OHDA-treated side compared to the vehicle-treated side, although there is a reduction of AR binding sites on both the vehicle- and 6OHDA-treated side in specific forebrain regions. These studies indicate that unilateral stereotaxic injection of 6OHDA into mice reduces noradrenergic LC neurons and reduces noradrenergic innervation to many forebrain regions, including the contralateral side.

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Sustained expression of brain-derived neurotrophic factor is required for maintenance of dendritic spines and normal behavior.

Publication Date: 2012 Apr 25 PMID: 22542678
Authors: Vigers, A. J. - Amin, D. S. - Talley-Farnham, T. - Gorski, J. A. - Xu, B. - Jones, K. R.
Journal: Neuroscience

Brain-derived neurotrophic factor (BDNF) plays important roles in the development, maintenance, and plasticity of the mammalian forebrain. These functions include regulation of neuronal maturation and survival, axonal and dendritic arborization, synaptic efficacy, and modulation of complex behaviors including depression and spatial learning. Although analysis of mutant mice has helped establish essential developmental functions for BDNF, its requirement in the adult is less well documented. We have studied late-onset forebrain-specific BDNF knockout (CaMK-BDNF(KO)) mice, in which BDNF is lost primarily from the cortex and hippocampus in early adulthood, well after BDNF expression has begun in these structures. We found that although CaMK-BDNF(KO) mice grew at a normal rate and can survive more than a year, they had smaller brains than wild-type siblings. The CaMK-BDNF(KO) mice had generally normal behavior in tests for ataxia and anxiety, but displayed reduced spatial learning ability in the Morris water task and increased depression in the Porsolt swim test. These behavioral deficits were very similar to those we previously described in an early-onset forebrain-specific BDNF knockout. To identify an anatomical correlate of the abnormal behavior, we quantified dendritic spines in cortical neurons. The spine density of CaMK-BDNF(KO) mice was normal at P35, but by P84, there was a 30% reduction in spine density. The strong similarities we find between early- and late-onset BDNF knockouts suggest that BDNF signaling is required continuously in the CNS for the maintenance of some forebrain circuitry also affected by developmental BDNF depletion.

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The role of mu-opioid receptor signaling in the dorsolateral periaqueductal gray on conditional and unconditional responding to threatening and aversive stimuli.

Publication Date: 2012 Apr 25 PMID: 22542677
Authors: Halladay, L. R. - Blair, H. T.
Journal: Neuroscience

Here we examined how mu-opioid receptor signaling in the periaqueductal gray (PAG) mediates conditional and unconditional responses to aversive stimuli. The mu-opioid agonist morphine (MOR) and/or the partially mu-selective antagonist naltrexone (NAL) were infused into dorsolateral PAG (dlPAG) during a fear conditioning task, in which rats were trained to fear an auditory conditional stimulus (CS) by pairing it with a unilateral eyelid shock unconditional stimulus (US). During drug-free test sessions, the CS elicited movement suppression responses (indicative of freezing) from trained rats that had not recently encountered the US. In trained rats that had recently encountered the US, the CS elicited flight behavior characterized by turning in the direction away from the eyelid where US delivery was anticipated. Infusions of MOR (30nmol/side) into dlPAG prior to the test session did not impair CS-evoked movement suppression, but did impair CS-evoked turning behaviors. MOR infusions also reduced baseline motor movement, but US-evoked reflex movements remained largely intact. NAL was infused at two dosages, denoted 1x (26nmol/side) and 10x (260nmol/side). Infusions of NAL into dlPAG did not affect CS- or US-evoked behavioral responses at the 1x dosage, but impaired CS-evoked movement suppression at the 10x dosage, both in the presence and absence of MOR. When rats were co-infused with MOR and NAL, MOR-induced effects were not reversed by either dosage of NAL, and some measures of MOR-induced movement suppression were enhanced by NAL at the 1x dosage. Based on these findings, we conclude that mu-opioid receptors in dlPAG may selectively regulate descending supraspinal motor pathways that drive active movement behaviors, and that interactions between MOR and NAL in dlPAG may be more complex than simple competition for binding at the mu receptor.

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Dendritic structure varies as a function of eccentricity in V1: A quantitative study of NADPH diaphorase neurons in the diurnal South American rodent agouti, Dasyprocta prymnolopha.

Publication Date: 2012 Apr 25 PMID: 22542676
Authors: da Rocha, E. G. - Freire, M. A. - Bahia, C. P. - Pereira, A. - Sosthenes, M. C. - Silveira, L. C. - Elston, G. N. - Picanco-Diniz, C. W.
Journal: Neuroscience

The cerebral cortex is often described as a composite of repeated units or columns, integrating the same basic circuit. The 'ice-cube' model of cortical organization, and 'canonical' circuit, born from insights into functional architecture, still require systematic comparative data. Here we probed the anatomy of an individual neuronal type within V1 to determine whether or not its dendritic trees are consistent with the 'ice-cube' model and theories of canonical circuits. In a previous report we studied the morphometric variability of NADPH-diaphorase (NADPH-d) neurons in the rat auditory, visual and somatosensory primary cortical areas. Our results suggested that the nitrergic cortical circuitry of primary sensory areas are differentially specialized, probably reflecting peculiarities of both habit and behavior of the species. In the present report we specifically quantified the dendritic trees of NADPH-d type I neurons as a function of eccentricity within V1. Individual neurons were reconstructed in 3D, and the size, branching and space-filling of their dendritic trees were correlated with their location within the visuotopic map. We found that NADPH-d neurons became progressively smaller and less branched with progression from the central visual representation to the intermediate and peripheral visual representation. This finding suggests that aspects of cortical circuitry may vary across the cortical mantle to a greater extent that envisaged as natural variation among columns in the 'ice-cube' model. The systematic variation in neuronal structure as a function of eccentricity warrants further investigation to probe the general applicability of columnar models of cortical organization and canonical circuits.

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Stress during development alters dendritic morphology in the nucleus accumbens and prefrontal cortex.

Publication Date: 2012 Apr 25 PMID: 22542675
Authors: Muhammad, A. - Carroll, C. - Kolb, B.
Journal: Neuroscience

The long-term effects of stress during development have been well characterized. However, the effects of developmental stress on the underlying neurological mechanisms related to the reward system are not well understood. The present report studied the long term effects of stress during development on the structural plasticity in the cortical and subcortical regions. Rats exposed to stress during embryonic development (prenatal stress; PS) or soon after birth (maternal separation; MS) were studied for structural alteration at the neuronal level in the nucleus accumbens (NAc), orbital frontal cortex (OFC), and medial prefrontal cortex (mPFC). The findings show that stress during development increased dendritic branching, length, and spine density in the NAc, and subregions of the PFC. PS experience increased dendritic branching and length in the mPFC apical and basilar dendrites. In contrast, a PS-associated decrease in dendritic branching and length was observed in the basilar branches of the OFC. MS resulted in an increase in dendritic growth and spine density in the subregions of the PFC. The effect of PS on neuroanatomy was more robust than MS despite the shorter duration and intensity. The altered dendritic growth and spine density associated with stress during development could have potential impact on NAc and PFC related behaviors.

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Distinct roles of neuroligin-1 and SynCAM1 in synapse formation and function in primary hippocampal neuronal cultures.

Publication Date: 2012 Apr 25 PMID: 22542674
Authors: Burton, S. D. - Johnson, J. W. - Zeringue, H. C. - Meriney, S. D.
Journal: Neuroscience

Neuroligins are a family of cell adhesion molecules critical in establishing proper central nervous system connectivity; disruption of neuroligin signaling in vivo precipitates a broad range of cognitive deficits. Despite considerable recent progress, the specific synaptic function of neuroligin-1 (NL1) remains unclear. A current model proposes that NL1 acts exclusively to mature pre-existent synaptic connections in an activity-dependent manner. A second element of this activity-dependent maturation model is that an alternate molecule acts upstream of NL1 to initiate synaptic connections. SynCAM1 (SC1) is hypothesized to function in this capacity, though several uncertainties remain regarding SC1 function. Using overexpression and chronic pharmacological blockade of synaptic activity, we now demonstrate that NL1 is capable of robustly recruiting synapsin-positive terminals independent of synaptic maturation and activity in 2-week old primary hippocampal neuronal cultures. We further report that neither SC1 overexpression nor knockdown of endogenous SC1 impacts synapsin punctum densities, suggesting that SC1 is not a limiting factor of synapse initiation in maturing hippocampal neurons in vitro. Consistent with these findings, we observed profoundly greater recruitment of synapsin-positive presynaptic terminals by NL1 than SC1 in a mixed-culture assay of artificial synaptogenesis between primary neurons and heterologous cells. Collectively, our results contend multiple aspects of the proposed model of NL1 and SC1 function and motivate an alternative model whereby SC1 may mature synaptic connections forged by NL1. Supporting this model, we present evidence that combined NL1 and SC1 overexpression triggers excitotoxic neurodegeneration through SC1 signaling at synaptic connections initiated by NL1.

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Stressor exposure of male and female juvenile mice influences later responses to stressors: Modulation of GABA(A) receptor subunit mRNA expression.

Publication Date: 2012 Apr 25 PMID: 22542673
Authors: Jacobson-Pick, S. - Audet, M. C. - McQuaid, R. J. - Kalvapalle, R. - Anisman, H.
Journal: Neuroscience

Stressors encountered during the juvenile period may have persistent effects on later behavioral and neurochemical functioning and may influence later responses to stressors. In the current investigation, we evaluated the influence of stressor exposure applied during the juvenile period (26-28days of age) on anxiety-related behavior, plasma corticosterone and on GABA(A) alpha2, alpha3, alpha5 and gamma2 mRNA expression within the prefrontal cortex (PFC) and amygdala measured during adulthood. These changes were monitored in the absence of a further challenge, as well as in response to either a social or a non-social psychogenic stressor administered during adulthood. Exposure to an acute adult stressor elicited anxiety in females and was still more pronounced among females that had also experienced the juvenile stressor. Among males, arousal and impulsivity predominated so that anxiety responses were less notable. Furthermore, experiencing the stressor as a juvenile influenced adult GABA(A) subunit expression, as did the adult stressor experience. These changes were differentially expressed in males and females. Moreover, these subunit variations were further moderated among mice that stressed as juveniles and were again exposed to an adult stressor. Interestingly, under conditions in which the juvenile stressor increased the expression of a particular subunit, exposure to a further stressor in adulthood resulted in the gamma-aminobutyric acid (GABA) subunit variations being attenuated in both sexes. The current results suggest that juvenile and adult stressor experiences elicit variations of GABA(A) receptor subunit expression that are region-specific as well as sexually-dimorphic. Stressful events during the juvenile period may have pronounced proactive effects on anxiety-related behaviors, but linking these to specific GABA(A) subunits is made difficult by the diversity of GABA changes that are evident as well as the dimorphic nature of these variations. Nevertheless, these GABA(A) sex-specific subunit variations may be tied to the differences in anxiety in males and females.

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Dopamine, serotonin and impulsivity.

Publication Date: 2012 Apr 25 PMID: 22542672
Authors: Dalley, J. W. - Roiser, J. P.
Journal: Neuroscience

Impulsive people have a strong urge to act without thinking. It is sometimes regarded as a positive trait but rash impulsiveness is also widely present in clinical disorders such as attention deficit hyperactivity disorder (ADHD), drug dependence, mania, and antisocial behaviour. Contemporary research has begun to make major inroads into unravelling the brain mechanisms underlying impulsive behaviour with a prominent focus on the limbic cortico-striatal systems. With this progress has come the understanding that impulsivity is a multi-faceted behavioural trait involving neurally and psychologically diverse elements. We discuss the significance of this heterogeneity for clinical disorders expressing impulsive behaviour and the pivotal contribution made by the brain dopamine and serotonin systems in the aetiology and treatment of behavioural syndromes expressing impulsive symptoms.

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Manganese induces p21 expression in PC12 cells at the transcriptional level.

Publication Date: 2012 Apr 25 PMID: 22542671
Authors: Zhao, F. - Zhang, J. - Cai, T. - Liu, X. - Liu, M. - Ke, T. - Chen, J. - Luo, W.
Journal: Neuroscience

Manganese is a common environmental and occupational pollutant. Excessive intake of manganese can cause toxicity known as manganism. Recently it has been demonstrated that unusual expression of cell-cycle proteins and aberrant cell-cycle progression in the central nervous system are involved in the pathogenesis of neurodegenerative diseases. The present studies were initiated to investigate whether p21 are induced after manganese exposure and its potential effects in vitro, with particular attention being given to understand the underlying regulatory mechanism of p21 induction by manganese in this process. We found that manganese induced DAergic cells injury and upregulation of p21 levels in nigrostriatal regions. Treatment of the PC12 cells with manganese resulted in a time- and concentration-dependent loss of cell viability. Analysis of cell-cycle profile indicated that manganese blocked cell-cycle progression by arresting the cell cycle at G2/M phase. Moreover, manganese treatment resulted in an increase in the mRNA and protein levels of p21, but did not have the same effect on other related factors. Silencing p21 by RNA interference showed a marked reversal of both G2/M arrest and the decrease in cell viability induced by manganese. Manganese did not stabilize the p21 protein and mRNA, and caused a marked increase in p21 mRNA levels together with an increase in its promoter activity, indicating a transcriptional mechanism. Overall, the in vivo and in vitro data suggest that exposure to manganese can increase p21 levels. An altered cell-cycle status of PC12 cells can be induced by manganese through p21 up-regulation, and the induction of p21 occurs at the transcriptional level via promoter activation and mRNA induction.

