Journal Of Comparative Neurology

Cortical connections to single digit representations in area 3b of somatosensory cortex in squirrel monkeys and prosimian galagos.

Publication Date: 2013 Jun 8 PMID: 23749740
Authors: Liao, C. C. - Gharbawie, O. A. - Qi, H. - Kaas, J. H.
Journal: J Comp Neurol

Ventral posterior nucleus of thalamus sends highly segregated inputs into each digit representation in area 3b of primary somatosensory cortex. However, the spatial organization of the connections that link digit representations of areas 3b with other somatosensory areas is less understood. Here we examined the cortical inputs to individual digit representations of area 3b in four squirrel monkeys and one prosimian galago. Retrograde tracers were respectively injected into neurophysiologically defined representations of individual digits of area 3b. Cortical tissues were cut in the horizontal plane in some cases and showed that feedback projections to individual digits overlapped extensively in the hand representations of areas 3b, 1, and parietal ventral (PV) and second somatosensory (S2) areas. Other regions with overlapping populations of labeled cells included area 3a and primary motor cortex (M1). The results were confirmed in other cases in which the cortical tissues were cut in the coronal plane. The same cases also showed that cells were primarily labeled in the infragranular layers and supragranular layers. Thus, feedback projections to individual digit representations in area 3b mainly originate from multiple digits and other portions of hand representations of areas 3b, 1, PV and S2. This organization is in stark contrast to the segregated thalamocortical inputs, which originate in single digit representations and terminate in the matching digit representation in the cortex. The organization of feedback connections could provide a substrate for the integration of information across the representations of adjacent digits in area 3b. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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Neuronal and nonneuronal cholinergic structures in the mouse gastrointestinal tract and spleen.

Publication Date: 2013 Jun 8 PMID: 23749724
Authors: Gautron, L. - Rutkowski, J. M. - Burton, M. D. - Wei, W. - Wan, Y. - Elmquist, J. K.
Journal: J Comp Neurol

Accumulating evidence demonstrates that acetylcholine can directly modulate immune function in peripheral tissues including the spleen and gastrointestinal tract. However, the anatomical relationships between the peripheral cholinergic system and immune cells located in these lymphoid tissues remain unclear due to inherent technical difficulties with currently available neuroanatomical methods. In this study, mice with specific expression of the tdTomato fluorescent protein in choline acetyltransferase (ChAT)-expressing cells were used to label preganglionic and postganglionic cholinergic neurons and their projections to lymphoid tissues. Notably, our anatomical observations revealed an abundant innervation in the intestinal lamina propria of the entire gastrointestinal tract principally originating from cholinergic enteric neurons. The aforementioned innervation frequently approached macrophages, plasma cells and lymphocytes located in the lamina propria and, to a lesser extent, lymphocytes in the interfollicular areas of Peyer's patches. In addition to the above innervation, we observed labeled epithelial cells in the gallbladder and lower intestines, as well as Microfold cells and T-cells within Peyer's patches. In contrast, we found only a sparse innervation in the spleen consisting of neuronal fibers of spinal origin present around arterioles and in lymphocyte-containing areas of the white pulp. Lastly, a small population of ChAT-expressing lymphocytes was identified in the spleen including both T- and B-cells. In summary, this study describes the variety of cholinergic neuronal and nonneuronal cells in a position to modulate gastrointestinal and splenic immunity in the mouse. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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Odd-skipped labels a group of distinct neurons associated with the mushroom body and optic lobe in the adult Drosophila brain.

Publication Date: 2013 Jun 8 PMID: 23749685
Authors: Levy, P. - Larsen, C.
Journal: J Comp Neurol

Olfactory processing has been intensively studied in Drosophila melanogaster. However we still know little about the descending neural pathways from the higher order processing centres and how these connect with other neural circuits. Here we describe, in detail, the adult projections patterns that arise from a cluster of 78 neurons, defined by the expression of the Odd-skipped transcription factor. We term these neurons Odd neurons. Using expression of genetically encoded axonal and dendritic markers we show that a subset of the Odd neurons project dendrites into the calyx of the MB and axons into the inferior protocerebrum. We exclude the possibility that the Odd neurons are part of the well-known Kenyon cells whose projections form the MB and conclude that the Odd neurons belong to a previously not described class of extrinsic MB neurons. In addition, 3 of the Odd neurons project into the lobula plate of the optic lobe and two of these cells extend axons ipsi and contralaterally in the brain. Anatomically, these cells do not resemble any previously described lobula plate tangential cells (LPTCs) in Drosophila. We show that the Odd neurons are predominantly cholinergic but also include a small number of GABAergic neurons. Finally, we provide evidence that the Odd neurons are a hemi lineage, suggesting they are born from a defined set of neuroblasts. Our anatomical analysis hints to the possibility that subgroups of Odd neurons could be involved in olfactory and visual processing. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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Withdrawal and restoration of central vagal afferents within the dorsal vagal complex following subdiaphragmatic vagotomy.

Publication Date: 2013 Jun 8 PMID: 23749657
Authors: Peters, J. H. - Gallaher, Z. R. - Ryu, V. - Czaja, K.
Journal: J Comp Neurol

Vagotomy, a severing of the peripheral axons of the vagus nerve, has been extensively utilized to determine the role of vagal afferents in viscerosensory signaling. Vagotomy is also an unavoidable component of some bariatric surgeries. While it is known that peripheral axons of the vagus nerve degenerate and then regenerate to a limited extent following vagotomy, very little is known about the response of central vagal afferents in the dorsal vagal complex to this type of damage. We tested the hypothesis that vagotomy results in the transient withdrawal of central vagal afferent terminals from their primary central target, the nucleus of the solitary tract (NTS). Sprague-Dawley rats underwent bilateral subdiaphragmatic vagotomy and were sacrificed 10, 30, or 60 days later. Plastic changes in vagal afferent fibers and synapses were investigated at the morphological and functional levels using a combination of an anterograde tracer, synapse specific markers, and patch-clamp electrophysiology in horizontal brain sections. Morphological data revealed that numbers of vagal afferent fibers and synapses in the NTS were significantly reduced 10 days following vagotomy and were restored to control levels by 30 days and 60 days, respectively. Electrophysiology revealed transient decreases in spontaneous glutamate release, glutamate release probability, and the number of primary afferent inputs. Our results demonstrate that subdiaphragmatic vagotomy triggers transient withdrawal and remodeling of central vagal afferent terminals in the NTS. The observed vagotomy-induced plasticity within this key feeding center of the brain may be partially responsible for the response of bariatric patients following gastric bypass surgery. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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Nuclear factor one b regulates neural stem cell differentiation and axonal projection of corticofugal neurons.

Publication Date: 2013 Jun 8 PMID: 23749646
Authors: Betancourt, J. - Katzman, S. - Chen, B.
Journal: J Comp Neurol

During development of the cerebral cortex, neural stem cells divide to expand the progenitor pool and generate basal progenitors, outer radial glia and cortical neurons. As these newly born neurons differentiate, they must properly migrate toward their final destination in the cortical plate, project axons to appropriate targets, and develop dendrites. However, a complete understanding of the precise genetic mechanisms regulating these steps is lacking. Here we show that a member of the nuclear factor one (NFI) family of transcription factors, NFIB, is essential for many of these processes in mice. We performed a detailed analysis of NFIB expression during cortical development, and investigated defects in cortical neurogenesis, neuronal migration and differentiation in NfiB-/- brains. We found that NFIB is strongly expressed in radial glia and corticofugal neurons throughout cortical development. However, in NfiB-/- cortices, radial glia failed to generate outer radial glia, subsequently resulting in a loss of late basal progenitors. In addition, corticofugal neurons showed a severe loss of axonal projections, while late-born cortical neurons displayed defects in migration and ectopically expressed the early-born neuronal marker, CTIP2. Furthermore, gene expression analysis, by RNA-sequencing, revealed a misexpression of genes that regulate the cell cycle, neuronal differentiation and migration in NfiB-/- brains. Together these results demonstrate the critical functions of NFIB in regulating cortical development. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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Subcellular organization of CaMKII in rat hippocampal pyramidal neurons.

Publication Date: 2013 Jun 8 PMID: 23749614
Authors: Ding, J. D. - Kennedy, M. B. - Weinberg, R. J.
Journal: J Comp Neurol

Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a key role in NMDA receptor-dependent long-term synaptic plasticity; its location is critical for signal transduction, and may provide clues that further elucidate its function. We therefore examined the subcellular localization of CaMKII in CA1 stratum radiatum of adult rat hippocampus, using immuno-electron microscopy after chemical fixation. When tissue was fixed quickly, the concentration of CaMKIIalpha (assessed by pre-embedding immunogold) was significantly higher in dendritic shafts than in spine heads. However, when fixed 5 minutes after perfusion with normal saline, the density of labeling decreased in dendritic shafts, while increasing in spine heads, implying rapid translocation into the spine during brief perimortem stress. Likewise, in quickly-fixed tissue, CaMKII within spine heads was found at comparable concentrations in the "proximal" half (adjacent to the spine neck) and the "distal" half (containing the PSD), while after delayed fixation, label density increased in the distal side of the spine head, suggesting that CaMKII within the spine head moves toward the PSD during this interval. To estimate its distribution at the synapse in vivo, we performed postembedding immunogold staining for CaMKII in quick-fixed tissue, finding that the enzyme did not concentrate primarily within the central matrix of the PSD. Rather, labeling density peaked ~40 nm inside the postsynaptic membrane, at the cytoplasmic fringe of the PSD. Labeling within 25 nm of the postsynaptic membrane concentrated at the lateral edge of the synapse. This lateral "PSD core" pool of CaMKII may play a special role in synaptic plasticity. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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Choline acetyltransferase-like Immunoreactivity in a physiologically distinct sub-type of olfactory non-spiking local interneurons in the cockroach (Periplaneta americana).

Publication Date: 2013 Jun 8 PMID: 23749599
Authors: Fusca, D. - Husch, A. - Baumann, A. - Kloppenburg, P.
Journal: J Comp Neurol

Behavioral and physiological studies have shown that local interneurons are pivotal for processing odor information in the insect antennal lobe. They mediate inhibitory and excitatory interactions between the glomerular pathways and ultimately shape the tuning profile of projection neurons. To identify putative cholinergic local interneurons in the antennal lobe of Periplaneta americana an antibody raised against the biosynthetic enzyme choline acetyltransferase (ChAT) was applied to individual morphologically and electrophysiologically characterized local interneurons. In non-spiking type IIa1 local interneurons, which were classified in this study, we found ChAT-like immunoreactivity suggesting that they are most likely excitatory. This is a well-defined population of neurons that generate Ca2+ driven spikelets upon depolarization and stimulation with odorants, but not Na+ driven action potentials, because they lack voltage activated transient Na+ currents. The non-spiking type IIa2 - and type IIb local interneurons, in which Ca2+ driven spikelets were absent, were not ChAT-like immunoreactive. The GABA-like immunoreactive, spiking type I local interneurons were not ChAT-like immunoreactive. In addition we showed that uniglomerular projection neurons with cell bodies located in the ventral portion of the ventrolateral somata group and projections along the inner antenno-cerebral tract exhibited ChAT-like immunoreactivity. Assigning potential transmitters and neuromodulators to distinct morphological and electrophysiological types of antennal lobe neurons is an important prerequisite for a detailed understanding of odor information processing in insects. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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Functional allocation of synaptic contacts in microcircuits from rods via rod bipolar to aii amacrine cells in the mouse retina.

Publication Date: 2013 Jun 8 PMID: 23749582
Authors: Tsukamoto, Y. - Omi, N.
Journal: J Comp Neurol

Retinal microcircuits for night vision at the absolute threshold are required to relay a single-photon rod signal reliably to ganglion cells via rod bipolar (RB) cells and AII amacrine cells. To assess the noise reduction of intercellular signal transmission in this rod-specific pathway, we quantified its synaptic connectivity by 3D reconstruction of a series of electron micrographs. In most cases (94%), each rod made ribbon synaptic contacts onto two adjacent RB cells. Conversely, each RB cell was contacted by 25 rods. Each RB axon terminal contacted 4-5 AII amacrine cells via 53 ribbon synapses. Thus, the signal from one rod may be represented as 106 replicates at two RB axons. Moreover, the two adjacent RB cells contacted 2-4 AII amacrine cells in common, where the signals relayed by two RB cells were reunited. In more detail, over 50% of each RB output was dominantly directed to a single preferred AII amacrine cell, though each RB cell also separately contacted another 1-3 AII amacrine cells. Most of the replicate signals at two RB axons were collected on a few AII amacrine cells via reunions, dominant connections, and electrical coupling by AII-AII gap junctions. Thus the original signal may be reliably represented by signal amplification with focal accumulation without gathering unnecessary noise from a wide surrounding area. This allocation of RB-AII synaptic contacts may serve as the structural basis for the physiological properties of the AII single-photon response that include high amplification, local adaptation, and regenerative acceleration. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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Central projections of lagenar primary neurons in the chick.