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Association of brain-derived neurotrophic factor and tyrosine kinase B receptor in pregnancy.

Publication Date: 2012 Apr 26 PMID: 22542551
Authors: Dhobale, M. - Mehendale, S. - Pisal, H. - D'Souza, V. - Joshi, S.
Journal: Neuroscience

Abnormal brain development in a compromised prenatal and/or early postnatal environment is thought to be a risk factor for several neurobehavioural disorders. However, the mechanisms underlying these are not well understood. We have earlier reported reduced placental docosahexaenoic acid (DHA) levels in preterm deliveries. We have hypothesized that increased oxidative stress and reduced DHA levels may lead to changes in the circulating levels of maternal and cord brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) levels. A total number of 96 women delivering preterm and 95 women delivering at term were recruited. Plasma BDNF levels were measured in both mother and cord blood plasma using the BDNF Immuno Assay kit. Placental TrkB levels were analysed using sandwich enzyme-linked immunosorbent assay (ELISA). Maternal plasma BDNF levels and placental TrkB levels were higher (p<0.05) while cord plasma BDNF levels were lower (p<0.01) in women delivering preterm as compared to term. There was a negative association between levels of placental TrkB and DHA (p=0.034). A negative association between maternal plasma BDNF levels and placental weight (p=0.001) was observed while a positive association was seen between cord plasma BDNF levels and gestation (p=0.025). The reduction in cord BDNF levels may have implications for altered neurodevelopment in childhood and later life. Studies need to be undertaken to follow up children born preterm for risk of neurobehavioural disorders like attention deficit hyperactivity disorder (ADHD) to understand the effect of altered BDNF at birth on neurodevelopment.

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Crosstalk between cdk5 and MEK-ERK signalling upon opioid receptor stimulation leads to upregulation of activator p25 and MEK1 inhibition in rat brain.

Publication Date: 2012 Apr 23 PMID: 22537847
Authors: Ramos-Miguel, A. - Garcia-Sevilla, J. A.
Journal: Neuroscience

Cyclin-dependent kinase 5 (cdk5) participates in opioid receptor signalling through complex molecular mechanisms. The acute effects of selective mu-(fentanyl) and delta-(SNC-80) opioid receptor agonists, as well as the chronic effects of morphine (the prototypic opiate agonist mainly acting at mu-receptors), modulating cdk5 and activators p35/p25 and their interactions with neurotoxic/apoptotic factors, dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32) and extracellular signal-regulated kinase (ERK) were quantified (Western Blot analyses) in the rat corpus striatum and/or cerebral cortex. To assess the involved mechanisms, MDL28170 was used to inhibit calpain activity and SL327 to disrupt MEK (ERK kinase)-ERK activation. Acute fentanyl (0.1mg/kg) and SNC-80 (10mg/kg) induced rapid (7-60min) 2- to 4-fold increases of p25 content, without induction of cdk5/p25 pro-apoptotic c-Jun NH(2)-terminal protein kinase or aberrant cleavage of poly(ADP-ribose)-polymerase-1, a hallmark of apoptosis. In contrast, fentanyl and SNC-80 stimulated cdk5-mediated p-Thr75 DARPP-32 (+116-166%; PKA inhibition) and p-Thr286 MEK1 (+21-82%; MEK inactivation), and this latter effect resulted in uncoupling of MEK to ERK signals. Calpain inhibition with MDL28170 (cleavage of p35 to p25) attenuated fentanyl-induced p25 accumulation (-57%), but not the stimulation of p-Thr286 MEK1 or p-Thr75 DARPP-32. MEK-ERK inhibition with SL327 fully prevented fentanyl-induced p25 upregulation. Notably, chronic morphine treatment (10-100mg/kg for 6days) also increased p25 content and p25/p35 ratio (and activated/inactivated MEK1) in rat brain cortex, which indicated that p25 upregulation persisted under the sustained stimulation of mu-opioid receptors. The results demonstrate that the acute stimulation of opioid receptors leads to upregulation of p25 activator through a MEK-ERK and calpain-dependent pathway, and to disruption of MEK-ERK signalling by a cdk5/p35-induced MEK1 inhibition. Moreover, the effects induced by the sustained stimulation of mu-receptors with morphine suggest the participation of cdk5/p25 complex in opiate-induced long-term neuroplasticity.

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Preservation of the hyperdirect pathway of basal ganglia in a rodent brain slice.

Publication Date: 2012 Apr 23 PMID: 22537846
Authors: Bosch, C. - Mailly, P. - Degos, B. - Deniau, J. M. - Venance, L.
Journal: Neuroscience

Basal ganglia are a network of interconnected nuclei, involved in motor control, goal-directed behaviors and procedural learning. Basal ganglia process information from the cerebral cortex through three main pathways. The striatum is the input nucleus of the direct (cortico-striato-nigral) and indirect (cortico-striato-pallido-subthalamo-nigral) pathways while the subthalamic nucleus (STN) is the input structure of the hyperdirect (cortico-subthalamo-nigral) pathway. Despite the fact that the hyperdirect pathway constitutes a central part of most of basal ganglia models, experimental studies concerning its synaptic transmission and plasticity are still lacking. This is mainly because in vitro brain slices do not preserve the hyperdirect pathway. Here, we address this by developing a hyperdirect pathway brain slice where cortico-subthalamo-nigral connections were preserved. We characterized the transmission properties and its monosynaptic features between the frontal cortex and the STN, and between the STN and the substantia nigra pars reticulata (SNr), the output nucleus of the hyperdirect pathway. Cortical stimulation evoked monosynaptic glutamatergic events in STN neurons with a mean latency of 11.3ms and a mean amplitude of 21pA. STN stimulations evoked monosynaptic glutamatergic events in SNr neurons with a mean latency of 2.5ms and a mean amplitude of 116pA. This brain slice also preserved a part of the direct and indirect pathways such as the cortico-striatal connection. This novel slice configuration containing the hyperdirect pathway is a useful tool to better understand the transmission and plasticity in this pathway and hence the physiology and the pathophysiology of basal ganglia.

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Overexpression of cellular prion protein (PrP(C)) prevents cognitive dysfunction and apoptotic neuronal cell death induced by amyloid-beta (Abeta(1-40)) administration in mice.

Publication Date: 2012 Apr 23 PMID: 22537845
Authors: Rial, D. - Piermartiri, T. C. - Duarte, F. S. - Tasca, C. I. - Walz, R. - Prediger, R. D.
Journal: Neuroscience

The cellular prion protein (PrP(C)) is a neuronal-anchored glycoprotein that has been associated with several functions in the CNS such as synaptic plasticity, learning and memory and neuroprotection. There is great interest in understanding the role of PrP(C) in the deleterious effects induced by the central accumulation of amyloid-beta (Abeta) peptides, a pathological hallmark of Alzheimer's disease, but the existent results are still controversial. Here we compared the effects of a single intracerebroventricular (i.c.v.) injection of aggregated Abeta(1-40) peptide (400pmol/mouse) on the spatial learning and memory performance as well as hippocampal cell death biomarkers in adult wild type (Prnp(+/+)), PrP(C) knockout (Prnp(0/0)) and the PrP(C) overexpressing Tg-20 mice. Tg-20 mice, which present a fivefold increase in PrP(C) expression in comparison to wild type mice, were resistant to the Abeta(1-40)-induced spatial learning and memory impairments as indicated by reduced escape latencies to find the platform and higher percentage of time spent in the correct quadrant during training and probe test sessions of the water maze task. The protection against Abeta(1-40)-induced cognitive impairments observed in Tg-20 mice was accompanied by a significant decrease in the hippocampal expression of the activated caspase-3 protein and Bax/Bcl-2 ratio as well as reduced hippocampal cell damage assessed by MTT and propidium iodide incorporation assays. These findings indicate that the overexpression of PrP(C) prevents Abeta(1-40)-induced spatial learning and memory deficits in mice and that this response is mediated, at least in part, by the modulation of programed cell death pathways.

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Morphine and MK-801 administration leads to alternative N-methyl-d-aspartate receptor 1 splicing and associated changes in reward seeking behavior and nociception on an operant orofacial assay.

Publication Date: 2012 Apr 21 PMID: 22531378
Authors: Anderson, E. M. - Del Valle-Pinero, A. Y. - Suckow, S. K. - Nolan, T. A. - Neubert, J. K. - Caudle, R. M.
Journal: Neuroscience

The NMDA receptor plays a large role in opioid-induced plastic changes in the nervous system. The expression levels of its NR1 subunit are altered dramatically by morphine but no changes in its alternative splicing have been reported. Changes in the splicing of the N1, C1, C2, and C2' cassettes can alter the pharmacology and regulation of this receptor. Western Blots run on brain tissue from rats made tolerant to morphine revealed altered splicing of the N1 cassettes in the accumbens and amygdala (AMY), and the C1 cassette in the AMY and the dorsal hippocampus (HIPP). After 3days of withdrawal C2'-containing NR1 subunits were down-regulated in each of these areas. These were not due to acute doses of morphine and may represent long-term alterations in drug-induced neuroplasticity. We also examined the effects of morphine tolerance on an operant orofacial nociception assay which forces an animal to endure an aversive heat stimulus in order to receive a sweet milk reward. Morphine decreased pain sensitivity as expected but also increased motivational reward seeking in this task. NMDAR antagonism potentiated this reward seeking behavior suggesting that instead of attenuating tolerance, MK-801 may actually alter the rewarding and/or motivational properties of morphine. When combined, MK-801 and morphine had an additive effect which led to altered splicing in the accumbens, AMY, and the HIPP. In conclusion, NR1 splicing may play a major role in the cognitive behavioral aspects especially in motivational reward-seeking behaviors.

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Transient expression of Xpn, an XLMR protein related to neurite extension, during brain development and participation in neurite outgrowth.

Publication Date: 2012 Apr 21 PMID: 22531377
Authors: Ishikawa, T. - Miyata, S. - Koyama, Y. - Yoshikawa, K. - Hattori, T. - Kumamoto, N. - Shingaki, K. - Katayama, T. - Tohyama, M.
Journal: Neuroscience

KIAA2022 has been implicated as a gene responsible for expressing X-linked mental retardation (XLMR) proteins in humans. However, the functional role of KIAA2022 in the human brain remains unclear. Here, we revealed that depletion of Kiaa2022 inhibits neurite outgrowth of PC12 cells, indicating that the gene participates in neurite extension. Thus, we termed Kiaa2022 as an XLMR protein related to neurite extension (Xpn). Using the mouse brain as a model and ontogenetic analysis of Xpn by real-time PCR, we clearly demonstrated that Xpn is expressed transiently during the late embryonic and perinatal stages. In situ hybridization histochemistry further revealed that Xpn-expressing neurons could be categorized ontogenetically into three types. The first type showed transient expression of Xpn during development. The second type maximally expressed Xpn during the late embryonic or perinatal stage. Thereafter, Xpn expression in this type of neuron decreased gradually throughout development. Nevertheless, a significant level of Xpn expression was detected even into adulthood. The third type of neurons initiated expression of Xpn during the embryonic stage, and continued to express the gene throughout the remaining developmental stages. Subsequent immunohistochemical analysis revealed that Xpn was localized to the nucleus and cytoplasm throughout brain development. Our findings indicate that Xpn may participate in neural circuit formation during developmental stages via nuclear and cytoplasmic Xpn. Moreover, disturbances of this neuronal circuit formation may play a role in the pathogenesis of mental retardation.

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Dynamics of phase-independent spectro-temporal tuning in primary auditory cortex of the awake ferret.

Publication Date: 2012 Apr 21 PMID: 22531376
Authors: Depireux, D. A. - Dobbins, H. D. - Marvit, P. - Shechter, B.
Journal: Neuroscience

Tuning of cortical neurons is often measured as a static property, or during a steady-state regime, despite a number of studies suggesting that tuning depends on when it is measured during a neuron's response (e.g., onset vs. sustained vs. offset). We have previously shown that phase-locked tuning to feature transients evolves as a dynamic quantity from the onset of the sound. In this follow-up study, we examined the phase-independent tuning during feature transients. Based on previous results, we hypothesized phase-independent tuning should evolve on the same timescale as phase-locked tuning. We used stimuli of constant level, but alternating between flat spectro-temporal envelope and a modulated envelope with well-defined spectral density and temporal periodicity. This allowed the measure of changes in tuning to novel spectro-temporal content, as happens during running speech and other sounds with rapid transitions without a confounding change in sound level. For 95% of neurons, tuning changed significantly from the onset, over the course of the response. For a majority of these cells, the change occurred within the first 40ms following a feature onset, often even around 10-20ms. This solidifies the idea that tuning can change rapidly from onset tuning to the sustained, steady-state tuning.

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Substance P-induced changes in cell genesis following diffuse traumatic brain injury.

Publication Date: 2012 Apr 21 PMID: 22531375
Authors: Carthew, H. L. - Ziebell, J. M. - Vink, R.
Journal: Neuroscience

Inhibition of substance P (SP) activity through the use of NK1 receptor antagonists has been shown to be a promising neuroprotective therapy following traumatic brain injury (TBI). Conversely, recent research has implicated SP in the stimulation of neurogenesis, suggesting that the neuropeptide has the potential to promote recovery following TBI. This study characterised the effects of SP and the NK1 antagonist, n-acetyl tryptophan (NAT), on cell proliferation following diffuse TBI. Adult male Sprague-Dawley rats were injured using the impact acceleration model of TBI and randomly assigned to one of five treatment groups: sham, vehicle control, NAT alone, SP alone or SP with NAT. Cellular proliferation was assessed with immunostaining for bromodeoxyuridine (BrdU) and cell-specific markers. Infusion of SP (+/-NAT) promoted cellular proliferation in the subventricular zone and dentate gyrus following TBI. This increase was largely associated with microglial proliferation and did not correspond with functional improvements. These results suggest that NAT treatment results in neuroprotection following TBI, mediated in part via inhibition of microglia.

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Xenon-induced inhibition of synchronized bursts in a rat cortical neuronal network.

Publication Date: 2012 Apr 21 PMID: 22531374
Authors: Uchida, T. - Suzuki, S. - Hirano, Y. - Ito, D. - Nagayama, M. - Gohara, K.
Journal: Neuroscience

Xenon (Xe) and other inert gases produce anesthesia via an inhibitory mechanism in neuronal networks. To better understand this mechanism, we measured the electrical signals from cultured rat cortical neuronal networks in a multi-electrode array (MEA) under an applied Xe pressure. We used the MEA to measure the firing of the neuronal network with and without Xe gas pressurized to 0.3MPa. The MEA system monitored neuronal spikes on 16 electrodes (each 50x50mum(2)) at a sampling rate of 20kHz. The embryo rat cortical cells were first cultured on MEAs without Xe for approximately 3weeks, at which time they produced synchronized bursts that indicate maturity. Then, with an applied Xe pressure, the synchronized bursts quickly ceased, whereas single spikes continued. The Xe-induced inhibition-recovery of neuronal network firing was reversible: after purging Xe from the system, the synchronized bursts gradually resumed. Thus, Xe did not inhibit single neuron firing, yet reversibly inhibited the synaptic transmission. This finding agrees with the channel-blocker and a modified-hydrate hypothesis of anesthesia, but not the lipid-solubility hypothesis.

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Gene delivery of antioxidant enzymes inhibits human immunodeficiency virus type 1 gp120-induced expression of caspases.

Publication Date: 2012 Apr 21 PMID: 22531373
Authors: Louboutin, J. P. - Agrawal, L. - Reyes, B. A. - van Bockstaele, E. J. - Strayer, D. S.
Journal: Neuroscience

Caspases are implicated in neuronal death in neurodegenerative and other central nervous system (CNS) diseases. In a rat model of human immunodeficiency virus type 1 (HIV-1) associated neurocognitive disorders (HAND), we previously characterized HIV-1 envelope gp120-induced neuronal apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. In this model, neuronal apoptosis occurred probably via gp120-induced reactive oxygen species (ROS). Antioxidant gene delivery blunted gp120-related apoptosis. Here, we studied the effect of gp120 on different caspases (3, 6, 8, 9) expression. Caspases production increased in the rat caudate-putamen (CP) 6h after gp120 injection into the same structure. The expression of caspases peaked by 24h. Caspases colocalized mainly with neurons. Prior gene delivery of the antioxidant enzymes Cu/Zn superoxide dismutase (SOD1) or glutathione peroxidase (GPx1) into the CP before injecting gp120 there reduced levels of gp120-induced caspases, recapitulating the effect of antioxidant enzymes on gp120-induced apoptosis observed by TUNEL. Thus, HIV-1 gp120 increased caspases expression in the CP. Prior antioxidant enzyme treatment mitigated production of these caspases, probably by reducing ROS levels.

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Effect of brain-derived neurotrophic factor on behavior and key members of the brain serotonin system in genetically predisposed to behavioral disorders mouse strains.

Publication Date: 2012 Apr 21 PMID: 22531372
Authors: Naumenko, V. S. - Kondaurova, E. M. - Bazovkina, D. V. - Tsybko, A. S. - Tikhonova, M. A. - Kulikov, A. V. - Popova, N. K.
Journal: Neuroscience

The effect of brain-derived neurotrophic factor (BDNF) on depressive-like behavior and serotonin (5-HT) system in the brain of antidepressant sensitive cataleptics (ASC)/Icg mouse strain, characterized by depressive-like behavior, in comparison with the parental nondepressive CBA/Lac mouse strain was examined. Significant decrease of catalepsy and tail suspension test (TST) immobility was shown 17days after acute central BDNF administration (300ng i.c.v.) in ASC mice. In CBA mouse strain, BDNF moderately decreased catalepsy without any effect on TST immobility time. Significant difference between ASC and CBA mice in the effect of BDNF on 5-HT system was revealed. It was shown that central administration of BDNF led to increase of 5-HT(1A) receptor gene expression but not 5-HT(1A) functional activity in ASC mice. Increased tryptophan hydroxylase-2 (Tph-2) and 5-HT(2A) receptor gene expression accompanied by 5-HT(2A) receptor sensitization was shown in BDNF-treated ASC but not in CBA mouse strain, suggesting BDNF induced increase in the brain 5-HT system functional activity and activation of neurogenesis in "depressive" ASC mice. There were no changes found in the 5-HT transporter mRNA level in BDNF-treated ASC and CBA mice. In conclusion, central administration of BDNF produced prolonged ameliorative effect on depressive-like behavior accompanied by increase of the Tph-2, 5-HT(1A) and 5-HT(2A) genes expression and 5-HT(2A) receptor functional activity in animal model of hereditary behavior disorders.

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Ectopic ependymal cells in striatum accompany neurogenesis in a rat model of stroke.

Publication Date: 2012 Apr 21 PMID: 22531371
Authors: Danilov, A. I. - Kokaia, Z. - Lindvall, O.
Journal: Neuroscience

Stroke-induced neurogenesis originates from a neural stem cell (NSC) niche in subventricular zone (SVZ). In mice, NSCs are concentrated in a so-called "neurogenic spot" in the lateral angle area of SVZ. We aimed to identify the "neurogenic spot" in the rat SVZ and to characterize the cellular changes in the ependymal cell compartment in this area at different time points after middle cerebral artery occlusion. The majority of ependymal cells outlining the ventricular wall did not proliferate, and their numbers in the "neurogenic spot" declined at 6 and 16weeks after stroke. Cells with the ultrastructural properties of ependymal cells were detected in the adjacent striatum. The number of these ectopic ependymal cells (EE cells) correlated positively with the magnitude of lateral ventricular enlargement and negatively with the ependymal cell number in the "neurogenic spot". EE cells were found along blood vessels, accumulated in the pericyst regions, and participated in scar formation but did not incorporate BrdU. We provide the first evidence for the occurrence of EE cells in the ischemic striatum following stroke.

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Lateral asymmetry of early seizure manifestations in experimental generalized epilepsy.

Publication Date: 2012 Apr 21 PMID: 22525136
Authors: Vinogradova, L. V. - Shatskova, A. B.
Journal: Neuroscience

Reorganization of seizure networks during epileptogenesis involves cortico-subcortical and interhemispheric interactions. In the audiogenic kindling (AK) model of generalized tonic-clonic seizures, upstream seizure propagation along ascending brainstem-to-forebrain pathways determines progressive intensification of repeated sound-induced convulsions. Full-blown audiogenic seizures are bilaterally symmetric and their repetition results in bisynchronous recruiting the cortex in secondary epileptogenesis. The present study describes lateral asymmetry of initial behavioral and EEG manifestations of audiogenic seizures and AK in Wistar and WAG/Rij rats with acoustic hypersensitivity. These rats exhibit consistent individual lateralization of running seizures (run directionality) induced by repeated binaural stimulation. Since this initial preconvulsive running reflects seizure onset in the auditory brainstem, the running asymmetry suggests non-symmetric early epileptic activation of brainstem substrates by sound in these rats. Repetition of the asymmetric brainstem seizures led to asynchronous recruiting the cortex into seizure network and lateralization of running seizures was predictive for asymmetry of early cortical seizure manifestations in Wistar and WAG/Rij rats. Both electrographic markers of AK, spreading depression (SD) and post-running afterdischarge, first appeared in the cortex ipsilateral to run direction, suggesting lateralized brainstem-to-forebrain seizure generalization during AK. At the population level, no bias in lateralization of running and SD was found in Wistar and WAG/Rij rats but incidence of secondary cortical seizures varied, depending on strain and run laterality. Among Wistar rats, cortical seizures developed more rarely in right-runners than in left-runners, suggesting enhanced resistance of the right hemisphere to epileptogenesis in rats of this strain. WAG/Rij rats with mixed (absence and audiogenic) epilepsy showed weak lateralization of early cortical seizures and no left-right difference in their incidence during AK. Present findings suggest (1) lateralized brainstem-to-forebrain seizure propagation and hemispheric difference in its facility in Wistar rats, (2) alterations of intra- and interhemispheric seizure propagation in WAG/Rij rats with genetic absence epilepsy.

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GABA(B) receptor-mediated selective peripheral analgesia by the non-proteinogenic amino acid, isovaline.

Publication Date: 2012 Apr 21 PMID: 22525135
Authors: Whitehead, R. A. - Puil, E. - Ries, C. R. - Schwarz, S. K. - Wall, R. A. - Cooke, J. E. - Putrenko, I. - Sallam, N. A. - Macleod, B. A.
Journal: Neuroscience

Peripherally restricted analgesics are desirable to avoid central nervous system (CNS) side effects of opioids. Nonsteroidal anti-inflammatory drugs produce peripheral analgesia but have significant toxicity. GABA(B) receptors represent peripheral targets for analgesia but selective GABA(B) agonists like baclofen cross the blood-brain barrier. Recently, we found that the CNS-impermeant amino acid, isovaline, produces analgesia without apparent CNS effects. On observing that isovaline has GABA(B) activity in brain slices, we examined the hypothesis that isovaline produces peripheral analgesia mediated by GABA(B) receptors. We compared the peripheral analgesic and CNS effect profiles of isovaline, baclofen, and GABA (a CNS-impermeant, unselective GABA(B) agonist). All three amino acids attenuated allodynia induced by prostaglandin E2 injection into the mouse hindpaw and tested with von Frey filaments. The antiallodynic actions of isovaline, baclofen, and GABA were blocked by the GABA(B) antagonist, CGP52432, and potentiated by the GABA(B) modulator, CGP7930. We measured Behavioural Hyperactivity Scores and temperature change as indicators of GABAergic action in the CNS. ED(95) doses of isovaline and GABA produced no CNS effects while baclofen produced substantial sedation and hypothermia. In a mouse model of osteoarthritis, isovaline restored performance during forced exercise to baseline values. Immunohistochemical staining of cutaneous layers of the analgesic test site demonstrated co-localization of GABA(B1) and GABA(B2) receptor subunits on fine nerve endings and keratinocytes. Isovaline represents a new class of peripherally restricted analgesics without CNS effects, mediated by cutaneous GABA(B) receptors.

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Notch signaling pathway regulates proliferation and differentiation of immortalized Muller cells under hypoxic conditions in vitro.

Publication Date: 2012 Apr 21 PMID: 22525134
Authors: Wang, Z. - Sugano, E. - Isago, H. - Murayama, N. - Tamai, M. - Tomita, H.
Journal: Neuroscience

Previous studies have indicated that Muller glia in chick and fish retinas can re-enter the cell cycle, express progenitor genes, and regenerate neurons via the Notch signaling pathway in response to retinal damage or growth factors. Here, we investigated the role of Notch signaling and the effect of hypoxia, as a means to induce retinal damage, on the proliferation of an immortalized Muller cell line (rMC-1 cells). Our data showed that rMC-1 cells expressed Muller glia and neural and retinal progenitor markers but did not express neuronal or retinal markers. Hypoxia increased rMC-1 cell proliferation by activating the positive cell-cycle regulators, cyclins A and D1, as well as the neural and retinal progenitor markers, Notch1, Hes1, nestin, Sox2, Msi1, Pax6, and NeuroD1. However, hypoxia did not significantly influence the expression of Muller glial markers GS, CRALBP, and cyclin D3 or the death of the rMC-1 cells. The increase in cell proliferation induced by hypoxia was greatly attenuated by blocking Notch signaling with the inhibitor DAPT, resulting in the reduced expression of positive cell-cycle regulators (cyclins A and D1) and neural and retinal progenitor markers (Notch1, Hes1, Sox2, Pax6, and NeuroD1). Blockade of the Notch signaling pathway by DAPT after hypoxia promoted the differentiation of rMC-1 cells to neurons, as demonstrated by the induction of neural marker (Tuj1), retinal amacrine (Syntaxin1), and retinal ganglion cell (Brn3b) markers, although the expression of the latter marker was low. Taken together, our data indicate that Notch signaling is required for proliferation under hypoxic conditions either by activating the positive cell-cycle regulators or by skewing their de-differentiation towards a neural progenitor lineage. These findings indicate that the Notch signaling pathway regulates hypoxia-induced proliferation and differentiation of Muller glia.

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Diverse populations of intrinsic cholinergic interneurons in the mouse olfactory bulb.