Publication Date: 2013 Jun 8 PMID: 23749554
Authors: Mahmoud, A. - Reed, C. - Maklad, A.
Journal: J Comp Neurol

Perception of linear acceleration, and head position is the function of the utricle and saccule in mammals. Non-mammalian vertebrates possess a third otolith endorgan, the macula lagena. Different functions have been ascribed to the lagena in arboreal birds, including hearing, equilibrium, homing behavior and magnetoreception. However, no conclusive evidence on the function of the lagena in birds is currently available. The current study is aimed at providing a neuroanatomical substrate for the function of the lagena in the chicken as an example of terrestrial birds. The afferents from the lagena of chick embryos (E19) to the brainstem and cerebellum were investigated by the sensitive lipophilic tracer, Neuro Vue Red, in postfixed ears. The results obtained revealed that all the main vestibular nuclei, including the tangential nucleus received lagenar projections. No lagenar terminals were found in auditory centers, including the cochlear nuclei. In the cerebellum, the labeled terminals were found variably in all of the cerebellar nuclei. In the cerebellar cortex, the labeled fibers were found mostly in the uvula with fewer afferents in the flocculus and paraflocculus. None were seen in the nodulus. The absence of lagenar afferent projections in auditory nuclei, and the presence of a projection pattern in the vestibular nuclei and cerebellum similar to that of the utricle and saccule suggest that the primary role of the lagena in the chick lies in the processing of vestibular information related to linear acceleration and static head position. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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Anterior insular cortex and emotional awareness.

Publication Date: 2013 Jun 8 PMID: 23749500
Authors: Gu, X. - Hof, P. R. - Friston, K. J. - Fan, J.
Journal: J Comp Neurol

This paper reviews the foundation for a role of the human anterior insular cortex (AIC) in emotional awareness, defined as the conscious experience of emotions. We first introduce the neuroanatomical features of AIC and existing findings on emotional awareness. Using empathy, the awareness and understanding of other people's emotional states, as a test case, we then present evidence to demonstrate: 1) AIC and anterior cingulate cortex (ACC) are commonly coactivated as revealed by a meta-analysis; 2) AIC is functionally dissociable from ACC; 3) AIC integrates stimulus-driven and top-down information; and 4) AIC is necessary for emotional awareness. We propose a model in which AIC serves two major functions: integrating bottom-up interoceptive signals with top-down predictions to generate a current awareness state; and providing descending predictions to visceral systems that provide a point of reference for autonomic reflexes. We argue that AIC is critical and necessary for, emotional awareness. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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Hilar interneuron vulnerability distinguishes aged rats with memory impairment.

Publication Date: 2013 Jun 8 PMID: 23749483
Authors: Spiegel, A. M. - Koh, M. T. - Vogt, N. M. - Rapp, P. R. - Gallagher, M.
Journal: J Comp Neurol

Hippocampal interneuron populations are reportedly vulnerable to normal aging. The relationship between interneuron network integrity and age-related memory impairment, however, has not been tested directly. That question was addressed in the present study using a well-characterized model in which outbred aged male Long Evans rats exhibit a spectrum of individual differences in hippocampal-dependent memory. Selected interneuron populations in the hippocampus were visualized for stereological quantification using a panel of immunocytochemical markers, including glutamic acid decarboxylase-67 (GAD67), somatostatin, and neuropeptide-Y. The overall pattern of results was that, while the numbers of GAD67 and somatostatin-positive interneurons declined with age across multiple fields of the hippocampus, alterations specifically related to the cognitive outcome of aging were exclusively observed in the hilus of the dentate gyrus. Because the total number of NeuN-immunoreactive hilar neurons was unaffected, the decline observed with other markers likely reflects a loss of target protein rather than neuron death. In support of that interpretation, treatment with the atypical antiepileptic levetiracetam at a low dose shown previously to improve behavioral performance fully restored hilar SOM expression in aged memory-impaired rats. Age-related decreases in GAD67 and somatostatin immunoreactive neuron number beyond the hilus were regionally selective and spared the CA1 field of the hippocampus entirely. Together these findings confirm the vulnerability of hippocampal interneurons to normal aging, and they highlight that the integrity of a specific subpopulation in the hilus is coupled with age-related memory impairment. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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Intraspinal stretch receptor neurons mediate different motor responses along the body in lamprey.

Publication Date: 2013 Jun 8 PMID: 23749436
Authors: Hsu, L. J. - Zelenin, P. V. - Grillner, S. - Orlovsky, G. N. - Deliagina, T. G.
Journal: J Comp Neurol

In lampreys, stretch receptor neurons (SRNs) are located at the margins of the spinal cord and activated by longitudinal stretch in that area caused by body bending. The aim of this study was a comprehensive analysis of motor responses to bending of the lamprey body in different planes and at different rostro-caudal levels. For this purpose, in vitro preparation of the spinal cord isolated together with notochord was used, and responses to bending were recorded from SRNs, as well as from motoneurons innervating the dorsal (dMNs) and ventral (vMNs) parts of a myotome. It was found that SRNs were activated on the convex (stretched) side of the preparation during bending both in the yaw and in the pitch plane. By contrast, responses of motoneurons depended on the site and plane of bending. In the yaw plane, concave responses to bending of rostral segments and convex responses to bending of mid-body segments prevailed. In the pitch plane, convex responses in dMNs and concave responses in vMNs to bending in mid-body segments prevailed. These spinal reflexes could contribute to feedback regulation of locomotor body undulations and to the control of body configuration during locomotion. After a longitudinal split of the spinal cord, only convex responses in motoneurons were present, suggesting an important role of contralateral networks in determining the type of motor response. Stimulation of the brainstem changed the type of motor response to bending, suggesting that these spinal reflexes can be modified by supraspinal signals in accordance with different motor behaviors. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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A novel variant of neuronal intranuclear rodlet immunoreactive for 40 kDa huntingtin associated protein and ubiquitin in the mouse brain.

Publication Date: 2013 Jun 8 PMID: 23749422
Authors: Milman, P. - Woulfe, J.
Journal: J Comp Neurol

Intranuclear rodlets (INRs), also known as rodlets of Roncoroni, are poorly understood intranuclear bodies originally identified within neuronal nuclei on the basis of their unique morphology. The mechanisms of their formation, their biochemical composition and their physiological significance remain unknown. Using double immunofluorescence staining of mouse brain sections, we have identified a novel variant of INR that is immunoreactive for the 40kDa huntingtin associated protein (Hap40) and ubiquitin, and provided evidence for the existence of additional INR subtypes sharing ubiquitin immunoreactivity as a common feature. We describe a selective association of these INRs with melanin concentrating hormone (MCH) and tyrosine hydroxylase immunoreactive neurons of the hypothalamus and the locus coeruleus, respectively. We also demonstrate for the first time that biochemically distinct INR subtypes can co-exist within a single nucleus where they engage in non-random spatial interactions. Our findings highlight the biochemical diversity and cell type specific expression of these enigmatic intranuclear structures. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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A comparative analysis of Tsc1 and Tsc2 single and double radial glial cell mutants.

Publication Date: 2013 Jun 8 PMID: 23749404
Authors: Mietzsch, U. - McKenna, J. 3rd - Reith, R. M. - Way, S. W. - Gambello, M. J.
Journal: J Comp Neurol

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with variable expressivity. Heterozygous mutations in either of two genes, TSC1 (hamartin) or TSC2 (tuberin), are responsible for most cases. Hamartin and tuberin form a heterodimer that functions as a major cellular inhibitor of the mTORC1 kinase. Genotype-phenotype studies suggest that TSC2 mutations are associated with a more severe neurologic phenotype, although the biologic basis for the difference between TSC1- and TSC2-based disease is unclear. Here we performed a study to compare and contrast the brain phenotypes of Tsc1 and Tsc2 single and double mutants. Using Tsc1 and Tsc2 floxed alleles and a radial glial transgenic Cre driver (FVB-Tg(GFAP-cre)25Mes/J), we deleted Tsc1 and/or Tsc2 in radial glial progenitor cells. Single and double mutants had remarkably similar phenotypes: early postnatal mortality, brain overgrowth, laminar disruption, astrogliosis, a paucity of oligodendroglia, and myelination defects. Double Tsc1/Tsc2 mutants died earlier than single mutants, and single mutants showed differences in the location of heterotopias and the organization of the hippocampal stratum pyramidale. The differences were not due to differential mTORC1 activation or feedback inhibition on Akt. These data provide further genetic evidence for individual hamartin and tuberin functions that may explain some of the genotype-phenotype differences seen in the human disease. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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Development of myelination and cholinergic innervation in the central auditory system of a prosimian primate (Otolemur garnetti).

Publication Date: 2013 Jun 8 PMID: 23749337
Authors: Miller, D. J. - Lackey, E. P. - Hackett, T. A. - Kaas, J. H.
Journal: J Comp Neurol

Change in the timeline of neurobiological growth is an important source of biological variation, and thus phenotypic evolution. However, no study has to-date investigated sensory system development in any of the prosimian primates that are thought to most closely resemble our earliest primate ancestors. Acetylcholine (ACh) is a neurotransmitter critical to normal brain function by regulating synaptic plasticity associated with attention and learning. Myelination is an important structural component of the brain because it facilitates rapid neuronal communication. In this work, we investigated the expression of acetylcholinesterase (AChE) and the density of myelinated axons throughout postnatal development in the inferior colliculus (IC), medial geniculate complex (MGC) and auditory cortex (auditory core, belt and parabelt) in Garnett's Greater Galago (Otolemur garnetti). We found that the IC and MGC exhibit relatively high myelinated fiber length density (MFLD) values at birth and attain adult-like values by the species-typical age at weaning. In contrast, neocortical auditory fields are relatively unmyelinated at birth and only attain adult-like MFLD values by the species-typical age at puberty. Analysis of AChE expression indicated that, in contrast to evidence from rodent samples, the adult-like distribution of AChE in the core area of auditory cortex, dense bands in layers I, IIIb/IV and Vb/VI, is present at birth. These data indicate the differential developmental trajectory of central auditory system structures and demonstrate the early onset of adult-like AChE expression in primary auditory cortex in Otolemur garnetti, suggesting the auditory system is more developed at birth in primates compared to rodents. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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Sensory neuroanatomy of stick insects highlights the evolutionary diversity of the orthopteroid subgenual organ complex.

Publication Date: 2013 Jun 8 PMID: 23749306
Authors: Strauss, J. - Lakes-Harlan, R.
Journal: J Comp Neurol

The subgenual organ is a scolopidial sense organ located in the tibia of many insects. In this study, the neuroanatomy of the subgenual organ complex of stick insects is clarified for two species, Carausius morosus and Siyploidea sipylus. Neuronal tracing shows a subgenual organ complex that consists of a subgenual organ and a distal organ. There are no differences in neuroanatomy between the three thoracic leg pairs, and the sensory structures are highly similar in both species. A comparison of the neuroanatomy with other orthopteroid insects highlights two features unique in Phasmatodea. The subgenual organ contains a set of densely arranged sensory neurons in the anterior-ventral part of the organ, and a distal organ with 16 - 17 scolopidial sensilla in C. morosus and 20 - 22 scolopidial sensilla in S. sipylus. The somata of sensory neurons in the distal organ are organized in a linear array extending distally into the tibia, with only few exceptions of closely associated neurons. The stick insect sense organs show a case of an elaborate scolopidial sense organ that evolved in addition to the subgenual organ. The neuroanatomy of stick insects is compared to that studied in other orthopteroid taxa (cockroaches, locusts, crickets, tettigoniids). The comparison of sensory structures indicates that elaborate scolopidial organs have evolved repeatedly among orthopteroids. The distal organ in stick insects has the highest number of sensory neurons known for distal organs so far. J. Comp. Neurol., 2013. (c) 2013 Wiley Periodicals, Inc.

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Muller cells express the cannabinoid CB2 receptor in the vervet monkey retina.

Publication Date: 2013 Aug 1 PMID: 23736981
Authors: Bouskila, J. - Javadi, P. - Casanova, C. - Ptito, M. - Bouchard, J. F.
Journal: J Comp Neurol

The presence of the cannabinoid receptor type 1 (CB1R) has been largely documented in the rodent and primate retinae in recent years. There is, however, some controversy concerning the presence of the CB2 receptor (CB2R) within the central nervous system. Only recently, CB2R has been found in the rodent retina, but its presence in the primate retina has not yet been demonstrated. The aim of this study was twofold: 1) to characterize the distribution patterns of CB2R in the monkey retina and compare this distribution with that previously reported for CB1R and 2) to resolve the controversy on the presence of CB2R in the neural component of the retina. We therefore thoroughly examined the cellular localization of CB2R in the vervet monkey (Chlorocebus sabeus) retina, using confocal microscopy. Our results demonstrate that CB2R, like CB1R, is present throughout the retinal layers, but with striking dissimilarities. Double labeling of CB2R and glutamine synthetase shows that CB2R is restricted to Muller cell processes, extending from the internal limiting membrane, with very low staining, to the external limiting membrane, with heavy labeling. We conclude that CB2R is indeed present in the retina but exclusively in the retinal glia, whereas CB1R is expressed only in the neuroretina. These results extend our knowledge on the expression and distribution of cannabinoid receptors in the monkey retina, although further experiments are still needed to clarify their role in retinal functions. J. Comp. Neurol. J. Comp. Neurol. 521:2399-2415, 2013. (c) 2013 Wiley Periodicals, Inc.

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Amygdala projections to the lateral bed nucleus of the stria terminalis in the macaque: Comparison with ventral striatal afferents.