Publication Date: 2012 Apr 21 PMID: 22525133
Authors: Krosnowski, K. - Ashby, S. - Sathyanesan, A. - Luo, W. - Ogura, T. - Lin, W.
Journal: Neuroscience

Cholinergic activities affect olfactory bulb (OB) information processing and associated learning and memory. However, the presence of intrinsic cholinergic interneurons in the OB remains controversial. As a result, morphological and functional properties of these cells are largely undetermined. We characterized cholinergic interneurons using transgenic mice that selectively mark choline acetyltransferase (ChAT)-expressing cells and immunolabeling. We found a significant number of intrinsic cholinergic interneurons in the OB. These interneurons reside primarily in the glomerular layer (GL) and external plexiform layer (EPL) and exhibit diverse distribution patterns of nerve processes, indicating functional heterogeneity. Further, we found these neurons express ChAT and vesicular acetylcholine transporter (VAChT), but do not immunoreact to glutamatergic, GABAergic or dopaminergic markers and are distinct from calretinin-expressing interneurons. Interestingly, the cholinergic population partially overlaps with the calbindin D28K-expressing interneuron population, revealing the neurotransmitter identity of this sub-population. Additionally, we quantitatively determined the density of VAChT labeled cholinergic nerve fibers in various layers of the OB, as well as the intensity of VAChT immunoreactivity within the GL, suggesting primary sites of cholinergic actions. Taken together, our results provide clear evidence showing the presence of a significant number of cholinergic interneurons and that these morphologically and distributionally diverse interneurons make up complex local cholinergic networks in the OB. Thus, our results suggest that olfactory information processing is modulated by dual cholinergic systems of local interneuron networks and centrifugal projections.

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Substance P release in response to cardiac ischemia from rat thoracic spinal dorsal horn is mediated by TRPV1.

Publication Date: 2012 Apr 21 PMID: 22525132
Authors: Steagall, R. J. - Sipe, A. L. - Williams, C. A. - Joyner, W. L. - Singh, K.
Journal: Neuroscience

Spinal cord stimulation (SCS) inhibits substance P (SP) release and decreases the expression of the transient receptor potential vanilloid 1 (TRPV1) in the spinal cord at thoracic 4 (T4) during cardiac ischemia in rat models (Ding et al., 2007). We hypothesized that activation of TRPV1 in the T4 spinal cord segment by intermittent occlusion of the left anterior descending coronary artery (CoAO) mediates spinal cord SP release. Experiments were conducted in urethane-anesthetized Sprague-Dawley male rats using SP antibody-coated microprobes to measure SP release at the central terminal endings of cardiac ischemic-sensitive afferent neurons (CISAN) in the spinal T4 dorsal horns. Vehicle, capsaicin (CAP; TRPV1 agonist) and capsazepine (CZP; TRPV1 antagonist) were injected into the left T4 prior to stimulation of CISAN by intermittent CoAO (with or without upper cervical SCS). CAP induced endogenous SP release from laminae I and II in the T4 spinal cord above baseline. Conversely, CZP injections significantly inhibited SP release from laminae I-VII in the T4 spinal cord segment below baseline. CZP also attenuated CoAO-induced SP release, while T4 injections of CZP with SCS completely restored SP release to basal levels during CoAO activation. CAP increased the number of c-Fos (a marker for CISAN activation) positive T4 dorsal horn neurons compared to sham-operated animals, while CZP (alone or during CoAO and SCS+CoAO) significantly reduced the number of c-Fos positive neurons. These results suggest that spinal release of the putative nociceptive transmitter SP occurs, at least in part, via a TRPV1 mechanism.

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Auditory perception of natural sound categories - An fMRI study.

Publication Date: 2012 Apr 20 PMID: 22522473
Authors: Sharda, M. - Singh, N. C.
Journal: Neuroscience

Despite an extremely rich and complex auditory environment, human beings categorize sounds effortlessly. While it is now well-known that this ability is a result of complex interaction of bottom-up processing of low-level acoustic features and top-down influences like evolutionary relevance, it is yet unclear how these processes drive categorization. The objective of the current study was to use functional neuroimaging to investigate the contribution of these two processes for category selectivity in the cortex. We used a set of ecologically valid sounds that belonged to three different categories: animal vocalizations, environmental sounds and human non-speech sounds, all matched on acoustic structure attributes like harmonic-to-noise ratio to minimize differences in bottom-up processing as well as matched for familiarity to rule out other top-down influences. Participants performed a loudness judgment task in the scanner and data were acquired using a sparse-temporal sampling paradigm. Our functional imaging results show that there is category selectivity in the cortex only for species-specific vocalizations and this is revealed in six clusters in the right and left STG/STS. Category selectivity was not observed for any other category of sounds. Our findings suggest a potential role of evolutionary relevance for cortical processing of sounds. While this seems to be an appealing proposition, further studies are required to explore the role of top-down mechanisms arising from such features to drive category selectivity in the brain.

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The trouble with spines in fragile X syndrome: density, maturity and plasticity.

Publication Date: 2012 Apr 20 PMID: 22522472
Authors: He, C. X. - Portera-Cailliau, C.
Journal: Neuroscience

Dendritic spines are the principal recipients of excitatory synaptic inputs and the basic units of neural computation in the mammalian brain. Alterations in the density, size, shape, and turnover of mature spines, or defects in how spines are generated and establish synapses during brain development, could all result in neuronal dysfunction and lead to cognitive and/or behavioral impairments. That spines are abnormal in fragile X syndrome (FXS) and in the best-studied animal model of this disorder, the Fmr1 knockout mouse, is an undeniable fact. But the trouble with spines in FXS is that the exact nature of their defect is still controversial. Here, we argue that the most consistent abnormality of spines in FXS may be a subtle defect in activity-dependent spine plasticity and maturation. We also propose some future directions for research into spine plasticity in FXS at the cellular and ultrastructural levels that could help solve a two-decade-long riddle about the integrity of synapses in this prototypical neurodevelopmental disorder.

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Rapamycin attenuates aggressive behavior in a rat model of pilocarpine-induced epilepsy.

Publication Date: 2012 Apr 20 PMID: 22522471
Authors: Huang, X. - McMahon, J. - Huang, Y.
Journal: Neuroscience

Psychiatric disorders are fairly common comorbidities of epilepsy in humans. Following pilocarpine-induced status epilepticus (SE), experimental animals not only developed spontaneous recurrent seizures, but also exhibited significantly elevated levels of aggressive behavior. The cellular and molecular mechanism triggering these behavioral alterations remains unclear. In the present study, we found that aggression is positively correlated with development of spontaneous seizures. Treatment with rapamycin, a potent mTOR (mammalian target of rapamycin pathway)-pathway inhibitor, markedly diminished aggressive behavior. Therefore, the mTOR pathway may have significance in the underlying molecular mechanism leading to aggression associated with epilepsy.

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Stress, anxiety, and dendritic spines: What are the connections?

Publication Date: 2012 Apr 20 PMID: 22522470
Authors: Leuner, B. - Shors, T. J.
Journal: Neuroscience

Stressful life events, especially those that induce fear, can produce a state of anxiety that is useful for avoiding similar fearful and potentially dangerous situations in the future. However, they can also lead to exaggerated states, which over time can produce mental illness. These changing states of readiness versus illness are thought to be regulated, at least in part, by alterations in dendritic and synaptic structure within brain regions known to be involved in anxiety. These regions include the amygdala, hippocampus, and prefrontal cortex. In this article, we review the reciprocal relationships between the expression of stress- and anxiety-related behaviors and stress-induced morphological plasticity as detected by changes in dendrites and spines in these three brain regions. We begin by highlighting the acute and chronic effects of stress on synaptic morphology in each area and describe some of the putative mechanisms that have been implicated in these effects. We then discuss the functional consequences of stress-induced structural plasticity focusing on synaptic plasticity as well as cognitive and emotional behaviors. Finally, we consider how these structural changes may contribute to adaptive behaviors as well as maladaptive responses associated with anxiety.

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Dendritic spine pathology in epilepsy: Cause or consequence?

Publication Date: 2012 Apr 20 PMID: 22522469
Authors: Wong, M. - Guo, D.
Journal: Neuroscience

Abnormalities in dendritic spines have commonly been observed in brain specimens from epilepsy patients and animal models of epilepsy. However, the functional implications and clinical consequences of this dendritic pathology for epilepsy are uncertain. Dendritic spine abnormalities may promote hyperexcitable circuits and seizures in some types of epilepsy, especially in specific genetic syndromes with documented dendritic pathology, but in these cases it is difficult to differentiate their effects on seizures versus other comorbidities, such as cognitive deficits and autism. In other situations, seizures themselves may cause damage to dendrites and dendritic spines and this seizure-induced brain injury may then contribute to progressive epileptogenesis, memory problems and other neurological deficits in epilepsy patients. The mechanistic basis of dendritic spine abnormalities in epilepsy has begun to be elucidated and suggests novel therapeutic strategies for treating epilepsy and its complications. This article is part of a Special Issue entitled: Spine Plasticity and Pathology in Brain Disorders. (c) 2012 Published by Elsevier Ltd on behalf of IBRO.

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Methods of dendritic spine detection: From Golgi to high-resolution optical imaging.

Publication Date: 2012 Apr 20 PMID: 22522468
Authors: Mancuso, J. J. - Chen, Y. - Li, X. - Xue, Z. - Wong, S. T.
Journal: Neuroscience

Dendritic spines, the bulbous protrusions that form the postsynaptic half of excitatory synapses, are one of the most prominent features of neurons and have been imaged and studied for over a century. In that time, changes in the number and morphology of dendritic spines have been correlated to the developmental process as well as the pathophysiology of a number of neurodegenerative diseases. Due to the sheer scale of synaptic connectivity in the brain, work to date has merely scratched the surface in the study of normal spine function and pathology. This review will highlight traditional approaches to the imaging of dendritic spines and newer approaches made possible by advances in microscopy, protein engineering, and image analysis. The review will also describe recent work that is leading researchers toward the possibility of a systematic and comprehensive study of spine anatomy throughout the brain.

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Neuropeptide Y receptor-expressing dorsal horn neurons: Role in nocifensive reflex and operant responses to aversive cold after CFA inflammation.

Publication Date: 2012 Apr 21 PMID: 22522467
Authors: Lemons, L. L. - Wiley, R. G.
Journal: Neuroscience

The spinal Neuropeptide Y (NPY) system is a potential target for development of new pain therapeutics. NPY and two of its receptors (Y1 and Y2) are found in the superficial dorsal horn of the spinal cord, a key area of nociceptive gating and modulation. Lumbar intrathecal injection of (NPY) is antinociceptive, reducing hyper-reflexia to thermal and mechanical stimulation, particularly after nerve injury and inflammation. We have also shown that intrathecal injection of the targeted cytotoxin, Neuropeptide Y-sap (NPY-sap), is also antinociceptive, reducing nocifensive reflex responses to noxious heat and formalin. In the present study, we sought to determine the role of dorsal horn Y1R-expressing neurons in pain by destroying them with NPY-sap and testing the rats on three operant tasks. Lumbar intrathecal NPY-sap (1) reduced Complete Freund's Adjuvant (CFA)-induced hyper-reflexia on the 10 degrees C cold plate, (2) reduced cold aversion on the thermal preference and escape tasks, (3) was analgesic to noxious heat on the escape task, (4) reduced the CFA-induced allodynia to cold temperatures experienced on the thermal preference, feeding interference, and escape tasks, and (5) did not inhibit or interfere with morphine analgesia.

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Hypothalamic vasopressin system regulation by maternal separation: Its impact on anxiety in rats.

Publication Date: 2012 Apr 20 PMID: 22522466
Authors: Zhang, L. - Hernandez, V. S. - Liu, B. - Medina, M. P. - Nava-Kopp, A. T. - Irles, C. - Morales, M.
Journal: Neuroscience

Maternal separation (MS) has been used to model the causal relationship between early life stress and the later stress-over-reactivity and affective disorders. Arginine vasopressin (AVP) is among several factors reported to be abnormal. The role of AVP on anxiety is still unclear. In order to further investigate this causal relationship and its possible role in anxiogenesis, male rat pups were separated from their dams for 3h daily (3hMS) from post-natal day (PND) 2 to PND15. Fos expression in AVP+ neurons in the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON) triggered by 3hMS, and AVP-mRNA expression, were examined at PND10 and PND21 respectively, whereas AVP-mRNA expression, PVN and SON volumes and plasma AVP concentration were assessed in adulthood. Elevated plus maze test (EPM) and Vogel conflict test (VCT) were also performed to evaluate unconditioned and conditioned anxious states at PND70-75. At PND10, a single 3hMS event increased Fos expression in AVP+ neurons fourfold in PVN and six to twelvefold in SON. AVP-mRNA was over-expressed in whole hypothalamus, PVN and SON between 122% and 147% at PND21 and PND63. Volumes of AVP-PVN and AVP-SON measured at PND75 had marked increases as well as AVP plasma concentration at 12h of water deprivation (WD). MS rats demonstrated a high conditioned anxious state under VCT paradigm whereas no difference was found under EPM. These data demonstrate direct relationships between enhanced AVP neuronal activation and a potentiated vasopressin system, and this latter one with high conditioned anxiety in MS male rats.

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Spatial summation of neurometabolic coupling in the central visual pathway.

Publication Date: 2012 Apr 20 PMID: 22522465
Authors: Li, B. - Freeman, R. D.
Journal: Neuroscience

Noninvasive neural imaging has become an important tool in both applied and theoretical applications. The hemodynamic properties that are measured in functional magnetic resonance imaging (fMRI), for example, are generally used to infer neuronal characteristics. In an attempt to provide empirical data to connect the hemodynamic measurements with neural function, we have conducted previous studies in which neural activity and tissue oxygen metabolic functions are determined together in co-localized regions of the central visual pathway. A basic question in this procedure is whether oxygen responses are coupled linearly in space and time with neural activity. We have previously examined temporal factors, and in the current study, spatial characteristics are addressed. We have recorded from neurons in the lateral geniculate nucleus (LGN) and striate cortex in anesthetized cats. In both structures, there is a classical receptive field (CRF) within which a neuron can be activated. There is also a region outside the CRF from which stimulation cannot activate the cell directly but can influence the response elicited from the CRF. In this investigation we have used several specific spatial stimulus patterns presented to either the CRF or the surrounding region or to both areas together in order to determine spatial response patterns. Within the CRF, we find that neural and metabolic responses sum in a nonlinear fashion but changes in these two measurements are closely coupled. For stimuli that extend beyond the CRF, neural activity is generally reduced while oxygen response exhibits uncoupled changes.

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Animal models of l-DOPA-induced dyskinesia: an update on the current options.

Publication Date: 2012 Jun 1 PMID: 22465440
Authors: Iderberg, H. - Francardo, V. - Pioli, E. Y.
Journal: Neuroscience

Major limitations to the pharmacotherapy of Parkinson's disease (PD) are the motor complications resulting from l-DOPA treatment. Abnormal involuntary movements (dyskinesia) affect a majority of the patients after a few years of l-DOPA treatment and can become troublesome and debilitating. Once dyskinesia has debuted, an irreversible process seems to have occurred, and the movement disorder becomes almost impossible to eliminate with adjustments in peroral pharmacotherapy. There is a great need to find new pharmacological interventions for PD that will alleviate parkinsonian symptoms without inducing dyskinesia. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate model is an excellent symptomatic model of PD and was the first model used to reproduce l-DOPA-induced dyskinesia experimentally. As it recapitulates the motor features of human dyskinesia, that is, chorea and dystonia, it is considered a reliable animal model to define novel therapies. Over the last decade, rodent models of l-DOPA-induced dyskinesia have been developed, having both face validity and predictive validity. These models have now become the first-line experimental tool for therapeutic screening purposes. The application of classical 6-hydroxydopamine (6-OHDA) lesion procedures to produce rodent models of dyskinesia has provided the field with more dynamic tools, since the versatility of toxin doses and injection coordinates allows for mimicking different stages of PD. This article will review models developed in non-human primate and rodents to reproduce motor complications induced by dopamine replacement therapy. The recent breakthroughs represented by mouse models and the relevance of rodents in relation to non-human primate models will be discussed. This article is part of a Special Issue entitled: Neuroscience Disease Models.

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Animal models of eating disorders.

Publication Date: 2012 Jun 1 PMID: 22465439
Authors: Kim, S. F.
Journal: Neuroscience

Feeding is a fundamental process for basic survival and is influenced by genetics and environmental stressors. Recent advances in our understanding of behavioral genetics have provided a profound insight on several components regulating eating patterns. However, our understanding of eating disorders, such as anorexia nervosa, bulimia nervosa, and binge eating, is still poor. The animal model is an essential tool in the investigation of eating behaviors and their pathological forms, yet development of an appropriate animal model for eating disorders still remains challenging due to our limited knowledge and some of the more ambiguous clinical diagnostic measures. Therefore, this review will serve to focus on the basic clinical features of eating disorders and the current advances in animal models of eating disorders. This article is part of a Special Issue entitled: Neuroscience Disease Models.

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Stress-induced impairments in prefrontal-mediated behaviors and the role of the N-methyl-d-aspartate receptor.

Publication Date: 2012 Jun 1 PMID: 22414923
Authors: Graybeal, C. - Kiselycznyk, C. - Holmes, A.
Journal: Neuroscience

The prefrontal cortex (PFC) mediates higher-order cognitive and executive functions that subserve various complex, adaptable behaviors, such as cognitive flexibility, attention, and working memory. Deficits in these functions typify multiple neuropsychiatric disorders that are caused or exacerbated by exposure to psychological stress. Here we review recent evidence examining the effects of stress on executive and cognitive functions in rodents and discuss an emerging body of evidence that implicates the N-methyl-d-aspartate receptor (NMDAR) as a potentially critical molecular mechanism mediating these effects. Future work in this area could open up new avenues for developing pharmacotherapies for ameliorating cognitive dysfunction in neuropsychiatric disease. This article is part of a Special Issue entitled: Neuroscience Disease Models.

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GABA(A) and GABA(B) receptors have opposite effects on synaptic glutamate release on the nucleus tractus solitarii neurons.

Publication Date: 2012 May 3 PMID: 22410341
Authors: Kang, Y. H. - Sun, B. - Park, Y. S. - Park, C. S. - Jin, Y. H.
Journal: Neuroscience

Cranial visceral afferent nerve transfers information about visceral organs to nucleus tractus solitarii (NTS) by releasing the excitatory neurotransmitter glutamate. Various endogenous modulators affect autonomic reflex responses by changing glutamatergic responses in the NTS. Although the expression of GABA(A) and GABA(B) receptors in glutamatergic terminals is known, their functional contribution on glutamate release is poorly characterized. Here, we used mechanically isolated NTS neurons to examine the mechanisms by which presynaptic GABA(A) and GABA(B) receptors modulate glutamatergic excitatory postsynaptic currents (EPSCs). EPSC were isolated by clamping voltage at equilibrium potential for chloride (-49 mV) without any GABA receptors antagonists. In all neurons, GABA(A) agonist, muscimol (1 and 10 muM), increased EPSC frequency (284.1+/-57% and 278.4+/-87% of control, respectively), but the GABA(B) agonist, baclofen (10 muM), decreased EPSC frequency (43+/-8% of control). The GABA(A) antagonist, gabazine (18 muM), decreased EPSC frequency in 50% of tested neurons, whereas GABA(B) antagonist, CGP (5 muM), increased the EPSC frequency in 36% of tested neurons. External application of GABA (1 and 30 muM) facilitating the EPSC frequency. The facilitation of the GABA(A) receptor-mediated release of glutamate was blocked by Na(+)-K(+)-Cl(-) cotransporter type 1 antagonist or Na(+) and Ca(2)(+) channel inhibitors indicating GABA(A) presynaptic depolarization. Thus, tonically released GABA activates GABA(A) and GABA(B) receptors to modulate the release of glutamate. These findings provide cellular mechanisms of heterosynaptic GABA-glutamate integration of peripheral visceral afferent signals in the NTS.

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The inhibitory action of the antimigraine nonsteroidal anti-inflammatory drug naproxen on P2X3 receptor-mediated responses in rat trigeminal neurons.

Publication Date: 2012 May 3 PMID: 22406417
Authors: Hautaniemi, T. - Petrenko, N. - Skorinkin, A. - Giniatullin, R.
Journal: Neuroscience

Enhanced nociceptive firing in trigeminal ganglion neurons is a likely reason for migraine pain. In experimental migraine-like conditions induced by the calcitonin gene-related peptide (CGRP), P2X3 receptors abundantly expressed in trigeminal neurons are highly responsive to the excitatory action of extracellular ATP. In this study, we tested whether naproxen, a common antimigraine medicine, could affect the function of P2X3 receptors in the presence or absence of the algogen nerve growth factor (NGF), the level of which is elevated in patients with chronic migraine. We used calcium imaging and patch clamp recordings from rat trigeminal neurons, which were activated by a relative specific P2X3 agonist alpha,beta-meATP or by high potassium-induced depolarization. In the absence of NGF, naproxen dose-dependently (0.1-1 mM) reduced intracellular calcium transients elicited by alpha,beta-meATP. Naproxen also led to a slight, but significant, reduction in calcium transients induced by potassium ions, indicating the involvement of voltage-gated calcium channels. The inhibitory action of 1 mM naproxen was enhanced after NGF pretreatment, suggesting that P2X3 receptors in sensitized neurons are more susceptible to inhibition by high doses of this nonsteroidal anti-inflammatory drug (NSAID). Using patch clamp recordings from HEK293 cells expressing P2X3 receptors, we tested the direct action of naproxen on P2X3 receptor-mediated membrane currents. In clinically relevant concentrations of 0.5 mM, naproxen produced a use-dependent blocking effect on ATP receptors. Kinetic analysis suggests that naproxen inhibited P2X3 receptors via facilitation of fast desensitization, which determines current decay in the continuous presence of the agonist. In summary, we present a novel fast mechanism for the antimigraine action of naproxen, which can act in synergy with the cyclooxygenase inhibition to attenuate headaches.

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Neuroprotective effects of extremely low-frequency electromagnetic fields on a Huntington's disease rat model: effects on neurotrophic factors and neuronal density.

Publication Date: 2012 May 3 PMID: 22406415
Authors: Tasset, I. - Medina, F. J. - Jimena, I. - Aguera, E. - Gascon, F. - Feijoo, M. - Sanchez-Lopez, F. - Luque, E. - Pena, J. - Drucker-Colin, R. - Tunez, I.
Journal: Neuroscience

There is evidence to suggest that the neuroprotective effect of exposure of extremely low-frequency electromagnetic fields (ELF-EMF) may be due, at least in part, to the effect of these fields on neurotrophic factors levels and cell survival, leading to an improvement in behavior. This study was undertaken to investigate the neuroprotective effects of ELFEF in a rat model of 3-nitropropionic acid (3NP)-induced Huntington's disease. Behavior patterns were evaluated, and changes in neurotrophic factor, cell damage, and oxidative stress biomarker levels were monitored in Wistar rats. Rats were given 3NP over four consecutive days (20 mg/kg body weight), whereas ELFEF (60 Hz and 0.7 mT) was applied over 21 days, starting after the last injection of 3NP. Rats treated with 3NP exhibited significantly different behavior in the open field test (OFT) and the forced swim test (FST), and displayed significant differences in neurotrophic factor levels and oxidative stress biomarkers levels, together with a neuronal damage and diminished neuronal density, with respect neuronal controls. ELFEF improved neurological scores, enhanced neurotrophic factor levels, and reduced both oxidative damage and neuronal loss in 3NP-treated rats. ELFEF alleviates 3NP-induced brain injury and prevents loss of neurons in rat striatum, thus showing considerable potential as a therapeutic tool.

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Relation between changes in neural responsivity and reductions in desire to eat high-calorie foods following gastric bypass surgery.

Publication Date: 2012 May 3 PMID: 22406414
Authors: Ochner, C. N. - Stice, E. - Hutchins, E. - Afifi, L. - Geliebter, A. - Hirsch, J. - Teixeira, J.
Journal: Neuroscience

Reductions in reward-related (e.g. striatal) neural activation have been noted following obesity surgery. It has been speculated that these postoperative neural changes may be related to documented postoperative changes in food preferences; however, this relation has not been previously established. In this study, functional magnetic resonance imaging and rating scales were used to assess neural responsivity, desire to eat (i.e. wanting), and liking for high- and low-calorie food cues in 14 females one month pre- and one month post-Roux-en-Y gastric bypass (RYGB) surgery. Pre- to post-RYGB changes in all variables were assessed, and postoperative changes in neural responsivity were regressed on postoperative changes in desire to eat and liking of foods. Results revealed significant postoperative reductions in mesolimbic (e.g. striatal) neural responsivity, desire to eat (wanting), and liking for high- relative to low-calorie food cues. Postoperative reductions in mesolimbic responsivity were associated with postoperative reductions in wanting, but not liking, for high- versus low-calorie foods. Interestingly, reductions in food wanting were also related to reductions in inhibitory (e.g. dorsolateral prefrontal cortex) activation following RYGB. Results are consistent with the hypothesized delineation between wanting and liking, supporting the notion that wanting, but not liking, is processed through the dopaminergic reward pathway. Concurrent reductions in both reward-related and inhibitory activation-predicted reductions in desire to eat might suggest that less dietary inhibition was elicited to resist potential overconsumption as the anticipated reward value of high-calorie foods decreased following RYGB.

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The protective effect of sonic hedgehog is mediated by the propidium iodide 3-kinase/AKT/Bcl-2 pathway in cultured rat astrocytes under oxidative stress.