Publication Date: 2013 May 21 PMID: 23696521
Authors: Decampo, D. M. - Fudge, J. L.
Journal: J Comp Neurol

The lateral bed nucleus of the stria terminalis (BSTL) is involved in mediating anxiety-related behaviors to sustained aversive stimuli. The BSTL forms part of the central extended amygdala, a continuum composed of the BSTL, the amygdala central nucleus, and cell columns running between the two. The central subdivision (BSTLcn), and the juxtacapsular subdivision (BSTLJ) are two BSTL regions that lie above the anterior commissure, near the ventral striatum. The amygdala, a heterogeneous structure that encodes emotional salience, projects to both the BSTL and ventral striatum. We placed small injections of retrograde tracers into the BSTL, focusing on the BSTLcn and BSTLJ, and analyzed the distribution of labeled cells in amygdala subregions. We compared this to the pattern of labeled cells following injections into the ventral striatum. All retrograde results were confirmed by anterograde studies. We found that the BSTLcn receives stronger amygdala inputs relative to the BSTLJ. Furthermore, the BSTLcn is defined by inputs from the corticoamygdaloid transition area and central nucleus, while the BSTLJ receives inputs mainly from the magnocellular accessory basal and basal nucleus. In the ventral striatum, the dorsomedial shell receives inputs that are similar, but not identical, to inputs to the BSTLcn. In contrast, amygdala projections to the ventral shell/core are similar to projections to the BSTLJ. These findings indicate that the BSTLcn and BSTLJ receive distinct amygdala afferent inputs and that the dorsomedial shell is a transition zone with the BSTLcn, while the ventral shell/core are transition zones with the BSTLJ. J. Comp. Neurol. , 2013. (c) 2013 Wiley Periodicals, Inc.

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Diverse neuronal lineages make stereotyped contributions to the Drosophila locomotor control center, the central complex.

Publication Date: 2013 May 21 PMID: 23696496
Authors: Yang, J. S. - Awasaki, T. - Yu, H. H. - He, Y. - Ding, P. - Kao, J. C. - Lee, T.
Journal: J Comp Neurol

SUMMARY: The Drosophila central brain develops from a fixed number of neuroblasts. Each neuroblast makes a clone of neurons that exhibit common trajectories. Here we identified 15 distinct clones that carry larval-born neurons innervating the Drosophila central complex (CX), which consists of four midline structures including the protocerebral bridge (PB), fan-shape body (FB), ellipsoid body (EB), and noduli (NO). Clonal analysis revealed that the small-field CX neurons, which establish intricate projections across different CX substructures, exist in four isomorphic groups that respectively derive from four complex posterior asense-negative lineages. About the region-characteristic large-field CX neurons, we found that two lineages make PB neurons, ten lineages produce FB neurons, three lineages generate EB neurons, and two lineages yield NO neurons. The diverse FB developmental origins reflect the discrete input pathways for different FB subcompartments. Clonal analysis enlightens both development and anatomy of the insect locomotor control center. J. Comp. Neurol. , 2013. (c) 2013 Wiley Periodicals, Inc.

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Conditional viral tracing reveals that steroidogenic factor 1-positive neurons of the dorsomedial subdivision of the ventromedial hypothalamus project to autonomic centers of the hypothalamus and hindbrain.

Publication Date: 2013 May 21 PMID: 23696474
Authors: Lindberg, D. - Chen, P. - Li, C.
Journal: J Comp Neurol

Excitation of neurons in the ventromedial hypothalamus (VMH), especially those residing in the dorsomedial part of the nucleus (VMHdm), evokes sympathetic nervous system (SNS) outflow, modulating a number of physiological functions including feeding and blood glucose homeostasis. However, the anatomical basis of VMH-mediated SNS activation has thus far proved elusive. To understand how VMH neurons exercise output functions and describe an anatomical link between these neurons and the SNS, we identified downstream neural targets of the VMHdm by injecting an adenoviral vector encoding Cre recombinase (Cre)-regulated farnesylated green fluorescent protein (GFPf ) into the VMHdm of mice that express Cre in neurons expressing the VMH-specific transcription factor steroidogenic factor 1 (SF1). We confirm previously described projection patterns of the VMHdm and report the existence of a formerly unidentified projection pathway to a number of autonomic centers in the brainstem. These VMH efferents travel caudally through the periaqueductal gray (PAG) and then ventrally through the lateral lemniscus to the ventral surface of the brain, where they eventually reach caudal autonomic centers including the C1 catecholamine cell group of the rostral ventrolateral medulla (RVLM) and the nucleus of the solitary tract (NTS), where VMH efferents make close contacts with catecholaminergic neurons. We also found that VMHdm fibers reach a number of brainstem areas, including the retrotrapezoid nucleus (RTN), which are important in regulating respiration. Thus, the present study indicates that the VMH may modulate sympathetic and autonomic activity via synaptic contacts in the RTN, NTS, and RVLM and provides significant anatomical evidence to support a role of the VMH in respiratory regulation. J. Comp. Neurol. , 2013. (c) 2013 Wiley Periodicals, Inc.

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Calretinin inputs are confined to motoneurons for upward eye movements in monkey.

Publication Date: 2013 May 21 PMID: 23696443
Authors: Zeeh, C. - Hess, B. J. - Horn, A. K.
Journal: J Comp Neurol

Motoneurons of extraocular muscles are controlled by different premotor pathways, whose selective damage may cause directionally-selective eye movement disorders. The fact that clinical disorders can affect only one direction, e.g. isolated up-/downgaze palsy or up/downbeat nystagmus, indicates that up- and downgaze pathways are organized separately. Recent work in monkey revealed that a subpopulation of premotor neurons of the vertical eye movement system contains the calcium-binding protein calretinin (CR). With combined tract-tracing and immunofluorescence, the motoneurons of vertically-pulling eye muscles in monkey were investigated for the presence of CR-positive afferent terminals. In the oculomotor nucleus, CR was specifically found in punctate profiles contacting superior rectus and inferior oblique motoneurons, as well as levator palpebrae motoneurons, all of which participate in upward eye movements. Double-immunoflourescence labelling revealed that CR-positive terminals lacked the GABA synthesizing enzyme glutamate decarboxylase, which is present in inhibitory afferents to all motoneurons mediating vertical eye movements. Therefore, CR-containing afferents are considered to be excitatory. In conclusion, a strong CR input is confined to motoneurons mediating upgaze, which derive from premotor pathways mediating saccades and smooth pursuit, but not from secondary vestibulo-ocular neurons in the magnocellular part of the medial vestibular nucleus. The functional significance of CR in these connections is unclear, but it may serve as a useful marker to locate upgaze pathways in the human brain. J. Comp. Neurol. , 2013. (c) 2013 Wiley Periodicals, Inc.

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The contribution of ciliary neurotrophic factor receptors to adult motor neuron survival in vivo is specific to insult type and distinct from that for embryonic motor neurons.

Publication Date: 2013 May 21 PMID: 23695797
Authors: Lee, N. - Rydyznski, C. E. - Spearry, R. P. - Robitz, R. - Maclennan, A. J.
Journal: J Comp Neurol

Exogenous ciliary neurotrophic factor (CNTF) promotes motor neuron (MN) survival following trauma and in genetic models of MN disease. Unconditional disruption of the mouse CNTF receptor alpha (CNTFRalpha) gene leads to MN loss, demonstrating a developmental role for endogenous CNTF receptor signaling. These data also suggest that CNTF receptors may promote adult MN survival and that appropriately manipulating the receptors could effectively treat adult MN disorders. This effort would greatly benefit from a better understanding of the roles played by CNTF receptors in adult MNs. We have previously found that adult onset disruption of CNTFRalpha in facial MNs of "floxed CNTFRalpha" mice by AAV-Cre vector injection leads to significantly more MN loss than in identically treated controls. While indicating that CNTF receptors can promote adult MN survival, the data did not distinguish between potential roles in MN maintenance versus roles in protecting MNs from the injection associated trauma or the toxicity of the chronic Cre recombinase (Cre) produced by the AAV-Cre. Here we use an inducible Cre gene construct to produce adult onset CNTFRalpha disruption in facial MNs without the traumatic and toxic effects of the AAV-Cre procedure. The MNs survive without CNTFRalpha, even when challenged by facial nerve crush or the injection associated trauma, thereby suggesting, in conjunction with our previous study, that endogenous CNTF receptor signaling can protect MNs against toxic insult, such as that produced by chronic Cre. The data also indicate that in vivo CNTF receptors play very different roles in adult and embryonic MNs. J. Comp. Neurol. , 2013. (c) 2013 Wiley Periodicals, Inc.

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Muller cells express the cannabinoid CB2 receptor in the vervet monkey retina.

Publication Date: 2013 Aug 1 PMID: 23630038
Authors: Bouskila, J. - Javadi, P. - Casanova, C. - Ptito, M. - Bouchard, J. F.
Journal: J Comp Neurol

The presence of the cannabinoid receptor type 1 (CB1R) has been largely documented in the rodent and primate retinae in recent years. There is, however, some controversy concerning the presence of the CB2 receptor (CB2R) within the central nervous system. Only recently, CB2R has been found in the rodent retina, but its presence in the primate retina has not yet been demonstrated. The aim of this study was twofold: 1) to characterize the distribution patterns of CB2R in the monkey retina and compare this distribution with that previously reported for CB1R and 2) to resolve the controversy on the presence of CB2R in the neural component of the retina. We therefore thoroughly examined the cellular localization of CB2R in the vervet monkey (Chlorocebus sabeus) retina, using confocal microscopy. Our results demonstrate that CB2R, like CB1R, is present throughout the retinal layers, but with striking dissimilarities. Double labeling of CB2R and glutamine synthetase shows that CB2R is restricted to Muller cell processes, extending from the internal limiting membrane, with very low staining, to the external limiting membrane, with heavy labeling. We conclude that CB2R is indeed present in the retina but exclusively in the retinal glia, whereas CB1R is expressed only in the neuroretina. These results extend our knowledge on the expression and distribution of cannabinoid receptors in the monkey retina, although further experiments are still needed to clarify their role in retinal functions. J. Comp. Neurol. J. Comp. Neurol. 521:2399-2415, 2013. (c) 2013 Wiley Periodicals, Inc.

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In vivo characterization of a bigenic fluorescent mouse model of Alzheimer's disease with neurodegeneration.

Publication Date: 2013 Jul 1 PMID: 23605442
Authors: Crowe, S. E. - Ellis-Davies, G. C.
Journal: J Comp Neurol

The loss of cognitive function in Alzheimer's disease (AD) patients is strongly correlated with the loss of neurons in various regions of the brain. We have created a new fluorescent bigenic mouse model of AD by crossing "H-line" yellow fluorescent protein (YFP) mice with the 5xFAD mouse model, which we call the 5XY mouse model. The 5xFAD mouse has been shown to have significant loss of L5 pyramidal neurons by 12 months of age. These neurons are transgenically labeled with YFP in the 5XY mouse, which enable longitudinal imaging of structural changes. In the 5XY mice, we observed an appearance of axonal dystrophies, with two distinct morphologies in the early stages of the disease progression. Simple swelling dystrophies are transient in nature and are not directly associated with amyloid plaques. Rosette dystrophies are more complex structures that remained stable throughout all imaging sessions, and always surrounded an amyloid plaque. Plaque growth was followed over 4 weeks, and significant growth was seen between weekly imaging sessions. In addition to axonal dystrophy appearance and plaque growth, we were able to follow spine stability in 4-month old 5XY mice, which revealed no significant loss of spines. 5XY mice also showed a striking shrinkage of the neocortex at older ages (12-14 months). The 5XY mouse model may be a valuable tool for studying specific events in the degeneration of the neocortex, and may suggest new avenues for therapeutic intervention.

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Neurochemical characterization of neurons expressing melanin-concentrating hormone receptor 1 in the mouse hypothalamus.

Publication Date: 2013 Jul 1 PMID: 23605441
Authors: Chee, M. J. - Pissios, P. - Maratos-Flier, E.
Journal: J Comp Neurol

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that acts via MCH receptor 1 (MCHR1) in the mouse. It promotes positive energy balance; thus, mice lacking MCH or MCHR1 are lean, hyperactive, and resistant to diet-induced obesity. Identifying the cellular targets of MCH is an important step to understanding the mechanisms underlying MCH actions. We generated the Mchr1-cre mouse that expresses cre recombinase driven by the MCHR1 promoter and crossed it with a tdTomato reporter mouse. The resulting Mchr1-cre/tdTomato progeny expressed easily detectable tdTomato fluorescence in MCHR1 neurons, which were found throughout the olfactory system, striatum, and hypothalamus. To chemically identify MCH-targeted cell populations that play a role in energy balance, MCHR1 hypothalamic neurons were characterized by colabeling select hypothalamic neuropeptides with tdTomato fluorescence. TdTomato fluorescence colocalized with dynorphin, oxytocin, vasopressin, enkephalin, thyrothropin-releasing hormone, and corticotropin-releasing factor immunoreactive cells in the paraventricular nucleus. In the lateral hypothalamus, neurotensin, but neither orexin nor MCH neurons, expressed tdTomato. In the arcuate nucleus, both Neuropeptide Y and proopiomelanocortin cells expressed tdTomato. We further demonstrated that some of these arcuate neurons were also targets of leptin action. Interestingly, MCHR1 was expressed in the vast majority of leptin-sensitive proopiomelanocortin neurons, highlighting their importance for the orexigenic actions of MCH. Taken together, this study supports the use of the Mchr1-cre mouse for outlining the neuroanatomical distribution and neurochemical phenotype of MCHR1 neurons.

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Quantitative analysis of axon bouton distribution of subthalamic nucleus neurons in the rat by single neuron visualization with a viral vector.

Publication Date: 2013 Jun 15 PMID: 23595816
Authors: Koshimizu, Y. - Fujiyama, F. - Nakamura, K. C. - Furuta, T. - Kaneko, T.
Journal: J Comp Neurol

The subthalamic nucleus (STN) of the basal ganglia plays a key role in motor control, and STN efferents are known to mainly target the external segment of the globus pallidus (GPe), entopeduncular nucleus (Ep), and substantia nigra (SN) with some axon collaterals to the other regions. However, it remains to be clarified how each STN neuron projects axon fibers and collaterals to those target nuclei of the STN. Here we visualized the whole axonal arborization of single STN neurons in the rat brain by using a viral vector expressing membrane-targeted green fluorescent protein, and examined the distribution of axon boutons in those target nuclei. The vast majority (8-9) of 10 reconstructed STN neurons projected to the GPe, SN, caudate-putamen (CPu), and Ep, which received, on average +/- SD, 457 +/- 425, 400 +/- 347, 126 +/- 143, and 106 +/- 100 axon boutons per STN neuron, respectively. Furthermore, the density of axon boutons in the GPe was highest among these nuclei. Although these target nuclei were divided into calbindin-rich and -poor portions, STN projection showed no exclusive preference for those portions. Since STN neurons mainly projected not only to the GPe, SN, and Ep but also to the CPu, the subthalamostriatal projection might serve as a positive feedback path for the striato-GPe-subthalamic disinhibitory pathway, or work as another route of cortical inputs to the striatum through the corticosubthalamostriatal disynaptic excitatory pathway.