Publication Date: 2012 May 3 PMID: 22402346
Authors: Xia, Y. P. - Dai, R. L. - Li, Y. N. - Mao, L. - Xue, Y. M. - He, Q. W. - Huang, M. - Huang, Y. - Mei, Y. W. - Hu, B.
Journal: Neuroscience

In our previous study, we found that the sonic hedgehog (Shh) signaling pathway is activated in neurons under oxidative stress and plays a neuro-protective role [Dai RL, et al. (2011) Neurochem Res 36:67-75]; we are led to postulate that the Shh might be released by astrocytes, thereby protecting neurons against oxidant injury. In primary cultured astrocytes of rats, we found that treatment with 100 muM H(2)O(2) for 24 h induced a significant increase in the mRNA and protein levels of Shh, Patched1, and Gli-1, and the increase was substantially greater in astrocytes than in neurons. In the coculture systems of astrocytes and neurons under the H(2)O(2) treatment, blocking the Shh signaling pathway with 5E1 (an antibody against the N-terminal domain of Shh) could block the neuroprotective activity of astrocytes on cocultured neurons. In this study, we found that treatment with H(2)O(2) (100-800 muM) for 24 h caused cell death of astrocytes in a concentration-dependent manner. MTT reduction and Trypan Blue exclusion assay showed that exogenous Shh increased survival rate of the H(2)O(2)-treated astrocytes, whereas pretreatment with cyclopamine (a specific inhibitor of the Shh signaling pathway) or 5E1 decreased the survival rate of the H(2)O(2)-treated astrocytes. Shh also inhibited H(2)O(2)-induced apoptosis of astrocytes, and this effect could be partially reversed by cyclopamine. We also found that Shh promoted the phosphorylation of AKT, but had no significant effect on p38 or extracellular signal regulated kinases 1 and 2 (ERK 1/2) in H(2)O(2)-treated astrocytes. Blocking Shh or phosphoinositide 3-kinases (PI3-K)/AKT signaling pathway with cyclopamine or LY294002 decreased the survival rate of astrocytes, induced cell apoptosis, upregulated the expression of Bax, and downregulated the expression of Bcl-2. We are led to conclude that the oxidative stress induces astrocytes to secrete endogenous Shh and exogenous administration of Shh might protect the astrocytes from oxidative stress by activating PI3-K/AKT/Bcl-2 pathway.

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Effects of stromal cell-derived factor 1alpha delivered at different phases of transient focal ischemia in rats.

Publication Date: 2012 May 3 PMID: 22402345
Authors: Yoo, J. - Seo, J. J. - Eom, J. H. - Hwang, D. Y.
Journal: Neuroscience

Endogenous stromal cell-derived factor 1alpha (SDF1alpha) has been implicated in postischemic tissue repair, suggesting SDF1alpha as a potential therapeutic molecule to treat stroke patients. In spite of its potential, no data are available regarding the short- and long-term effects of SDF1alpha when it is delivered at different phases of stroke. In our study, adenovirus expressing SDF1alpha gene (AV-SDF1alpha) was introduced into the boundary of the infarcted area either 3 days before or 1 week after ischemia, and behavioral performance was measured over 5 weeks. Immediate behavioral and structural amelioration was evident when AV-SDF1alpha was injected 3 days before ischemia, which might be the result of SDF1alpha-mediated neuroprotection as supported by the TUNEL staining and Western blot analysis of active caspase-3. In addition, increase in neurogenesis, neuroblast migration, and neural differentiation was also apparent in the AV-SDF1alpha-injected brain, which contributed to further amelioration at later time points ("delayed response"). On the contrary, when AV-SDF1alpha was introduced 1 week post-ischemia (in the subacute phase), significant behavioral recovery became apparent beginning 5 weeks after viral delivery. Taken together, the therapeutic efficacy of SDF1alpha varied considerably depending on when SDF1alpha overexpression was initiated; initiating SDF1alpha overexpression before ischemia exerted both immediate and delayed beneficial effects, whereas initiating overexpression in the subacute phase exerted only a delayed response.

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Lipopolysaccharide induces paired immunoglobulin-like receptor B (PirB) expression, synaptic alteration, and learning-memory deficit in rats.

Publication Date: 2012 May 3 PMID: 22395112
Authors: Deng, X. H. - Ai, W. M. - Lei, D. L. - Luo, X. G. - Yan, X. X. - Li, Z.
Journal: Neuroscience

Some typical immune proteins are expressed in the nervous system, among which the paired-immunoglobulin-like receptor B (PirB) is a receptor for major histocompatibility complex class I antigen (MHC-I), but may play a physiological role in the brain for neuronal circuitry stability by inhibiting synaptic plasticity. Chronic neuroinflammation is common to many neurodegenerative diseases and is often associated with neuronal/synaptic damage and dysfunction. Here we examined the expression of PirB in the rat brain following intracerebral application of lipopolysaccharide (LPS), which has been shown to induce proinflammatory changes and cognitive deficits in rodents. One month after unilateral intrahippocampal LPS injection (10 mug in 4 mul phosphate-buffered saline, PBS), increased protein levels and immunoreactivity of PirB were detected in the ipsilateral hippocampal formation and cortex of the experimental group relative to vehicle (PBS) control. The increased PirB labeling was localized to astrocytes and neurons. Reduced synaptophysin protein levels and immunoreactivity were also found in the ipsilateral hippocampal formation and cortex in LPS-treated rats relative to controls. Morris water maze tests indicated that hippocampus-dependent spatial learning and memory were impaired in LPS-treated animals. Our findings add new experimental data for an upregulation of immune proteins in neuronal and glial cells in the brain in a model of endotoxin-induced neuroinflammation, synaptic alteration, and cognitive decline. The results suggest that PirB modulation may be involved in the pathological process under neurodegenerative conditions.

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Orexinergic modulation of GABAergic neurotransmission to cardiac vagal neurons in the brain stem nucleus ambiguus changes during development.

Publication Date: 2012 May 3 PMID: 22390944
Authors: Dergacheva, O. - Bateman, R. - Byrne, P. - Mendelowitz, D.
Journal: Neuroscience

Cardiac vagal neurons (CVNs) in the nucleus ambiguus (NA) are the major determinant of parasympathetic activity to the heart. Spontaneous GABAergic neurotransmission to CVNs is modulated by hypothalamic neuropeptide orexin-A in postnatal days 2-5 (P5) rats; however, during early postnatal development, orexin expression changes, and the role of orexin-A in modulating CVN activity at other stages of development is unknown. In this study, we compared changes in GABAergic inhibitory postsynaptic currents (IPSCs) in CVNs evoked by orexin-A in P5, P16-20 (P20), and P27-30 (P30) rats using an in vitro brain stem slice preparation. Bath-applied orexin-A enhanced GABAergic IPSCs in all CVNs tested in P5 and P30 animals and in the majority of neurons tested in P20 pups. Focal application of orexin-A ejected from a pipette positioned within 30 mum of the patched CVN did not alter GABAergic signaling in P5 pups. In contrast, in both P20 and P30 rats, focal application of orexin-A inhibited GABAergic IPSCs, and this inhibition persisted in the presence of tetrodotoxin. These results indicate orexin-A facilitates GABAergic IPSCs likely by activating preceding GABAergic neurons that project to CVNs. Orexin-A also likely acts at GABAergic presynaptic terminals surrounding CVNs within the NA to inhibit GABA release. The latter mechanism is absent in P5 pups but occurs in P20 and P30 rats. In conclusion, this study elucidates an important maturation of the parasympathetic cardiac control system. Alterations in these developmental mechanisms may play a role in pathogenesis of disorders related to a specific stage of development maturation.

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Haloperidol and clozapine block formation of autophagolysosomes in rat primary neurons.

Publication Date: 2012 May 3 PMID: 22390943
Authors: Park, J. - Chung, S. - An, H. - Kim, J. - Seo, J. - Kim, D. H. - Yoon, S. Y.
Journal: Neuroscience

Early intervention and maintenance treatment for schizophrenia patients may prolong the duration of exposure to antipsychotic agents; however, there have been few studies on the neurotoxicity of these agents. Here, we investigated the effects of antipsychotics on cell viability and autophagy in rat primary neurons. Cultured cortical neurons obtained from rat embryos were treated with various concentrations of haloperidol and clozapine, and the neuronal toxicity was assessed by measuring lactate dehydrogenase (LDH) activity and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetr azolium (MTS) assay. Autophagosomes were quantitated by measuring the level of microtubule-associated protein 1A/1B-light chain 3 (LC3-II) by Western blot and immunofluorescence staining. Autophagic flux was assayed using bafilomycin A1 and GFP-mCherry-LC3 transfection. Haloperidol and clozapine decreased the viability of neurons in vitro in a concentration- and time-dependent manner. We also observed increased accumulation of autophagosomes after antipsychotic treatment. Using bafilomycin A1 and GFP-mCherry-LC3 transfection, we discovered that haloperidol and clozapine inhibited autophagosome turnover resulting in a dysfunctional autophagic process, including impaired lysosomal fusion. Together, these results suggest that haloperidol and clozapine negatively affect neuronal viability, possibly by blocking autophagolysosome formation.

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Functional interactions between the paraventricular hypothalamic nucleus and raphe magnus. A comparative study of an integrated homeostatic analgesic mechanism.

Publication Date: 2012 May 3 PMID: 22390942
Authors: Condes-Lara, M. - Rojas-Piloni, G. - Martinez-Lorenzana, G. - Diez-Martinez, D. C. - Rodriguez-Jimenez, J.
Journal: Neuroscience

This work compares the effects of electrical stimulation of the paraventricular hypothalamic nucleus (PVN) and the raphe magnus nucleus (RMg) on the single-unit response from dorsal spinal cord neurons activated by nociceptive receptive field stimulation. We evaluated the effects of stimulating the PVN or RMg individually or simultaneously, as well as PVN stimulation after RMg electrolytic lesion. PVN or RMg stimulation suppressed the A-delta, C fiber, and postdischarge, and we demonstrated that their simultaneous stimulation increases the duration and intensity of suppressive effects. RMg lesion increased the peripheral responses, but PVN stimulation continued to be suppressive. The intrathecal administration of 20 mul of a 10(-)(5) M solution of a specific oxytocin antagonist strongly reduced the PVN effects, and 20 mul of 10(-)(6) M naloxone significantly reduced the RMg suppression of receptive field responses. Some spinal cord cells presented a short-latency, evoked action potential (6.8 ms and a variability of +/-0.5 ms) produced by the RMg stimulation. This is interpreted as a direct postsynaptic action of the RMg on the spinal cord cells. We never found similar responses produced by the PVN, and therefore, we propose that the PVN effects are presynaptic. Finally, the immunohistochemical experiments confirmed the oxytocinergic and the vasopresinergic innervation used by the PVN projection to the RMg, and they raise the possibility that other neurotransmitters are involved. We conclude that the PVN and the RMg form part of a homeostatic analgesic mechanism acting on the same spinal cord cells to block the noxious information, but using different mechanisms. Both structures, and others, contribute to the homeostatic mechanism of endogenous analgesia.

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Transient nerve root compression load and duration differentially mediate behavioral sensitivity and associated spinal astrocyte activation and mGLuR5 expression.

Publication Date: 2012 May 3 PMID: 22387561
Authors: Nicholson, K. J. - Guarino, B. B. - Winkelstein, B. A.
Journal: Neuroscience

Injury to the cervical nerve roots is a common source of neck pain. Animal models of nerve root compression have previously established the role of compression magnitude and duration in nerve root-mediated pain and spinal inflammation; yet, the response of the spinal glutamatergic system to transient nerve root compression and its relationship to compression mechanics have not been studied. The glutamate receptor, mGluR5, has a central role in pain, and its expression by neurons and astrocytes in the spinal cord may be pivotal for neuronal-glial signaling. This study quantified spinal GFAP and mGluR5 expression following nerve root compressions of different magnitudes and durations in the rat. Compression to the C7 nerve root was applied for a duration that was either above (10 min) or below (3 min) the critical duration for mediating afferent discharge rates during compression. To also test for the effect of the magnitude of the compression load, either a 10 gf or a 60 gf was applied to the nerve root for each duration. Mechanical allodynia was assessed, and the C7 spinal cord was harvested on day 7 for immunofluorescent analysis. Double labeling was used to localize the expression of mGluR5 on astrocytes (GFAP) and neurons (MAP2). Seven days after injury, 10 min of compression produced significantly greater behavioral sensitivity (P<0.001) and spinal GFAP expression (P=0.002) than 3 min of compression, regardless of the compression magnitude. Nerve root compression at 60 gf produced a significant increase (P<0.001) in spinal mGluR5 for both of the durations studied. There was no difference in the distribution of mGluR5 between astrocytes and neurons following nerve root compression of any type. The glutamatergic and glial systems are differentially modulated by the mechanics of nerve root compression despite the known contribution of glia to pain through glutamatergic signaling.

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Aging profoundly delays functional recovery from gustatory nerve injury.

Publication Date: 2012 May 3 PMID: 22387273
Authors: He, L. - Yadgarov, A. - Sharif, S. - McCluskey, L. P.
Journal: Neuroscience

The peripheral taste system remains plastic during adulthood. Sectioning the chorda tympani (CT) nerve, which sends sensory information from the anterior tongue to the central nervous system, causes degeneration of distal fibers and target taste buds. However, taste function is restored after about 40 days in young adult rodents. We tested whether aging impacts the reappearance of neural responses after unilateral CT nerve injury. Taste bud regeneration was minimal at day 50-65 after denervation, and most aged animals died before functional recovery could be assessed. A subset (n=3/5) of old rats exhibited normal CT responses at day 85 postsectioning, suggesting the potential for efficient recovery. The aged taste system is fairly resilient to sensory receptor loss and major functional changes in normal aging. However, injury to the taste system reveals a surprising vulnerability in old rodents. The gustatory system provides an excellent model to study mechanisms underlying delayed recovery from peripheral nerve injury. Strategies to accelerate recovery and restore normal function will be of interest, as the elderly population continues to grow.

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Salubrinal, an endoplasmic reticulum stress blocker, modulates sleep homeostasis and activation of sleep- and wake-regulatory neurons.