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Scene from above: retinal ganglion cell topography and spatial resolving power in the giraffe (Giraffa camelopardalis).

Publication Date: 2013 Jun 15 PMID: 23595815
Authors: Coimbra, J. P. - Hart, N. S. - Collin, S. P. - Manger, P. R.
Journal: J Comp Neurol

The giraffe (Giraffa camelopardalis) is a browser that uses its extensible tongue to selectively collect leaves during foraging. As the tallest extant terrestrial mammal, its elevated head height provides panoramic surveillance of the environment. These aspects of the giraffe's ecology and phenotype suggest that vision is of prime importance. Using Nissl-stained retinal wholemounts and stereological methods, we quantitatively assessed the retinal specializations in the ganglion cell layer of the giraffe. The mean total number of retinal ganglion cells was 1,393,779 and their topographic distribution revealed the presence of a horizontal visual streak and a temporal area. With a mean peak of 14,271 cells/mm(2), upper limits of spatial resolving power in the temporal area ranged from 25 to 27 cycles/degree. We also observed a dorsotemporal extension (anakatabatic area) that tapers toward the nasal retina giving rise to a complete dorsal arch. Using neurofilament-200 immunohistochemistry, we also detected a dorsal arch formed by alpha ganglion cells with density peaks in the temporal (14-15 cells/mm(2)) and dorsonasal (10 cells/mm(2)) regions. As with other artiodactyls, the giraffe shares the presence of a horizontal streak and a temporal area which, respectively, improve resolution along the horizon and in the frontal visual field. The dorsal arch is related to the giraffe's head height and affords enhanced resolution in the inferior visual field. The alpha ganglion cell distribution pattern is unique to the giraffe and enhances acquisition of motion information for the control of tongue movement during foraging and the detection of predators.

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Identification of distinct tyraminergic and octopaminergic neurons innervating the central complex of the desert locust, Schistocerca gregaria.

Publication Date: 2013 Jun 15 PMID: 23595814
Authors: Homberg, U. - Seyfarth, J. - Binkle, U. - Monastirioti, M. - Alkema, M. J.
Journal: J Comp Neurol

The central complex is a group of modular neuropils in the insect brain with a key role in visual memory, spatial orientation, and motor control. In desert locusts the neurochemical organization of the central complex has been investigated in detail, including the distribution of dopamine-, serotonin-, and histamine-immunoreactive neurons. In the present study we identified neurons immunoreactive with antisera against octopamine, tyramine, and the enzymes required for their synthesis, tyrosine decarboxylase (TDC) and tyramine beta-hydroxylase (TBH). Octopamine- and tyramine immunostaining in the central complex differed strikingly. In each brain hemisphere tyramine immunostaining was found in four neurons innervating the noduli, 12-15 tangential neurons of the protocerebral bridge, and about 17 neurons that supplied the anterior lip region and parts of the central body. In contrast, octopamine immunostaining was present in two bilateral pairs of ascending fibers innervating the upper division of the central body and a single pair of neurons with somata near the esophageal foramen that gave rise to arborizations in the protocerebral bridge. Immunostaining for TDC, the enzyme converting tyrosine to tyramine, combined the patterns seen with the tyramine- and octopamine antisera. Immunostaining for TBH, the enzyme converting tyramine to octopamine, in contrast, was strikingly similar to octopamine immunolabeling. We conclude that tyramine and octopamine act as neurotransmitters/modulators in distinct sets of neurons of the locust central complex with TBH likely being the rate-limiting enzyme for octopamine synthesis in a small subpopulation of TDC-containing neurons.

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Retinorecipient areas in the diurnal murine rodent Arvicanthis niloticus: A disproportionally large superior colliculus.

Publication Date: 2013 Jun 1 PMID: 23559407
Authors: Gaillard, F. - Karten, H. J. - Sauve, Y.
Journal: J Comp Neurol

The Nile grass rat (Arvicanthis niloticus) has a high proportion of cone photoreceptors ( approximately 30-40%) compared with that in the common laboratory mouse and rat ( approximately 1-3%) and may prove a preferable murine model with which to study cone-driven information processing in retina and primary visual centers. However, other than regions involved in circadian control, little is known about the retinorecipient structures in this rodent. We undertook a detailed analysis of the retinal projections as revealed after intravitreal injection of the anterograde tracer cholera toxin subunit B. Retinal efferents were evaluated in 45 subcortical structures. Contralateral projections were always dominant. Major contralateral inputs consisted of the suprachiasmatic nucleus, dorsolateral geniculate nucleus (dLGN), intergeniculate leaflet, ventral geniculate nucleus (magnocellular part), lateroposterior thalamic nucleus, all six pretectal nuclei, superficial layers of the superior colliculus (SC), and the main nuclei of the accessory optic system. Terminals from the contralateral eye were also localized in an unnamed field rostromedial to the dLGN as well as in the subgeniculate thalamic nucleus. Ipsilateral inputs were found mainly in the suprachiasmatic nucleus, dLGN, intergeniculate leaflet, internal sector of the magnocellular part of the ventral geniculate nucleus, olivary pretectal nucleus, and SC optic layer. Retinal afferents were not detected in the basal forebrain or the dorsal raphe nucleus. Morphometric measurements revealed that the superficial layers of the SC are disproportionately enlarged relative to other retinorecipient regions and brain size compared with rats and mice. We suggest that this reflects the selective projection of cone-driven retinal ganglion cells to the SC. J. Comp. Neurol. 521:1699-1726, 2013. (c) 2012 Wiley Periodicals, Inc.

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Muscarinic cholinergic receptor M1 in the rat basolateral amygdala: ultrastructural localization and synaptic relationships to cholinergic axons.

Publication Date: 2013 Jun 1 PMID: 23559406
Authors: Muller, J. F. - Mascagni, F. - Zaric, V. - McDonald, A. J.
Journal: J Comp Neurol

Muscarinic neurotransmission in the anterior basolateral amygdalar nucleus (BLa) mediated by the M1 receptor (M1R) is critical for memory consolidation. Although knowledge of the subcellular localization of M1R in the BLa would contribute to an understanding of cholinergic mechanisms involved in mnemonic function, there have been no ultrastructural studies of this receptor in the BLa. In the present investigation, immunocytochemistry at the electron microscopic level was used to determine which structures in the BLa express M1R. The innervation of these structures by cholinergic axons expressing the vesicular acetylcholine transporter (VAChT) was also studied. All perikarya of pyramidal neurons were labeled, and about 90% of dendritic shafts and 60% of dendritic spines were M1R+. Some dendrites had spines suggesting that they belonged to pyramidal cells, whereas others had morphological features typical of interneurons. M1R immunoreactivity (M1R-ir) was also seen in axon terminals, most of which formed asymmetrical synapses. The main targets of M1R+ terminals forming asymmetrical synapses were dendritic spines, most of which were M1R+. The main targets of M1R+ terminals forming symmetrical synapses were M1R+ perikarya and dendritic shafts. About three-quarters of VAChT+ cholinergic terminals formed synapses; the main postsynaptic targets were M1R+ dendritic shafts and spines. In some cases M1R-ir was seen near the postsynaptic membrane of these processes, but in other cases it was found outside of the active zone of VAChT+ synapses. These findings suggest that M1R mechanisms in the BLa are complex, involving postsynaptic effects as well as regulating release of neurotransmitters from presynaptic terminals.

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An important landmark in scientific publishing.

Publication Date: 2013 Jun 1 PMID: 23508768
Authors: Karten, H. J. - Glaser, J. R. - Hof, P. R.
Journal: J Comp Neurol

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Otto Friedrich Karl Deiters (1834-1863).

Publication Date: 2013 Jun 15 PMID: 23436306
Authors: Deiters, V. S. - Guillery, R. W.
Journal: J Comp Neurol

Otto Deiters, for whom the lateral vestibular nucleus and the supporting cells of the outer auditory hair cells were named, died in 1863 aged 29. He taught in the Bonn Anatomy Department, had an appointment in the University Clinic, and ran a small private practice. He published articles on the cell theory, the structure and development of muscle fibers, the inner ear, leukaemia, and scarlet fever. He was the second of five surviving children in an academic family whose private correspondence revealed him to be a young man with limited social skills and high ambitions to complete a deeply original study of the brainstem and spinal cord. However, first his father and then his younger brother died, leaving him and his older brother responsible for a suddenly impecunious family as he failed to gain academic promotion. Otto died of typhus two years after his younger brother's death, leaving his greatest scientific achievement to be published posthumously. He showed that most nerve cells have a single axon and several dendrites; he recognized the possibility that nerve cells might be functionally polarized and produced the first illustrations of synaptic inputs to dendrites from what he termed a second system of nerve fibers.

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Early remodeling of muller cells in the rd/rd mouse model of retinal dystrophy.

Publication Date: 2013 Aug 1 PMID: 23348616
Authors: Chua, J. - Nivison-Smith, L. - Fletcher, E. L. - Trenholm, S. - Awatramani, G. B. - Kalloniatis, M.
Journal: J Comp Neurol

We studied the anatomical remodeling and gliosis of retinal Muller cells in the rd/rd mouse model of photoreceptor degeneration. A computational calculation of glutamine synthetase immunoreactivity was developed so we could specifically quantify changes in Muller cell anatomy between control mice (C57Bl/6) and the dystrophic strain. We found no change in the number of Muller cell somata between mice strains, indicating no cell proliferation as a function of development and degeneration. The retinal area occupied by the total Muller cell body (soma and processes) was significantly less in the rd/rd mouse retina compared with control mice. When only the outer retina was considered, we found rd/rd Muller cell processes were dramatically reduced during the cone phase of photoreceptor degeneration. However, at older ages an increase in Muller cell processes was seen. Conversely, glial fibrillary acidic protein (GFAP) expression showed a significant increase during cone degeneration followed by a reduction in older ages. Muller cell electrophysiology, particularly K(+) currents and membrane potential, was similar between rd/rd and control Muller cells during cone degeneration. Together, these results show that glial remodeling in the rd/rd retina follows separate phases-an initial conservative glial response involving the loss of Muller cells processes, hyperexpression of GFAP, and preservation of normal electrophysiology followed by an active growth of Muller cell processes, glial seal formation, and attenuation of GFAP expression after complete photoreceptor loss. J. Comp. Neurol. 521:2439-2453, 2013. (c) 2013 Wiley Periodicals, Inc.

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In vivo characterization of a bigenic fluorescent mouse model of Alzheimer's disease with neurodegeneration.

Publication Date: 2013 Jul 1 PMID: 23348594
Authors: Crowe, S. E. - Ellis-Davies, G. C.
Journal: J Comp Neurol

The loss of cognitive function in Alzheimer's disease (AD) patients is strongly correlated with the loss of neurons in various regions of the brain. We have created a new fluorescent bigenic mouse model of AD by crossing "H-line" yellow fluorescent protein (YFP) mice with the 5xFAD mouse model, which we call the 5XY mouse model. The 5xFAD mouse has been shown to have significant loss of L5 pyramidal neurons by 12 months of age. These neurons are transgenically labeled with YFP in the 5XY mouse, which enable longitudinal imaging of structural changes. In the 5XY mice, we observed an appearance of axonal dystrophies, with two distinct morphologies in the early stages of the disease progression. Simple swelling dystrophies are transient in nature and are not directly associated with amyloid plaques. Rosette dystrophies are more complex structures that remained stable throughout all imaging sessions, and always surrounded an amyloid plaque. Plaque growth was followed over 4 weeks, and significant growth was seen between weekly imaging sessions. In addition to axonal dystrophy appearance and plaque growth, we were able to follow spine stability in 4-month old 5XY mice, which revealed no significant loss of spines. 5XY mice also showed a striking shrinkage of the neocortex at older ages (12-14 months). The 5XY mouse model may be a valuable tool for studying specific events in the degeneration of the neocortex, and may suggest new avenues for therapeutic intervention.

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Mapping kainate activation of inner neurons in the rat retina.

Publication Date: 2013 Aug 1 PMID: 23348566
Authors: Nivison-Smith, L. - Sun, D. - Fletcher, E. L. - Marc, R. E. - Kalloniatis, M.
Journal: J Comp Neurol

Kainate receptors mediate fast, excitatory synaptic transmission for a range of inner neurons in the mammalian retina. However, allocation of functional kainate receptors to known cell types and their sensitivity remains unresolved. Using the cation channel probe 1-amino-4-guanidobutane agmatine (AGB), we investigated kainate sensitivity of neurochemically identified cell populations within the structurally intact rat retina. Most inner retinal neuron populations responded to kainate in a concentration-dependent manner. OFF cone bipolar cells demonstrated the highest sensitivity of all inner neurons to kainate. Immunocytochemical localization of AGB and macromolecular markers confirmed that type 2 bipolar cells were part of this kainate-sensitive population. The majority of amacrine (ACs) and ganglion cells (GCs) showed kainate responses with different sensitivities between major neurochemical classes (gamma-aminobutyric acid [GABA]/glycine ACs > glycine ACs > GABA ACs; glutamate [Glu]/weakly GABA GCs > Glu GCs). Conventional and displaced cholinergic ACs were highly responsive to kainate, whereas dopaminergic ACs do not appear to express functional kainate receptors. These findings further contribute to our understanding of neuronal networks in complex multicellular tissues. J. Comp. Neurol. 521:2416-2438, 2013. (c) 2013 Wiley Periodicals, Inc.