Publication Date: 2012 May 3 PMID: 22387272
Authors: Methippara, M. - Mitrani, B. - Schrader, F. X. - Szymusiak, R. - McGinty, D.
Journal: Neuroscience

Endoplasmic reticulum (ER) stress has been associated with the regulation of sleep and wake. We have previously shown that i.c.v. administration of a specific ER stress modulator, Salubrinal (SALUB), which inhibits global protein translation by blocking the dephosphorylation of eukaryotic initiation factor 2alpha (p-eIF2alpha), increased non-rapid eye movement (NREM) sleep. Here we report on the relationship between ER stress response and sleep homeostasis by measuring the amount and intensity of homeostatic recovery sleep in response to the i.c.v. administration of SALUB in adult freely behaving rats. We have also tested the hypothesis that SALUB induces sleep by activating sleep-promoting neurons and inhibiting wake-promoting neurons in the basal forebrain (BF) and hypothalamus by quantifying the effects of SALUB treatment on c-Fos expression in those neuronal groups. The present study found that i.c.v. administration of SALUB significantly modified the homeostatic sleep response. SALUB administered during sleep deprivation increased sleep intensity, indicated by slow-wave activity (SWA), during recovery sleep, whereas its administration during recovery sleep increased the amount of recovery sleep. We also found that SALUB induced c-Fos activation of GABAergic neurons in the sleep-promoting rostral median preoptic nucleus while simultaneously reducing c-Fos activation of wake-promoting lateral hypothalamic orexin-expressing neurons and magnocellular BF cholinergic neurons. The current findings suggest that ER stress pathway plays a role in the homeostatic control of NREM sleep in response to sleep deprivation and provides a mechanistic explanation for the sleep modulation by molecules signaling the need for brain protein synthesis.

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A cardiovascular role for fractalkine and its cognate receptor, CX3CR1, in the rat nucleus of the solitary tract.

Publication Date: 2012 May 3 PMID: 22387113
Authors: Ruchaya, P. J. - Paton, J. F. - Murphy, D. - Yao, S. T.
Journal: Neuroscience

The nucleus of the solitary tract (NTS), an integral vasomotor region located in the hindbrain, is important for cardiovascular homeostasis. Fractalkine (FKN) and its cognate receptor, CX3CR1, are constitutively expressed in the normal rat brain. The physiological significance of this cytokine and its receptor are not well established. In this study, we sought to identify the expression of FKN and CX3CR1 in subnuclei of the NTS and to elucidate their functional relevance. Using immunohistochemistry, we found expression of FKN and CX3CR1 throughout the entire rostro-caudal axis of the NTS in normal adult male Sprague-Dawley rats. When FKN was unilaterally microinjected directly into the commissural and sub-postremal, but not rostral, NTS, blood pressure and heart rate were significantly decreased when compared with saline controls. The FKN-induced depressor and bradycardic responses were inhibited by pretreatment with a phosphoinositide 3-kinase inhibitor, LY294002. These data suggest that the cytokine, FKN, and its receptor, CX3CR1, may modulate cardiovascular responses in the NTS of normal healthy rats via the phosphoinositide 3-kinase intracellular signaling pathway.

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Morphology and innervation of the vestibular lagena in pigeons.

Publication Date: 2012 May 3 PMID: 22387112
Authors: Zakir, M. - Wu, L. Q. - Dickman, J. D.
Journal: Neuroscience

The morphological characteristics of the pigeon lagena were examined using histology, scanning electron microscopy, and biotinylated dextran amine (BDA) neural tracers. The lagena epithelium was observed to lie partially in a parasagittal plane, but was also U-shaped with orthogonal (lateral) directed tips. Hair cell planar polarities were oriented away from a central reversal line that ran nearly the length of the epithelium. Similar to the vertebrate utricle and saccule, three afferent classes were observed based upon their terminal innervation pattern, which include calyx, dimorph, and bouton fibers. Calyx and dimorph afferents innervated the striola region of the lagena, whereas bouton afferents innervated the extrastriola and a small region of the central striola known as the type II band. Calyx units had large calyceal terminal structures that innervated only type I hair cells. Dimorph afferents innervated both type I and II hair cells, with calyx and bouton terminals. Bouton afferents had the largest most complex innervation patterns and the greatest terminal areas contacting many hair cells.

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Postnatal dendritic development in lumbar motoneurons in mutant superoxide dismutase 1 mouse model of amyotrophic lateral sclerosis.

Publication Date: 2012 May 3 PMID: 22387111
Authors: Filipchuk, A. A. - Durand, J.
Journal: Neuroscience

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motoneuron (MN) degeneration and muscle paralysis. Cu/Zn superoxide dismutase (SOD1) mutant mice develop an ALS-like phenotype similar to that seen in human. Recently it has been shown in SOD1 mice that the excitability and morphology of spinal MNs are altered at postnatal age, long before overt clinical symptoms. In the present study, we examined the morphology of lumbar MNs in wild-type (WT) and SOD1(G85R) mice at two postnatal ages (P3-P4 and P8-P9) when differences in size and excitability were reported. Detailed morphological analysis was performed in MNs intracellularly labeled with Neurobiotin and 3D-reconstructed using the Neurolucida system. We showed that SOD1 MNs exhibited longer terminal segments than in the WT MNs at age P3-P4. This excessive elongation was followed by pathological ramification of all individual dendrites between P4 and P8. Abnormal bifurcations occurred at the terminal tips, and distance between consecutive bifurcations remained stable. Most dendrites of SOD1 MNs performed in average two successive iterations of bifurcation during this short time. Our results suggest that the SOD1 MNs switch from excessive elongation to overbranching in a few days at early postnatal life, which might be a compensatory reaction to the possible variation of synaptic input.

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Hydrogen-rich saline alleviates experimental noise-induced hearing loss in guinea pigs.

Publication Date: 2012 May 3 PMID: 22387110
Authors: Zhou, Y. - Zheng, H. - Ruan, F. - Chen, X. - Zheng, G. - Kang, M. - Zhang, Q. - Sun, X.
Journal: Neuroscience

OBJECTIVE: To examine the efficiency of hydrogen-rich saline in the treatment of intensive noise-induced cochlear injury. MATERIALS AND METHODS: Forty guinea pigs were assigned to one of four groups: HS+NOISE (i.p. injection hydrogen-rich saline), NS+NOISE (i.p. injection normal saline), NOISE ALONE (noise control), and NO TREATMENT (normal control) groups. The HS+NOISE, NS+NOISE, and NOISE ALONE groups were exposed to intensive noise (4 h at 115 dB SPL noise of 4000+/-100 Hz). The auditory brainstem response (ABR) was used to examine the hearing threshold in each group. Distortion product otoacoustic emission (DPOAE) was used to examine outer hair cell function. We also examined cochlear morphology to evaluate inner and outer hair cell trauma induced by noise exposure. Hydrogen-rich saline was administered twice daily for 6 days (2.5 ml/kg, i.p.) 24 h after noise exposure. RESULTS: Baseline ABR thresholds and DPOAE values were normal in all groups at the measured frequencies (2, 4, 8, and 16 kHz) before noise exposure. The ABR threshold shift was 50-55 dB across the frequencies tested, and average DPOAE declined in the NOISE ALONE, NS+NOISE, and HS+NOISE groups 24 h after noise exposure. However, the changes in cochlear parameters were different between groups. The HS+NOISE group showed a significantly decreased ABR threshold value as compared with the NS+NOISE or NOISE ALONE group (P<0.01) on day 7. The mean DPOAE recovered to some extent in the three noise exposure groups, but at most frequencies the HS+NOISE group showed significantly increased DPOAE on day 7 as compared with the NS+NOISE group or NOISE ALONE group (P<0.01). Surface Corti organ preparations stained with succinate dehydrogenase (SDH) showed that most outer hair cells (OHCs) were still dropsical and a few were missing 7 days after noise exposure in the NS+NOISE group. Only a few OHCs were slightly dropsical in the HS+NOISE group. The numbers of missing hair cells 7 days after noise exposure were significantly greater in the NOISE ONLY and NS+NOISE groups than the HS+NOISE group (P<0.01). CONCLUSIONS: Hydrogen-rich saline can alleviate experimental noise-induced hearing loss in guinea pigs, partially by preventing the death of cochlear hair cells after intensive noise exposure.

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Aging affects L-arginine and its metabolites in memory-associated brain structures at the tissue and synaptoneurosome levels.

Publication Date: 2012 May 3 PMID: 22387109
Authors: Rushaidhi, M. - Jing, Y. - Kennard, J. T. - Collie, N. D. - Williams, J. M. - Zhang, H. - Liu, P.
Journal: Neuroscience

L-arginine, one of the most metabolically versatile amino acids, can be metabolized to form a number of bioactive molecules. The present study systematically investigated age-related changes in L-arginine and its metabolites in the hippocampus, parahippocampal region, and prefrontal cortex at the tissue (crude homogenates) and synaptoneurosome (a subcellular preparation enriched for synaptic material) levels. As aging leads to reduced water content in the brain, age-related changes in neurochemical levels in tissue homogenates normalized by wet tissue weight and protein level were compared. There were significant differences in L-arginine, L-citrulline, L-ornithine, agmatine, putrescine, spermidine, spermine, and glutamate, but not GABA, in the CA1, CA2/3, and dentate gyrus sub-regions of the hippocampus and the prefrontal, entorhinal, perirhinal, and postrhinal cortices in 24 (aged) and 4 (young) months old rats in a region-specific manner. The overall pattern of age-related changes in amino acids (L-arginine, L-citrulline, L-ornithine, glutamate, and GABA) was largely similar between homogenates and synaptoneurosomes, whereas the pattern for the amines (agmatine, putrescine, spermidine, and spermine) was quite different. Furthermore, the pattern of age-related changes in neurochemical levels in tissue homogenates normalized by wet tissue weight and protein level was very similar for all 9 neurochemicals measured. These findings suggest that there are differential effects of aging on L-arginine metabolism at the tissue and synaptoneurosome levels and that the way of data normalization (tissue weight vs. protein level) has no or very minor effects on 9 neurochemicals measured.

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Effects of interaction of an early experience of reward through maternal contact or its denial with social stress during adolescence on the serotonergic system and the stress responsiveness of adult female rats.

Publication Date: 2012 May 3 PMID: 22381469
Authors: Raftogianni, A. - Diamantopoulou, A. - Alikaridis, F. - Stamatakis, A. - Stylianopoulou, F.
Journal: Neuroscience

Experiences during critical periods, such as the neonatal and adolescence, play a critical role in determining adult stress-coping behavior. Based on the aforementioned we developed an experimental protocol, which included a neonatal experience and a social stress during adolescence. The serotonergic system is known as an important modulator of coping ability and, in general, emotional balance in both normal and pathological states, such as depression and anxiety, for which females are more vulnerable. Thus in the present work we used female rats and determined 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), and 5-hydroxytryptamine receptor type 1A (5-HT(1A)) receptor levels in the prefrontal cortex (PFC) and the amygdala (AMY). During postnatal days 10-13 (PND 10-13) rat pups were exposed to a T-maze, one arm of which lead to the mother. One group of animals was allowed contact with the mother (rewarded-receiving expected reward (RER)), whereas the other was denied the expected reward (DER). High performance liquid chromatography (HPLC) analysis revealed that in both the PFC and in AMY, adult RER animals had higher basal 5-HT levels. Furthermore, in the AMY of this group of animals, higher levels of 5-HT(1A) receptors were detected by Western blot analysis. In adulthood rats were exposed to the Forced Swimming Test/Stress (FST/S). RER animals not exposed to the adolescent stress exhibited longer immobility time during both the first and second day of FST. Corticosterone levels following the FST fell faster in the DER animals. Adolescent stress affected the responses to the adult FSS only in the DER animals, which had decreased 5-HT in the AMY and increased immobility time on both days of the FST, compared with the DER, not stressed in adolescence. The phenotype of the DER animals is in line with the "match-mismatch" hypothesis, which states that if two events during critical periods of life "match" in being mildly stressful, their interaction can be adaptive.

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Phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 may not always represent its kinase activity in a rat model of focal cerebral ischemia with or without ischemic preconditioning.

Publication Date: 2012 May 3 PMID: 22366512
Authors: Takahashi, T. - Steinberg, G. K. - Zhao, H.
Journal: Neuroscience

The extracellular signal-regulated kinase (ERK) 1/2 protein requires a dual phosphorylation at conserved threonine and tyrosine residues to be fully activated under normal physiological conditions. Thus, ERK1/2 kinase activity is often defined by the quantity of phosphorylated kinase. However, this may not accurately represent its true activity under certain pathological conditions. We investigated whether ERK1/2 kinase activity is proportional to its phosphorylation state in a rat focal ischemia model with and without rapid ischemic preconditioning. We showed that phosphorylated-ERK1/2 protein levels were increased 2.6+/-0.07-fold, and ERK1/2 kinase activity was increased 10.6+/-1.9-fold in animals receiving ischemic preconditioning alone without test ischemia compared with sham group (P<0.05, n=6/group), suggesting that phosphorylated-ERK1/2 protein levels represent its kinase activity under these conditions. However, preconditioning plus test ischemia robustly blocked ERK1/2 kinase activity, whereas it increased phosphorylated-ERK1/2 protein levels beyond those receiving test ischemia alone, suggesting that phosphorylated-ERK1/2 protein levels were not representative of actual kinase activity in this pathological condition. In conclusion, protein phosphorylation levels of ERK1/2 do not always correspond to kinase activity, thus, measuring the true kinase activity is essential.

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Regional dissociation of paradigm-specific synapse remodeling during memory consolidation in the adult rat dentate gyrus.

Publication Date: 2012 May 3 PMID: 22285310
Authors: Scully, D. - Fedriani, R. - Desouza, I. E. - Murphy, K. J. - Regan, C. M.
Journal: Neuroscience

Arising from studies on the amnesia that follows site-specific physical or chemical lesions, the acquisition and consolidation of certain behavioral tasks has been demonstrated to be associated with different hippocampal subregions. Although not absolute, spatial learning is reliant on the dorsal region of the hippocampus, whereas avoidance- and fear-conditioning tasks appear to be dependent on its more ventral aspects. Thus, if learning-associated synapse remodeling is a true feature of memory consolidation it must also follow these regional dissociations. We therefore determined if the learning-associated increases in synapse density that occur in the mid-molecular layer of the dentate gyrus at the 6-h post-training time and the frequency of polysialylated cells at the infragranular zone that occur at the 12-h post-training time were dissociated to specific hippocampal subregions following training in either a massed water maze task or light-dark passive avoidance response. Synapse remodeling was found to occur only in the dorsal hippocampus following spatial learning. We could not, however, discern any regional dissociation of neural remodeling following avoidance conditioning. These results point to strong associations between learning and specific groups of novel synapses during consolidation of spatial learning and avoidance conditioning paradigms.

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Tests and models of nociception and pain in rodents.

Publication Date: 2012 Jun 1 PMID: 22244975
Authors: Barrot, M.
Journal: Neuroscience

Nociception and pain is a large field of both neuroscience and medical research. Over time, various tests and models were developed in rodents to provide tools for fundamental and translational research on the topic. Tests using thermal, mechanical, and chemical stimuli, measures of hyperalgesia and allodynia, models of inflammatory or neuropathic pain, constitute a toolbox available to researchers. These tests and models allowed rapid progress on the anatomo-molecular basis of physiological and pathological pain, even though they have yet to translate into new analgesic drugs. More recently, a growing effort has been put forth trying to assess pain in rats or mice, rather than nociceptive reflexes, or at studying complex states affected by chronic pain. This aids to further improve the translational value of preclinical research in a field with balanced research efforts between fundamental research, preclinical work, and human studies. This review describes classical tests and models of nociception and pain in rodents. It also presents some recent and ongoing developments in nociceptive tests, recent trends for pain evaluation, and raises the question of the appropriateness between tests, models, and procedures. This article is part of a Special Issue entitled: Neuroscience Disease Models.

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Methylene blue administration fails to confer neuroprotection in two amyotrophic lateral sclerosis mouse models.

Publication Date: 2012 May 3 PMID: 22230045
Authors: Audet, J. N. - Soucy, G. - Julien, J. P.
Journal: Neuroscience

Approximately 20% cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Recent studies have shown that methylene blue (MB) was efficient in conferring protection in several neurological disorders. MB was found to improve mitochondrial function, to reduce reactive oxygen species, to clear aggregates of toxic proteins, and to act as a nitric oxide synthase inhibitor. These pleiotropic effects of relevance to ALS pathogenesis led us to test MB in two models of ALS, SOD1(G93A) mice and TDP-43(G348C) transgenic mice. Intraperitoneal administration of MB at two different doses was initiated at the beginning of disease onset, at 90 days of age in SOD1(G93A) and at 6 months of age in TDP-43(G348C) mice. Despite its established neuroprotective properties, MB failed to confer protection in both mouse models of ALS. The lifespan of SOD1(G93A) mice was not affected by MB treatment. The declines in motor function, reflex score, and body weight of SOD1(G93A) mice remained unchanged. MB treatment had no effect on motor neuron loss and aggregation or misfolding of SOD1. A combination of MB with lithium also failed to provide benefits in SOD1(G93A) mice. In TDP-43(G348C) mice, MB failed to improve motor function. Cytosolic translocation of TDP-43, ubiquitination and inflammation remained also unchanged after MB treatment of TDP-43(G348C) mice.

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Neurotoxin-based models of Parkinson's disease.

Publication Date: 2012 Jun 1 PMID: 22108613
Authors: Bove, J. - Perier, C.
Journal: Neuroscience

Animal experimentation in the Parkinson's disease (PD) field is a classic example of how the use of animal models to study diseases can have a significant impact on human health. Among the different neurotoxin-based animal models of PD that are presently available, the 6-hydroxydopamine (6-OHDA) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models have been established and validated as useful models for the development of therapeutic strategies aimed to treat motor symptoms and to study alterations of the basal ganglia that occur in this disease. The 6-OHDA rat model and the MPTP primate model have contributed enormously to translate animal experimentation into clinical practice, including pharmacological treatments and deep brain stimulation of the subthalamic nucleus. These models, along with the MPTP mouse model, are helping to elucidate the pathogenic mechanism of neurodegeneration in PD. The roles of oxidative stress, apoptosis, mitochondrial dysfunction, inflammation, and impairment of the protein degradation pathways have also come under careful consideration thanks to these models. The more recently developed paraquat and rotenone rodent models are also contributing to our understanding of neuronal cell death. However, none of the neuroprotective strategies that have worked in the pre-clinical stage have thus far been successfully translated to a clinical setting to treat PD patients. At the same time, the lack of any effective neuroprotective strategy for PD is preventing the validation of any one particular model as a screening tool for such neuroprotective strategies. Therefore, it seems that we are trapped in a vicious circle that casts doubt on the suitability of the neurotoxin-based models for this purpose. Here, we discuss how epidemiological data may help to validate a specific model with data linking a lower risk of developing PD with nutritional/consumption habits or with a specific chronic drug therapy. This article is part of a Special Issue entitled: Neuroscience Disease Models.

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Animal models of multiple system atrophy.

Publication Date: 2012 Jun 1 PMID: 21963351
Authors: Fernagut, P. O. - Tison, F.
Journal: Neuroscience

Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative disorder clinically characterized by a variable combination of dysautonomia, levodopa-unresponsive parkinsonian and cerebellar symptoms. Neurodegeneration in MSA occurs in the substantia nigra, putamen, inferior olive, pontine and brainstem nuclei, as well as intermediolateral cell column of the spinal cord. MSA is recognized as a synucleinopathy due to the accumulation of insoluble alpha-synuclein in oligodendroglial cytoplasmic inclusions. Several animal models have been developed in order to reproduce various clinical and pathological features of MSA. Using "double toxin-double lesion" or "single toxin-double lesion", neurotoxin-based models were designed in rats, mice and non-human primates to reproduce the neuropathology of MSA in the nigrostriatal system while gene-based models were developed in mice to reproduce the accumulation of insoluble alpha-synuclein in oligodendrocytes. Both approaches have then been merged to create optimized, dual-hit models. This review describes the different animal models of MSA, their respective advantages and limitations and their usefulness to decipher the pathophysiology of MSA then to define efficient symptomatic and disease-modifying therapies. This article is part of a Special Issue entitled: Neuroscience Disease Models.

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Current animal models of obsessive compulsive disorder: an update.

Publication Date: 2012 Jun 1 PMID: 21925243
Authors: Albelda, N. - Joel, D.
Journal: Neuroscience

During the last 30 years there have been many attempts to develop animal models of obsessive compulsive disorder (OCD), in the hope that they may provide a route for furthering our understanding and treatment of this disorder. The present review provides the reader with an overview of the currently active animal models of OCD, their strengths and limitations, so that the reader can use the review as a guide for establishing new animal models of OCD, evaluating existing animal models and choosing among them according to one's needs. We review current genetic, pharmacological, neurodevelopmental and behavioral animal models of OCD, and evaluate their face validity (derived from phenomenological similarity between the behavior in the animal model and the specific symptoms of the human condition), predictive validity (derived from similarity in response to treatment) and construct validity (derived from similarity in the underlying mechanisms [physiological or psychological]). On the basis of this evaluation we discuss the usefulness of the different models for screening drugs for anti-compulsive activity, detecting new targets for high frequency stimulation, studying the neural mechanisms of OCD and unraveling the role of gonadal hormones. We then describe potential new treatment strategies that emerge from the convergence of data obtained in different models on the one hand, and how different models can be used to model different subtypes or dimensions of OCD, on the other hand. This article is part of a Special Issue entitled: Neuroscience Disease Models.

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The science of making drug-addicted animals.

Publication Date: 2012 Jun 1 PMID: 21864653
Authors: Ahmed, S. H.
Journal: Neuroscience

Research involving animal models of drug addiction can be viewed as a sort of reverse psychiatry. Contrary to clinicians who seek to treat addicted people to become and remain abstinent, researchers seek to make drug-naive animals addicted to a drug with known addictive properties in humans. The goals of this research are to better understand the neuroscience of drug addiction and, ultimately, to translate this knowledge into effective treatments for people with addiction. The present review will not cover the vast literature that has accumulated over the past 50 years on animal models of drug addiction. It is instead more modestly devoted to recent research spanning the past decade on drug self-administration-based models of addiction in the rat (the animal species most frequently used in the field), with a special focus on current efforts to model compulsive cocaine use as opposed to nonaddictive use. Surprisingly, it turns out that modeling compulsive cocaine use in rats is possible but more difficult than previously thought. In fact, it appears that resilience to cocaine addiction is the norm in rats. As in human cocaine users, only few individual rats would be vulnerable. This conclusion has several important implications for future research on the neuroscience of cocaine addiction and on preclinical medication development. This article is part of a Special Issue entitled: Neuroscience Disease Models.

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Aberrant striatal synaptic plasticity in monogenic parkinsonisms.

Publication Date: 2012 Jun 1 PMID: 21839811
Authors: Madeo, G. - Martella, G. - Schirinzi, T. - Ponterio, G. - Shen, J. - Bonsi, P. - Pisani, A.
Journal: Neuroscience

In the recent past, the pathogenesis of Parkinson's disease (PD) has evolved from a neurodegenerative disorder considered entirely sporadic to a disease with an unequivocal genetic component. Indeed, different inherited forms of PD have been discovered and characterized, although the functional roles of the gene products identified are still under intense investigation. To gain a better understanding of the cellular and molecular pathogenic mechanisms of hereditary forms of PD, different animal models have been generated. Although most of the rodent models display neither obvious behavioral impairment nor evidence for neurodegeneration, remarkable abnormalities of dopamine-mediated neurotransmission and corticostriatal synaptic plasticity have been described, indicative of a fundamental distortion of network function within the basal ganglia. The picture emerging from a critical review of recent data on monogenic parkinsonisms suggests that mutations in PD genes might cause developmental rearrangements in the corticobasal ganglia circuitry, compensating the dopaminergic dysfunction observed both in mice and humans, in order to maintain proper motor function. This article is part of a Special Issue entitled: Neuroscience Disease Models.

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Avoiding mouse traps in schizophrenia genetics: lessons and promises from current and emerging mouse models.

Publication Date: 2012 Jun 1 PMID: 21821099
Authors: Kvajo, M. - McKellar, H. - Gogos, J. A.
Journal: Neuroscience

Schizophrenia is one of the most common psychiatric disorders, but despite progress in identifying the genetic factors implicated in its development, the mechanisms underlying its etiology and pathogenesis remain poorly understood. Development of mouse models is critical for expanding our understanding of the causes of schizophrenia. However, translation of disease pathology into mouse models has proven to be challenging, primarily due to the complex genetic architecture of schizophrenia and the difficulties in the re-creation of susceptibility alleles in the mouse genome. In this review we highlight current research on models of major susceptibility loci and the information accrued from their analysis. We describe and compare the different approaches that are necessitated by diverse susceptibility alleles, and discuss their advantages and drawbacks. Finally, we discuss emerging mouse models, such as second-generation pathophysiology models based on innovative approaches that are facilitated by the information gathered from the current genetic mouse models. This article is part of a Special Issue entitled: Neuroscience Disease Models.

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Functional interactions within striatal microcircuit in animal models of Huntington's disease.

Publication Date: 2012 Jun 1 PMID: 21756979
Authors: Ghiglieri, V. - Bagetta, V. - Calabresi, P. - Picconi, B.
Journal: Neuroscience

Mutant huntingtin (mhtt) causes loss of synaptic plasticity and selective degeneration of striatal medium spiny neurons (MSNs), a core pathological feature of Huntington's disease (HD). However, projecting neurons become dysfunctional in the very early stages, long before death and this dysfunctional state may contribute to disease. Interneurons appear to be more resistant to the effects of mhtt and play important roles in supporting the activity of projecting neurons. Therefore, early modifications in the plasticity or in the pattern of cortical and striatal interneuronal activity may also be a factor in the alteration of the corticostriatal pathway in HD. While new models of HD provide information on the onset of complex behavioral changes, the mechanisms underlying alterations of the striatal microcircuit and their role in HD pathogenesis are still unclear. As a consequence, despite the development of new compounds, no adequate treatment is so far available to stop or reverse HD. Electrophysiological studies provide crucial information on neuronal dysfunction and circuit changes that underlie or precede symptoms. Here we review recent papers in which HD models have been used to study various aspects of neuronal physiology of corticostriatal pathway. We will also discuss advantages and limitations of rodent models compared to primate models and current challenges of therapies aimed at rescuing striatal function in HD. This article is part of a Special Issue entitled: Neuroscience Disease Models.

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