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Retinorecipient areas in the diurnal murine rodent Arvicanthis niloticus: a disproportionally large superior colliculus.

Publication Date: 2013 Jun 1 PMID: 23322547
Authors: Gaillard, F. - Karten, H. J. - Sauve, Y.
Journal: J Comp Neurol

The Nile grass rat (Arvicanthis niloticus) has a high proportion of cone photoreceptors ( approximately 30-40%) compared with that in the common laboratory mouse and rat ( approximately 1-3%) and may prove a preferable murine model with which to study cone-driven information processing in retina and primary visual centers. However, other than regions involved in circadian control, little is known about the retinorecipient structures in this rodent. We undertook a detailed analysis of the retinal projections as revealed after intravitreal injection of the anterograde tracer cholera toxin subunit B. Retinal efferents were evaluated in 45 subcortical structures. Contralateral projections were always dominant. Major contralateral inputs consisted of the suprachiasmatic nucleus, dorsolateral geniculate nucleus (dLGN), intergeniculate leaflet, ventral geniculate nucleus (magnocellular part), lateroposterior thalamic nucleus, all six pretectal nuclei, superficial layers of the superior colliculus (SC), and the main nuclei of the accessory optic system. Terminals from the contralateral eye were also localized in an unnamed field rostromedial to the dLGN as well as in the subgeniculate thalamic nucleus. Ipsilateral inputs were found mainly in the suprachiasmatic nucleus, dLGN, intergeniculate leaflet, internal sector of the magnocellular part of the ventral geniculate nucleus, olivary pretectal nucleus, and SC optic layer. Retinal afferents were not detected in the basal forebrain or the dorsal raphe nucleus. Morphometric measurements revealed that the superficial layers of the SC are disproportionately enlarged relative to other retinorecipient regions and brain size compared with rats and mice. We suggest that this reflects the selective projection of cone-driven retinal ganglion cells to the SC.

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Overexpression of nerve growth factor by murine smooth muscle cells: Role of the p75 neurotrophin receptor on sympathetic and sensory sprouting.

Publication Date: 2013 Aug 1 PMID: 23322532
Authors: Petrie, C. N. - Smithson, L. J. - Crotty, A. M. - Michalski, B. - Fahnestock, M. - Kawaja, M. D.
Journal: J Comp Neurol

Elevating levels of nerve growth factor (NGF) can have pronounced effects on the survival and maintenance of distinct populations of neurons. We have generated a line of transgenic mice in which NGF is expressed under the control of the smooth muscle alpha-actin promoter. These transgenic mice have augmented levels of NGF protein in the descending colon and urinary bladder, so these tissues display increased densities of NGF-sensitive sympathetic efferents and sensory afferents. Here we provide a thorough examination of sympathetic and sensory axonal densities in the descending colon and urinary bladder of NGF transgenic mice with and without the expression of the p75 neurotrophin receptor (p75NTR). In response to elevated NGF levels, sympathetic axons (immunostained for tyrosine hydroxylase) undergo robust collateral sprouting in the descending colon and urinary bladder of adult transgenic mice (i.e., those tissues having smooth muscle cells); this sprouting is not augmented in the absence of p75NTR expression. As for sensory axons (immunostained for calcitonin gene-related peptide) in the urinary bladders of transgenic mice, fibers undergo sprouting that is further increased in the absence of p75NTR expression. Sympathetic axons are also seen invading the sensory ganglia of transgenic mice; these fibers form perineuronal plexi around a subpopulation of sensory somata. Our results reveal that elevated levels of NGF in target tissues stimulate sympathetic and sensory axonal sprouting and that an absence of p75NTR by sensory afferents (but not by sympathetic efferents) leads to a further increase of terminal arborization in certain NGF-rich peripheral tissues. J. Comp. Neurol. 521:2621-2643, 2013. (c) 2013 Wiley Periodicals, Inc.

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Differential changes in the cellular composition of the developing marsupial brain.

Publication Date: 2013 Aug 1 PMID: 23322491
Authors: Seelke, A. M. - Dooley, J. C. - Krubitzer, L. A.
Journal: J Comp Neurol

Throughout development both the body and the brain change at remarkable rates. Specifically, the number of cells in the brain undergoes dramatic nonlinear changes, first exponentially increasing in cell number and then decreasing in cell number. Different cell types, such as neurons and glia, undergo these changes at different stages of development. The current investigation used the isotropic fractionator method to examine the changes in cellular composition at multiple developmental milestones in the short-tailed opossum, Monodelphis domestica. Here we report several novel findings concerning marsupial brain development and organization. First, during the later stages of neurogenesis (P18), neurons make up most of the cells in the neocortex, although the total number of neurons remains the same throughout the life span. In contrast, in the subcortical regions, the number of neurons decreases dramatically after P18, and a converse relationship is observed for nonneuronal cells. In the cerebellum, the total number of cells gradually increases until P180 and then remains constant, and then the number of neurons is consistent across the developmental ages examined. For the three major structures examined, neuronal density and the percentage of neurons within a structure are highest during neurogenesis and then decrease after this point. Finally, the total number of neurons in the opossum brain is relatively low compared with other small-brained mammals such as mice. The relatively low number of neurons and correspondingly high number of nonneurons suggests that in the marsupial brain nonneurons may play a significant role in signal processing. J. Comp. Neurol. 521:2602-2620, 2013. (c) 2013 Wiley Periodicals, Inc.

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Intra-areal and corticocortical circuits arising in the dysgranular zone of rat primary somatosensory cortex that processes deep somatic input.

Publication Date: 2013 Aug 1 PMID: 23322443
Authors: Kim, U. - Lee, T.
Journal: J Comp Neurol

Somesthesis-guided exploration of the external world requires cortical processing of both cutaneous and proprioceptive information and their integration into motor commands to guide further haptic movement. In the past, attention has been given mostly to the cortical circuits processing cutaneous information for somatic motor integration. By comparison, little has been examined about how cortical circuits are organized for higher order proprioceptive processing. Using the rat cortex as a model, we characterized the intrinsic and corticocortical circuits arising in the major proprioceptive region of the primary somatosensory cortex (SI) that is conventionally referred to as the dysgranular zone (DSZ). We made small injections of biotinylated dextran amine (BDA) as an anterograde tracer in various parts of the DSZ, revealing three distinct principles of its cortical circuit organization. First, its intrinsic circuits extend mainly along the major axis of DSZ to organize multiple patches of interconnections. Second, the central and peripheral regions of DSZ produce differential patterns of intra-areal and corticocortical circuits. Third, the projection fields of DSZ encompass only selective regions of the second somatic (SII), posterior parietal (PPC), and primary motor (MI) cortices. These projection fields are at least partially separated from those of SI cutaneous areas. We hypothesize, based on these observations, that the cortical circuits of DSZ facilitate a modular integration of proprioceptive information along its major axis and disseminate this information to only selective parts of higher order somatic and MI cortices in parallel with cutaneous information. J. Comp. Neurol. 521:2585-2601, 2013. (c) 2013 Wiley Periodicals, Inc.

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Morphological analysis of the primary center receiving spatial information transferred by the waggle dance of honeybees.

Publication Date: 2013 Aug 1 PMID: 23297020
Authors: Ai, H. - Hagio, H.
Journal: J Comp Neurol

The waggle dancers of honeybees encodes roughly the distance and direction to the food source as the duration of the waggle phase and the body angle during the waggle phase. It is believed that hive-mates detect airborne vibrations produced during the waggle phase to acquire distance information and simultaneously detect the body axis during the waggle phase to acquire direction information. It has been further proposed that the orientation of the body axis on the vertical comb is detected by neck hairs (NHs) on the prosternal organ. The afferents of the NHs project into the prothoracic and mesothoracic ganglia and the dorsal subesophageal ganglion (dSEG). This study demonstrates somatotopic organization within the dSEG of the central projections of the mechanosensory neurons of the NHs. The terminals of the NH afferents in dSEG are in close apposition to those of Johnston's organ (JO) afferents. The sensory axons of both terminate in a region posterior to the crossing of the ventral intermediate tract (VIT) and the maxillary dorsal commissures I and III (MxDCI, III) in the subesophageal ganglion. These features of the terminal areas of the NH and JO afferents are common to the worker, drone, and queen castes of honeybees. Analysis of the spatial relationship between the NH neurons and the morphologically and physiologically characterized vibration-sensitive interneurons DL-Int-1 and DL-Int-2 demonstrated that several branches of DL-Int-1 are in close proximity to the central projection of the mechanosensory neurons of the NHs in the dSEG. J. Comp. Neurol. 521:2570-2584, 2013. (c) 2013 Wiley Periodicals, Inc.

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Cell death atlas of the postnatal mouse ventral forebrain and hypothalamus: Effects of age and sex.

Publication Date: 2013 Aug 1 PMID: 23296992
Authors: Ahern, T. H. - Krug, S. - Carr, A. V. - Murray, E. K. - Fitzpatrick, E. - Bengston, L. - McCutcheon, J. - De Vries, G. J. - Forger, N. G.
Journal: J Comp Neurol

Naturally occurring cell death is essential to the development of the mammalian nervous system. Although the importance of developmental cell death has been appreciated for decades, there is no comprehensive account of cell death across brain areas in the mouse. Moreover, several regional sex differences in cell death have been described for the ventral forebrain and hypothalamus, but it is not known how widespread the phenomenon is. We used immunohistochemical detection of activated caspase-3 to identify dying cells in the brains of male and female mice from postnatal day (P) 1 to P11. Cell death density, total number of dying cells, and regional volume were determined in 16 regions of the hypothalamus and ventral forebrain (the anterior hypothalamus, arcuate nucleus, anteroventral periventricular nucleus, medial preoptic nucleus, paraventricular nucleus, suprachiasmatic nucleus, and ventromedial nucleus of the hypothalamus; the basolateral, central, and medial amygdala; the lateral and principal nuclei of the bed nuclei of the stria terminalis; the caudate-putamen; the globus pallidus; the lateral septum; and the islands of Calleja). All regions showed a significant effect of age on cell death. The timing of peak cell death varied between P1 to P7, and the average rate of cell death varied tenfold among regions. Several significant sex differences in cell death and/or regional volume were detected. These data address large gaps in the developmental literature and suggest interesting region-specific differences in the prevalence and timing of cell death in the hypothalamus and ventral forebrain. J. Comp. Neurol. 521:2551-2569, 2013. (c) 2013 Wiley Periodicals, Inc.

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Differential connectivity of short- vs. long-range extrinsic and intrinsic cortical inputs to perirhinal neurons.

Publication Date: 2013 Aug 1 PMID: 23296922
Authors: Unal, G. - Pare, J. F. - Smith, Y. - Pare, D.
Journal: J Comp Neurol

The perirhinal cortex plays a critical role in recognition and associative memory. However, the network properties that support perirhinal contributions to memory are unclear. To shed light on this question, we compared the synaptic articulation of short- and long-range inputs from the perirhinal cortex or temporal neocortex with perirhinal neurons in rats. Iontophoretic injections of the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHAL) were performed at different rostrocaudal levels of the ventral temporal neocortex or perirhinal cortex, and electron microscopic observations of anterogradely labeled (PHAL(+) ) axon terminals found at perirhinal sites adjacent to or rostrocaudally distant from the injection sites were performed. After neocortical injections, the density of PHAL(+) axons in the perirhinal cortex decreased steeply with rostrocaudal distance from the injection sites, much more so than following perirhinal injections. Otherwise, similar results were obtained with neocortical and perirhinal injections. In both cases, most (76-86%) PHAL(+) axon terminals formed asymmetric synapses, typically with spines (type A, 83-89%) and less frequently with dendritic profiles (type B, 11-17%). The remaining terminals formed symmetric synapses with dendritic profiles (type C, 14-23%). Type B and C synapses were 2.4-2.6 times more frequent in short- than long-range connections. The postsynaptic elements in type A-C synapses were identified with immunocytochemistry for CAMKIIalpha, a marker of glutamatergic cortical neurons. Type A and C terminals contacted CAMKIIalpha-positive principal cells, whereas type B synapses contacted presumed inhibitory neurons. Overall, these results suggest that principal perirhinal neurons are subjected to significantly more inhibition from short- than from long-range cortical inputs, an organization that likely impacts perirhinal contributions to memory. J. Comp. Neurol. 521:2538-2550, 2013. (c) 2013 Wiley Periodicals, Inc.

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Selective coexpression of synaptic proteins, alpha-synuclein, cysteine string protein-alpha, synaptophysin, synaptotagmin-1, and synaptobrevin-2 in vesicular acetylcholine transporter-immunoreactive axons in the guinea pig ileum.

Publication Date: 2013 Aug 1 PMID: 23296877
Authors: Sharrad, D. F. - Gai, W. P. - Brookes, S. J.
Journal: J Comp Neurol

Parkinson's disease is a neurodegenerative disorder characterized by Lewy bodies and neurites composed mainly of the presynaptic protein alpha-synuclein. Frequently, Lewy bodies and neurites are identified in the gut of Parkinson's disease patients and may underlie associated gastrointestinal dysfunctions. We recently reported selective expression of alpha-synuclein in the axons of cholinergic neurons in the guinea pig and human distal gut; however, it is not clear whether alpha-synuclein expression varies along the gut, nor how closely expression is associated with other synaptic proteins. We used multiple-labeling immunohistochemistry to quantify which neurons in the guinea pig ileum expressed alpha-synuclein, cysteine string protein-alpha (CSPalpha), synaptophysin, synaptotagmin-1, or synaptobrevin-2 in their axons. Among the 10 neurochemically defined axonal populations, a significantly greater proportion of vesicular acetylcholine transporter-immunoreactive (VAChT-IR) varicosities (80% +/- 1.7%, n = 4, P < 0.001) contained alpha-synuclein immunoreactivity, and a significantly greater proportion of alpha-synuclein-IR axons also contained VAChT immunoreactivity (78% +/- 1.3%, n = 4) compared with any of the other nine populations (P < 0.001). Among synaptophysin-, synaptotagmin-1-, synaptobrevin-2-, and CSPalpha-IR varicosities, 98% +/- 0.7%, 96% +/- 0.7%, 88% +/- 1.6%, and 85% +/- 2.9% (n = 4) contained alpha-synuclein immunoreactivity, respectively. Among alpha-synuclein-IR varicosities, 96% +/- 0.9%, 99% +/- 0.6%, 83% +/- 1.9%, and 87% +/- 2.3% (n = 4) contained synaptophysin-, synaptotagmin-1-, synaptobrevin-2-, and CSPalpha immunoreactivity, respectively. We report a close association between the expression of alpha-synuclein and the expression of other synaptic proteins in cholinergic axons in the guinea pig ileum. Selective expression of alpha-synuclein may relate to the neurotransmitter system utilized and predispose cholinergic enteric neurons to degeneration in Parkinson's disease. J. Comp. Neurol. 521:2523-2537, 2013. (c) 2013 Wiley Periodicals, Inc.

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GABAergic inputs from direct and indirect striatal projection neurons onto cholinergic interneurons in the primate putamen.

Publication Date: 2013 Aug 1 PMID: 23296794
Authors: Gonzales, K. K. - Pare, J. F. - Wichmann, T. - Smith, Y.
Journal: J Comp Neurol

Striatal cholinergic interneurons (ChIs) are involved in reward-dependent learning and the regulation of attention. The activity of these neurons is modulated by intrinsic and extrinsic gamma-aminobutyric acid (GABA)ergic and glutamatergic afferents, but the source and relative prevalence of these diverse regulatory inputs remain to be characterized. To address this issue, we performed a quantitative ultrastructural analysis of the GABAergic and glutamatergic innervation of ChIs in the postcommissural putamen of rhesus monkeys. Postembedding immunogold localization of GABA combined with peroxidase immunostaining for choline acetyltransferase showed that 60% of all synaptic inputs to ChIs originate from GABAergic terminals, whereas 21% are from putatively glutamatergic terminals that establish asymmetric synapses, and 19% from other (non-GABAergic) sources of symmetric synapses. Double pre-embedding immunoelectron microscopy using substance P and Met-/Leu-enkephalin antibodies to label GABAergic terminals from collaterals of "direct" and "indirect" striatal projection neurons, respectively, revealed that 47% of the indirect pathway terminals and 36% of the direct pathway terminals target ChIs. Together, substance P- and enkephalin-positive terminals represent 24% of all synapses onto ChIs in the monkey putamen. These findings show that ChIs receive prominent GABAergic inputs from multiple origins, including a significant contingent from axon collaterals of direct and indirect pathway projection neurons. J. Comp. Neurol. 521:2502-2522, 2013. (c) 2013 Wiley Periodicals, Inc.

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Expression of voltage-gated calcium channel alpha2 delta4 subunits in the mouse and rat retina.

Publication Date: 2013 Aug 1 PMID: 23296739
Authors: De Sevilla Muller, L. P. - Liu, J. - Solomon, A. - Rodriguez, A. - Brecha, N. C.
Journal: J Comp Neurol

High-voltage activated Ca channels participate in multiple cellular functions, including transmitter release, excitation, and gene transcription. Ca channels are heteromeric proteins consisting of a pore-forming alpha1 subunit and auxiliary alpha2 delta and beta subunits. Although there are reports of alpha2 delta4 subunit mRNA in the mouse retina and localization of the alpha2 delta4 subunit immunoreactivity to salamander photoreceptor terminals, there is a limited overall understanding of its expression and localization in the retina. alpha2 delta4 subunit expression and distribution in the mouse and rat retina were evaluated by using reverse transcriptase polymerase chain reaction, western blot, and immunohistochemistry with specific primers and a well-characterized antibody to the alpha2 delta4 subunit. alpha2 delta4 subunit mRNA and protein are present in mouse and rat retina, brain, and liver homogenates. Immunostaining for the alpha2 delta4 subunit is mainly localized to Muller cell processes and endfeet, photoreceptor terminals, and photoreceptor outer segments. This subunit is also expressed in a few displaced ganglion cells and bipolar cell dendrites. These findings suggest that the alpha2 delta4 subunit participates in the modulation of L-type Ca(2+) current regulating neurotransmitter release from photoreceptor terminals and Ca(2+) -dependent signaling pathways in bipolar and Muller cells. J. Comp. Neurol. 521:2486-2501, 2013. (c) 2013 Wiley Periodicals, Inc.

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Immunohistochemical distribution of calretinin and calbindin (D-28k) in the brain of the cladistian Polypterus senegalus.

Publication Date: 2013 Aug 1 PMID: 23296683
Authors: Grana, P. - Folgueira, M. - Huesa, G. - Anadon, R. - Yanez, J.
Journal: J Comp Neurol

Polypteriform fishes are believed to be basal to other living ray-finned bony fishes, and they may be useful for providing information of the neural organization that existed in the brain of the earliest ray-finned fishes. The calcium-binding proteins calretinin (CR) and calbindin-D28k (CB) have been widely used to characterize neuronal populations in vertebrate brains. Here, the distribution of the immunoreactivity against CR and CB was investigated in the olfactory organ and brain of Polypterus senegalus and compared to the distribution of these molecules in other ray-finned fishes. In general, CB-immunoreactive (ir) neurons were less abundant than CR-ir cells. CR immunohistochemistry revealed segregation of CR-ir olfactory receptor neurons in the olfactory mucosa and their bulbar projections. Our results confirmed important differences between pallial regions in terms of CR immunoreactivity of cell populations and afferent fibers. In the habenula, these calcium-binding proteins revealed right-left asymmetry of habenular subpopulations and segregation of their interpeduncular projections. CR immunohistochemistry distinguished among some thalamic, pretectal, and posterior tubercle-derived populations. Abundant CR-ir populations were observed in the midbrain, including the tectum. CR immunoreactivity was also useful for characterizing a putative secondary gustatory/visceral nucleus in the isthmus, and for distinguishing territories in the primary viscerosensory column and octavolateral region. Comparison of the data obtained within a segmental neuromeric context indicates that some CB-ir and CR-ir populations in polypteriform fishes are shared with other ray-finned fishes, but other positive structures appear to have evolved following the separation between polypterids and other ray-finned fishes. J. Comp. Neurol. 521:2454-2485, 2013. (c) 2013 Wiley Periodicals, Inc.

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Differential dendritic targeting of AMPA receptor subunit mRNAs in adult rat hippocampal principal neurons and interneurons.

Publication Date: 2013 Jun 15 PMID: 23296627
Authors: Cox, D. J. - Racca, C.
Journal: J Comp Neurol

In hippocampal neurons, AMPA receptors (AMPARs) mediate fast excitatory postsynaptic responses at glutamatergic synapses, and are involved in various forms of synaptic plasticity. Dendritic local protein synthesis of selected AMPAR subunit mRNAs is considered an additional mechanism to independently and rapidly control the strength of individual synapses. We have used fluorescent in situ hybridization and immunocytochemistry to analyze the localization of AMPAR subunit (GluA1-4) mRNAs and their relationship with the translation machinery in principal cells and interneurons of the adult rat hippocampus. The mRNAs encoding all four AMPAR subunits were detected in the somata and dendrites of CA3 and CA1 pyramidal cells and those of six classes of CA1 gamma-aminobutyric acid (GABA)ergic interneurons. GluA1-4 subunit mRNAs were highly localized to the apical dendrites of pyramidal cells, whereas in interneurons they were present in multiple dendrites. In contrast, in the dentate gyrus, GluA1-4 subunit mRNAs were virtually restricted to the somata and were absent from the dendrites of granule cells. These different regional and cell type-specific labeling patterns also correlated with the localization of markers for components of the protein synthesis machinery. Our results support the local translation of GluA1-4 mRNAs in dendrites of hippocampal pyramidal cells and CA1 interneurons but not in granule cells of the dentate gyrus. Furthermore, the regional and cell type-specific differences we observed suggest that each cell type uses distinct ways of regulating the local translation of AMPAR subunits.

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Forebrain GABAergic projections to locus coeruleus in mouse.

Publication Date: 2013 Jul 1 PMID: 23296594
Authors: Dimitrov, E. L. - Yanagawa, Y. - Usdin, T. B.
Journal: J Comp Neurol

The noradrenergic locus coeruleus (LC) regulates arousal, memory, sympathetic nervous system activity, and pain. Forebrain projections to LC have been characterized in rat, cat, and primates, but not systematically in mouse. We surveyed mouse forebrain LC-projecting neurons by examining retrogradely labeled cells following LC iontophoresis of Fluoro-Gold and anterograde LC labeling after forebrain injection of biotinylated dextran amine or viral tracer. Similar to other species, the central amygdalar nucleus (CAmy), anterior hypothalamus, paraventricular nucleus, and posterior lateral hypothalamic area (PLH) provide major LC inputs. By using mice expressing green fluorescent protein in gamma-aminobutyric acid (GABA)ergic neurons, we found that more than one-third of LC-projecting CAmy and PLH neurons are GABAergic. LC colocalization of biotinylated dextran amine, following CAmy or PLH injection, with either green fluorescent protein or glutamic acid decarboxylase (GAD)65/67 immunoreactivity confirmed these GABAergic projections. CAmy injection of adeno-associated virus encoding channelrhodopsin-2-Venus showed similar fiber labeling and association with GAD65/67-immunoreactive (ir) and tyrosine hydroxylase (TH)-ir neurons. CAmy and PLH projections were densest in a pericoerulear zone, but many fibers entered the LC proper. Close apposition between CAmy GABAergic projections and TH-ir processes suggests that CAmy GABAergic neurons may directly inhibit noradrenergic principal neurons. Direct LC neuron targeting was confirmed by anterograde transneuronal labeling of LC TH-ir neurons following CAmy or PLH injection of a herpes virus that expresses red fluorescent protein following activation by Cre recombinase in mice that express Cre recombinase in GABAergic neurons. This description of GABAergic projections from the CAmy and PLH to the LC clarifies important forebrain sources of inhibitory control of central nervous system noradrenergic activity.

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Corticospinal sprouting occurs selectively following dorsal rhizotomy in the macaque monkey.

Publication Date: 2013 Jul 1 PMID: 23239125
Authors: Darian-Smith, C. - Lilak, A. - Alarcon, C.
Journal: J Comp Neurol

The corticospinal tract in the macaque and human forms the major descending pathway involved in volitional hand movements. Following a unilateral cervical dorsal root lesion, by which sensory input to the first three digits (D1-D3) is removed, monkeys are initially unable to perform a grasp retrieval task requiring sensory feedback. Over several months, however, they recover much of this capability. Past studies in our laboratory have identified a number of changes in the afferent circuitry that occur as function returns, but do changes to the efferent pathways also contribute to compensatory recovery? In this study we examined the role of the corticospinal tract in pathway reorganization following a unilateral cervical dorsal rhizotomy. Several months after animals received a lesion, the corticospinal pathways originating in the primary somatosensory and motor cortex were labeled, and terminal distribution patterns on the two sides of the cervical cord were compared. Tracers were injected only into the region of D1-D3 representation (identified electrophysiologically). We observed a strikingly different terminal labeling pattern post lesion for projections originating in the somatosensory versus motor cortex. The terminal territory from the somatosensory cortex was significantly smaller compared with the contralateral side (area mean = 0.30 vs. 0.55 mm2), indicating retraction or atrophy of terminals. In contrast, the terminal territory from the motor cortex did not shrink, and in three of four animals, aberrant terminal label was observed in the dorsal horn ipsilateral to the lesion, indicating sprouting. These differences suggest that cortical regions play a different role in post-injury recovery

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Site of origin of and sex differences in the vasopressin innervation of the mouse (Mus musculus) brain.

Publication Date: 2013 Jul 1 PMID: 23239101
Authors: Rood, B. D. - Stott, R. T. - You, S. - Smith, C. J. - Woodbury, M. E. - De Vries, G. J.
Journal: J Comp Neurol

Defining how arginine vasopressin (AVP) acts centrally to regulate homeostasis and behavior is problematic, as AVP is made in multiple nuclei in the hypothalamus (i.e., paraventricular [PVN], supraoptic [SON], and suprachiasmatic [SCN]) and extended amygdala (i.e., bed nucleus of the stria terminalis [BNST] and medial amygdala [MeA]), and these groups of neurons have extensive projections throughout the brain. To understand the function of AVP, it is essential to know the site of origin of various projections. In mice, we used gonadectomy to eliminate gonadal steroid hormone-dependent expression of AVP in the BNST and MeA and electrolytic lesions to eliminate the SCN, effectively eliminating those AVP-immunoreactive projections; we also quantified AVP-immunoreactive fiber density in gonadectomized and sham-operated male and female mice to examine sex differences in AVP innervation. Our results suggest that the BNST/MeA AVP system innervates regions containing major modulatory neurotransmitters (e.g., serotonin and dopamine) and thus may be involved in regulating behavioral state. Furthermore, this system may be biased toward the regulation of male behavior, given the numerous regions in which males have a denser AVP-immunoreactive innervation than females. AVP from the SCN is found in regions important for the regulation of hormone output and behavior. Innervation from the PVN and SON is found in brain regions that likely work in concert with the well-known peripheral AVP actions of controlling homeostasis and stress response; female-biased sex differences in this system may be related to the heightened stress response observed in females.

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Pre-target axon sorting in the avian auditory brainstem.

Publication Date: 2013 Jul 1 PMID: 23239056
Authors: Kashima, D. T. - Rubel, E. W. - Seidl, A. H.
Journal: J Comp Neurol

Topographic organization of neurons is a hallmark of brain structure. The establishment of the connections between topographically organized brain regions has attracted much experimental attention, and it is widely accepted that molecular cues guide outgrowing axons to their targets in order to construct topographic maps. In a number of systems afferent axons are organized topographically along their trajectory as well, and it has been suggested that this pre-target sorting contributes to map formation. Neurons in auditory regions of the brain are arranged according to their best frequency (BF), the sound frequency they respond to optimally. This BF changes predictably with position along the so-called tonotopic axis. In the avian auditory brainstem, the tonotopic organization of the second- and third-order auditory neurons in nucleus magnocellularis (NM) and nucleus laminaris (NL) has been well described. In this study we examine whether the decussating NM axons forming the crossed dorsal cochlear tract (XDCT) and innervating the contralateral NL are arranged in a systematic manner. We electroporated dye into cells in different frequency regions of NM to anterogradely label their axons in XDCT. The placement of dye in NM was compared to the location of labeled axons in XDCT. Our results show that NM axons in XDCT are organized in a precise tonotopic manner along the rostrocaudal axis, spanning the entire rostrocaudal extent of both the origin and target nuclei. We propose that in the avian auditory brainstem, this pretarget axon sorting contributes to tonotopic map formation in NL.

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Androgen receptors mediate masculinization of astrocytes in the rat posterodorsal medial amygdala during puberty.

Publication Date: 2013 Jul 1 PMID: 23239016
Authors: Johnson, R. T. - Breedlove, S. M. - Jordan, C. L.
Journal: J Comp Neurol

Astrocytes in the posterodorsal portion of the medial amygdala (MePD) are sexually dimorphic in adult rats: males have more astrocytes in the right MePD and more elaborate processes in the left MePD than do females. Functional androgen receptors (ARs) are required for masculinization of MePD astrocytes, as these measures are demasculinized in adult males carrying the testicular feminization mutation (Tfm) of the AR gene, which renders AR dysfunctional. We now report that the number of astrocytes is already sexually dimorphic in the right MePD of juvenile 25-day-old (P25) rats. Because Tfm males have as many astrocytes as wild-type males at this age, this prepubertal sexual dimorphism is independent of ARs. After P25, astrocyte number increases in the MePD of all groups, but activation of ARs augments this increase in the right MePD, where more astrocytes are added in males than in Tfm males. Consequently, by adulthood, females and Tfm males have equivalent numbers of astrocytes in the right MePD. Sexual dimorphism in astrocyte arbor complexity in the left MePD arises after P25, and is entirely AR-dependent. Thus, masculinization of MePD astrocytes is a result of both AR-independent processes before the juvenile period and AR-dependent processes afterward.

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NMDA-like receptors in the nervous system of the crab Neohelice granulata: a neuroanatomical description.

Publication Date: 2013 Jul 1 PMID: 23238970
Authors: Hepp, Y. - Tano, M. C. - Pedreira, M. E. - Freudenthal, R. A.
Journal: J Comp Neurol

N-Methyl-D-aspartate receptors (NMDARs) are involved in learning and memory processes in vertebrates and invertebrates. In Neohelice granulata, NMDARs are involved in the storage of associative memories (see references in text). The aim of this work was to characterize this type of glutamate receptor in Neohelice and to describe its distribution in the central nervous system (CNS). As a first step, a detailed study of the CNS of N. granulata was performed at the neuropil level, with special focus on one of the main structures involved in this type of memory, the supraesophageal ganglion, called central brain. The characterization of the NMDAR was achieved by identifying the essential subunit of these receptors, the NR1-like subunit. The NR1-like signals were found via western blot and immunohistochemistry techniques in each of the major ganglia: the eyestalk ganglia, the central brain, and the thoracic ganglion. Western blots yielded two bands for the crab NR1-like subunit, at approximately 88 and approximately 84 kDa. This subunit is present in all the major ganglia, and shows a strong localization in synaptosomal membranes. NMDARs are distributed throughout the majority of each ganglion but show prominent signal intensity in some distinguishable neuropils and neurons. This is the first general description of the N. granulata nervous system as a whole and the first study of NMDARs in the CNS of decapods. The preferential localization of the receptor in some neuropils and neurons indicates the presence of possible new targets for memory processing and storage.

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Neurogenesis is required for behavioral recovery after injury in the visual system of Xenopus laevis.

Publication Date: 2013 Jul 1 PMID: 23238877
Authors: McKeown, C. R. - Sharma, P. - Sharipov, H. E. - Shen, W. - Cline, H. T.
Journal: J Comp Neurol

Nonmammalian vertebrates have a remarkable capacity to regenerate brain tissue in response to central nervous system (CNS) injury. Nevertheless, it is not clear whether animals recover lost function after injury or whether injury-induced cell proliferation mediates recovery. We address these questions using the visual system and visually-guided behavior in Xenopus laevis tadpoles. We established a reproducible means to produce a unilateral focal injury to optic tectal neurons without damaging retinotectal axons. We then assayed a tectally-mediated visual avoidance behavior to evaluate behavioral impairment and recovery. Focal ablation of part of the optic tectum prevents the visual avoidance response to moving stimuli. Animals recover the behavior over the week following injury. Injury induces a burst of proliferation of tectal progenitor cells based on phospho-histone H3 immunolabeling and experiments showing that Musashi-immunoreactive tectal progenitors incorporate the thymidine analog chlorodeoxyuridine after injury. Pulse chase experiments indicate that the newly-generated cells differentiate into N-beta-tubulin-immunoreactive neurons. Furthermore, in vivo time-lapse imaging shows that Sox2-expressing neural progenitors divide in response to injury and generate neurons with elaborate dendritic arbors. These experiments indicate that new neurons are generated in response to injury. To test if neurogenesis is necessary for recovery from injury, we blocked cell proliferation in vivo and found that recovery of the visual avoidance behavior is inhibited by drugs that block cell proliferation. Moreover, behavioral recovery is facilitated by changes in visual experience that increase tectal progenitor cell proliferation. Our data indicate that neurogenesis in the optic tectum is critical for recovery of visually-guided behavior after injury.

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Glucagon-like peptide-1 in the rat brain: distribution of expression and functional implication.

Publication Date: 2013 Jul 1 PMID: 23238833
Authors: Gu, G. - Roland, B. - Tomaselli, K. - Dolman, C. S. - Lowe, C. - Heilig, J. S.
Journal: J Comp Neurol

Glucagon-like-peptide 1 (GLP-1) is expressed not only in gut endocrine cells, but also in cells in the caudal brainstem and taste buds. To better understand the functions of central GLP-1, GLP-1 expression was immunohistochemically profiled in normal rat brain and its distribution correlated with FOS induction following systemic administration of a GLP-1 receptor agonist, exendin-4. In the present study, only a small number of GLP-1-immunoreactive cell bodies were observed in the nucleus of the solitary tract (NTS). However, these neurons send abundant projections to other regions of the brain, in particular the forebrain, including the paraventricular and dorsomedial nuclei of the hypothalamus, the central nucleus of the amygdala, the oval nucleus of the bed nuclei of the stria terminalis, and the paraventricular nucleus of the thalamus. Intraperitoneal administration of exendin-4 resulted in extensive FOS expression in areas of the forebrain and the hindbrain. In the forebrain, FOS expression was largely confined to regions where a high density of GLP-1-immunoreactive terminals was also localized. The majority of GLP-1-immunoreactive cells in the NTS were not FOS-positive. FOS-positive cells appeared to represent a different population from those expressing GLP-1. Thus, GLP-1-containing neurons in the brainstem may not be involved in receiving and relaying to other regions of the brain the physiological signals of prandial GLP-1 secreted by intestinal L-cells. Projections of GLP-1-containing neurons to the distinctive structures in the forebrain imply that central GLP-1 may play an important role in the behavioral and metabolic integration of autonomic control and arousal in the rat.

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Neural pathways mediating control of reproductive behavior in male Japanese quail.

Publication Date: 2013 Jun 15 PMID: 23225613
Authors: Wild, J. M. - Balthazart, J.
Journal: J Comp Neurol

The sexually dimorphic medial preoptic nucleus (POM) in Japanese quail has for many years been the focus of intensive investigations into its role in reproductive behavior. The present study delineates a sequence of descending pathways that finally reach sacral levels of the spinal cord housing motor neurons innervating cloacal muscles involved in reproductive behavior. We first retrogradely labeled the motor neurons innervating the large cloacal sphincter muscle (mSC) that forms part of the foam gland complex (Seiwert and Adkins-Regan [1998] Brain Behav Evol 52:61-80) and then putative premotor nuclei in the brainstem, one of which was nucleus retroambigualis (RAm) in the caudal medulla. Anterograde tracing from RAm defined a bulbospinal pathway, terminations of which overlapped the distribution of mSC motor neurons and their extensive dorsally directed dendrites. Descending input to RAm arose from an extensive dorsomedial nucleus of the intercollicular complex (DM-ICo), electrical stimulation of which drove vocalizations. POM neurons were retrogradely labeled by injections of tracer into DM-ICo, but POM projections largely surrounded DM, rather than penetrated it. Thus, although a POM projection to ICo was shown, a POM projection to DM must be inferred. Nevertheless, the sequence of projections in the male quail from POM to cloacal motor neurons strongly resembles that in rats, cats, and monkeys for the control of reproductive behavior, as largely defined by Holstege et al. ([1997], Neuroscience 80:587-598).

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Characterization of multiple bistratified retinal ganglion cells in a purkinje cell protein 2-Cre transgenic mouse line.

Publication Date: 2013 Jun 15 PMID: 23224947
Authors: Ivanova, E. - Lee, P. - Pan, Z. H.
Journal: J Comp Neurol

Retinal ganglion cells are categorized into multiple classes, including multiple types of bistratified ganglion cells (BGCs). The recent use of transgenic mouse lines with specific type(s) of ganglion cells that are labeled by fluorescent markers has facilitated the morphological and physiological studies of BGCs, particularly the directional-selective BGCs. The most important benefit from using transgenic animals is the capability to perform in vivo gene manipulation. In particular, the Cre/LoxP recombination system has become a powerful tool, allowing gene deletion, overexpression, and ectopic expression in a cell type-specific and temporally controlled fashion. The key to this tool is the availability of Cre mouse lines with cell or tissue type-specific expression of Cre recombinase. In this study we characterized the Cre-positive retinal ganglion cells in a PCP2 (Purkinje cell protein 2)-cre mouse line. We found that all of the Cre-positive retinal ganglion cells were BGCs. Based on morphological criteria, we determined that they can be grouped into five types. The On- and Off-dendrites of three of these types stratified outside of the cholinergic bands and differed from directional selective ganglion cells (DSGCs) morphologically. These cells were negative for Brn-3b and positive for both calretinin and CART retina markers. The remaining two types were identified as putative On-Off and On-DSGCs. This Cre mouse line could be useful for further studies of the molecular and functional properties of BGCs in mice.

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Molecular cloning and characterization of chicken neuronal intermediate filament protein alpha-internexin.

Publication Date: 2013 Jun 15 PMID: 23224860
Authors: Liu, C. H. - Chien, C. L.
Journal: J Comp Neurol

alpha-Internexin is one of the neuronal intermediate filament (IF) proteins, which also include low-, middle-, and high-molecular-weight neurofilament (NF) triplet proteins, designated NFL, NFM, and NFH, respectively. The expression of alpha-internexin occurs in most neurons as they begin differentiation and precedes the expression of the NF triplet proteins in mammals. However, little is known about the gene sequence and physiological function of alpha-internexin in avians. In this study we describe the molecular cloning of the mRNA sequence encoding the chicken alpha-internexin (chkINA) protein from embryonic brains. The gene structure and predicted amino acid sequence of chkINA exhibited high similarity to those of its zebrafish, mouse, rat, bovine, and human homologs. Data from transient-transfection experiments show that the filamentous pattern of chkINA was found in transfected cells and colocalized with other endogenous IFs, as demonstrated via immunocytochemistry using a chicken-specific antibody. The expression of chkINA was detected at the early stage of development and increased during the developmental process of the chicken. chkINA was expressed widely in chicken brains and colocalized with NF triplet proteins in neuronal processes, as assessed using immunohistochemistry. We also found that chkINA was expressed abundantly in the developing cerebellum and was the major IF protein in the parallel processes of granule neurons. Thus, we suggest that chkINA is a neuron-specific IF protein that may be a useful marker for studies of chicken brain development.

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Expression patterns of Pax6 and Pax7 in the adult brain of a urodele amphibian, Pleurodeles waltl.

Publication Date: 2013 Jun 15 PMID: 23224769
Authors: Joven, A. - Morona, R. - Gonzalez, A. - Moreno, N.
Journal: J Comp Neurol

Expression patterns of Pax6, Pax7, and, to a lesser extent, Pax3 genes were analyzed by a combination of immunohistochemical techniques in the central nervous system of adult specimens of the urodele amphibian Pleurodeles waltl. Only Pax6 was found in the telencephalon, specifically the olfactory bulbs, striatum, septum, and lateral and central parts of the amygdala. In the diencephalon, Pax6 and Pax7 were distinct in the alar and basal parts, respectively, of prosomere 3. The distribution of Pax6, Pax7, and Pax3 cells correlated with the three pretectal domains. Pax7 specifically labeled cells in the dorsal mesencephalon, mainly in the optic tectum, and Pax6 cells were the only cells found in the tegmentum. Large populations of Pax7 cells occupied the rostral rhombencephalon, along with lower numbers of Pax6 and Pax3 cells. Pax6 was found in most granule cells of the cerebellum. Pax6 cells also formed a column of scattered neurons in the reticular formation and were found in the octavolateral area. The rhombencephalic ventricular zone of the alar plate expressed Pax7. Dorsal Pax7 cells and ventral Pax6 cells were found along the spinal cord. Our results show that the expression of Pax6 and Pax7 is widely maintained in the brains of adult urodeles, in contrast to the situation in other tetrapods. This discrepancy could be due to the generally pedomorphic features of urodele brains. Although the precise role of these transcription factors in adult brains remains to be determined, our findings support the idea that they may also function in adult urodeles.

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Diversity of thalamorecipient spine morphology in cat visual cortex and its implication for synaptic plasticity.

Publication Date: 2013 Jun 15 PMID: 23184851
Authors: da Costa, N. M.
Journal: J Comp Neurol

A feature of spine synapses is the existence of a neck connecting the synapse on the spine head to the dendritic shaft. As with a cable, spine neck resistance (R(neck)) increases with increasing neck length and is inversely proportional to the cross-sectional area of the neck. A synaptic current entering a spine with a high R(neck) will lead to greater local depolarization in the spine head than would a similar input applied to a spine with a lower R(neck). This could make spines with high R(neck) more sensitive to plastic changes since voltage sensitive conductances, such as N-methyl-D-aspartic acid (NMDA) channels can be more easily activated. This hypothesis was tested using serial section electron microscopic reconstructions of thalamocortical spine synapses and spine necks located on spiny stellate cells and corticothalamic cells from area 17 of cats. Thalamic axons and corticothalamic neurons were labeled by injections of the tracer biotinylated dextran amine (BDA) in the dorsal lateral geniculate nucleus (dLGN) of anesthetized cats and spiny stellates were filled intracellularly in vivo with horseradish peroxidase. Twenty-eight labeled spines that formed synapses with dLGN boutons were collected from three spiny stellate and four corticothalamic cells and reconstructed in 3D from serial electron micrographs. Spine length, spine diameter, and the area of the postsynaptic density were measured from the 3D reconstructions and R(neck) of the spine was estimated. No correlation was found between the postsynaptic density size and the estimated spine R(neck). This suggests that forms of plasticity that lead to larger synapses are independent of spine neck resistance.

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Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex.

Publication Date: 2013 Jul 1 PMID: 23184811
Authors: Agster, K. L. - Mejias-Aponte, C. A. - Clark, B. D. - Waterhouse, B. D.
Journal: J Comp Neurol

The brainstem nucleus locus coeruleus (LC) is the sole source of norepinephrine (NE)-containing fibers in the mammalian cortex. Previous studies suggest that the density of noradrenergic fibers in rat is relatively uniform across cortical regions and that cells in the nucleus discharge en masse. This implies that activation of the LC results in equivalent release of NE throughout the cortex. However, it is possible that there could be differences in the density of axonal varicosities across regions, and that these differences, rather than a difference in fiber density, may contribute to the regulation of NE efflux. Quantification of dopamine beta-hydroxylase (DbetaH)-immunostained varicosities was performed on several cortical regions and in the ventral posterior medial (VPM) thalamus by using unbiased sampling methods. The density of DbetaH varicosities is greater in the prefrontal cortex than in motor, somatosensory, or piriform cortices, greater in superficial than in deep layers of cortex, and greater in the VPM than in the somatosensory cortex. Our results provide anatomical evidence for non-uniform release of NE across functionally discrete cortical regions. This morphology may account for a differential, region-specific, impact of LC output on different cortical areas.

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Postsynaptic muscarinic m2 receptors at cholinergic and glutamatergic synapses of mouse brainstem motoneurons.

Publication Date: 2013 Jun 15 PMID: 23184757
Authors: Csaba, Z. - Krejci, E. - Bernard, V.
Journal: J Comp Neurol

In many brain areas, few cholinergic synapses are identified. Acetylcholine is released into the extracellular space and acts through diffuse transmission. Motoneurons, however, are contacted by numerous cholinergic terminals, indicating synaptic cholinergic transmission on them. The muscarinic m2 receptor is the major acetylcholine receptor subtype of motoneurons; therefore, we analyzed the localization of the m2 receptor in correlation with synapses by electron microscopic immunohistochemistry in the mouse trigeminal, facial, and hypoglossal motor nuclei. In all nuclei, m2 receptors were localized at the membrane of motoneuronal perikarya and dendrites. The m2 receptors were concentrated at cholinergic synapses located on the perikarya and most proximal dendrites. However, m2 receptors at cholinergic synapses represented only a minority (<10%) of surface m2 receptors. The m2 receptors were also enriched at glutamatergic synapses in both motoneuronal perikarya and dendrites. A relatively large proportion (20-30%) of plasma membrane-associated m2 receptors were located at glutamatergic synapses. In conclusion, the effect of acetylcholine on motoneuron populations might be mediated through a synaptic as well as diffuse type of transmission.

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De novo expression of neurokinin-1 receptors by spinoparabrachial lamina I pyramidal neurons following a peripheral nerve lesion.

Publication Date: 2013 Jun 1 PMID: 23172292
Authors: Saeed, A. W. - Ribeiro-da-Silva, A.
Journal: J Comp Neurol

Lamina I of the spinal dorsal horn is a major site of integration and transmission to higher centers of nociceptive information from the periphery. One important primary afferent population that transmits such information to the spinal cord expresses substance P (SP). These fibers terminate in contact with lamina I projection neurons that express the SP receptor, also known as the neurokinin-1 receptor (NK-1r). Three types of lamina I projection neurons have been described: multipolar, fusiform, and pyramidal. Most neurons of the first two types are thought to be nociceptive and express the NK-1r, whereas most pyramidal neurons are nonnociceptive and do not express the NK-1r. In this immunocytochemical and behavioral study, we induced a neuropathic pain-like condition in the rat by means of a polyethylene cuff placed around in the sciatic nerve. We document that this lesion led to a de novo expression of NK-1r on pyramidal neurons as well as a significant increase in SP-immunoreactive innervation onto these neurons. These phenotypic changes were evident at the time of onset of neuropathic pain-related behavior. Additionally, we show that, after a noxious stimulus (intradermal capsaicin injection), these NK-1r on pyramidal neurons were internalized, providing evidence that these neurons become responsive to peripheral noxious stimulation. We suggest that the changes following nerve lesion in the phenotype and innervation pattern of pyramidal neurons are of significance for neuropathic pain and/or limb temperature regulation.

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Efferent projections of neuropeptide Y-expressing neurons of the dorsomedial hypothalamus in chronic hyperphagic models.

Publication Date: 2013 Jun 1 PMID: 23172177
Authors: Lee, S. J. - Kirigiti, M. - Lindsley, S. R. - Loche, A. - Madden, C. J. - Morrison, S. F. - Smith, M. S. - Grove, K. L.
Journal: J Comp Neurol

The dorsomedial hypothalamus (DMH) has long been implicated in feeding behavior and thermogenesis. The DMH contains orexigenic neuropeptide Y (NPY) neurons, but the role of these neurons in the control of energy homeostasis is not well understood. NPY expression in the DMH is low under normal conditions in adult rodents but is significantly increased during chronic hyperphagic conditions such as lactation and diet-induced obesity (DIO). To understand better the role of DMH-NPY neurons, we characterized the efferent projections of DMH-NPY neurons using the anterograde tracer biotinylated dextran amine (BDA) in lactating rats and DIO mice. In both models, BDA- and NPY-colabeled fibers were limited mainly to the hypothalamus, including the paraventricular nucleus of the hypothalamus (PVH), lateral hypothalamus/perifornical area (LH/PFA), and anteroventral periventricular nucleus (AVPV). Specifically in lactating rats, BDA-and NPY-colabeled axonal swellings were in close apposition to cocaine- and amphetamine-regulated transcript (CART)-expressing neurons in the PVH and AVPV. Although the DMH neurons project to the rostral raphe pallidus (rRPa), these projections did not contain NPY immunoreactivity in either the lactating rat or the DIO mouse. Instead, the majority of BDA-labeled fibers in the rRPa were orexin positive. Furthermore, DMH-NPY projections were not observed within the nucleus of the solitary tract (NTS), another brainstem site critical for the regulation of sympathetic outflow. The present data suggest that NPY expression in the DMH during chronic hyperphagic conditions plays important roles in feeding behavior and thermogenesis by modulating neuronal functions within the hypothalamus, but not in the brainstem.

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Laminar and connectional organization of a multisensory cortex.

Publication Date: 2013 Jun 1 PMID: 23172137
Authors: Foxworthy, W. A. - Clemo, H. R. - Meredith, M. A.
Journal: J Comp Neurol

The transformation of sensory signals as they pass through cortical circuits has been revealed almost exclusively through studies of the primary sensory cortices, for which principles of laminar organization, local connectivity, and parallel processing have been elucidated. In contrast, almost nothing is known about the circuitry or laminar features of multisensory processing in higher order, multisensory cortex. Therefore, using the ferret higher order multisensory rostral posterior parietal (PPr) cortex, the present investigation employed a combination of multichannel recording and neuroanatomical techniques to elucidate the laminar basis of multisensory cortical processing. The proportion of multisensory neurons, the share of neurons showing multisensory integration, and the magnitude of multisensory integration were all found to differ by layer in a way that matched the functional or connectional characteristics of the PPr. Specifically, the supragranular layers (L2/3) demonstrated among the highest proportions of multisensory neurons and the highest incidence of multisensory response enhancement, while also receiving the highest levels of extrinsic inputs, exhibiting the highest dendritic spine densities, and providing a major source of local connectivity. In contrast, layer 6 showed the highest proportion of unisensory neurons while receiving the fewest external and local projections and exhibiting the lowest dendritic spine densities. Coupled with a lack of input from principal thalamic nuclei and a minimal layer 4, these observations indicate that this higher level multisensory cortex shows functional and organizational modifications from the well-known patterns identified for primary sensory cortical regions.

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Hypothalamic and other connections with dorsal CA2 area of the mouse hippocampus.

Publication Date: 2013 Jun 1 PMID: 23172108
Authors: Cui, Z. - Gerfen, C. R. - Young, W. S. 3rd
Journal: J Comp Neurol

The CA2 area is an important, although relatively unexplored, component of the hippocampus. We used various tracers to provide a comprehensive analysis of CA2 connections in C57BL/6J mice. Using various adeno-associated viruses that express fluorescent proteins, we found a vasopressinergic projection from the paraventricular nuclei of the hypothalamus (PVN) to the CA2 as well as a projection from pyramidal neurons of the CA2 to the supramammillary nuclei. These projections were confirmed by retrograde tracing. As expected, we observed CA2 afferent projections from neurons in ipsilateral entorhinal cortical layer II as well as from bilateral dorsal CA2 and CA3 using retrograde tracers. Additionally, we saw CA2 neuronal input from bilateral medial septal nuclei, vertical and horizontal limbs of the nucleus of diagonal band of Broca, supramammillary nuclei (SUM), and median raphe nucleus. Dorsal CA2 injections of adeno-associated virus expressing green fluorescent protein revealed axonal projections primarily to dorsal CA1, CA2, and CA3 bilaterally. No projection was detected to the entorhinal cortex from the dorsal CA2. These results are consistent with recent observations that the dorsal CA2 forms disynaptic connections with the entorhinal cortex to influence dynamic memory processing. Mouse dorsal CA2 neurons send bilateral projections to the medial and lateral septal nuclei, vertical and horizontal limbs of the diagonal band of Broca, and SUM. Novel connections from the PVN and to the SUM suggest important regulatory roles for CA2 in mediating social and emotional input for memory processing.

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Periadolescent maturation of the prefrontal cortex is sex-specific and is disrupted by prenatal stress.

Publication Date: 2013 Jun 1 PMID: 23172080
Authors: Markham, J. A. - Mullins, S. E. - Koenig, J. I.
Journal: J Comp Neurol

The prefrontal cortex (PFC) undergoes dramatic, sex-specific maturation during adolescence. Adolescence is a vulnerable window for developing mental illnesses that show significant sexual dimorphisms. Gestational stress is associated with increased risk for both schizophrenia, which is more common among men, and cognitive deficits. We have shown that male, but not female, rats exposed to prenatal stress develop postpubertal deficits in cognitive behaviors supported by the prefrontal cortex. Here we tested the hypothesis that repeated variable prenatal stress during the third week of rat gestation disrupts periadolescent development of prefrontal neurons in a sex-specific fashion. Using Golgi-Cox stained tissue, we compared dendritic arborization and spine density of prelimbic layer III neurons in prenatally stressed and control animals at juvenile (day 20), prepubertal (day 30), postpubertal (day 56), and adult (day 90) ages (N = 115). Dendritic ramification followed a sex-specific pattern that was disrupted during adolescence in prenatally stressed males, but not in females. In contrast, the impact of prenatal stress on the female PFC was not evident until adulthood. Prenatal stress also caused reductions in brain and body weights, and the latter effect was more pronounced among males. Additionally, there was a trend toward reduced testosterone levels for adult prenatally stressed males. Our findings indicate that, similarly to humans, the rat PFC undergoes sex-specific development during adolescence and furthermore that this process is disrupted by prenatal stress. These findings may be relevant to both the development of normal sex differences in cognition as well as differential male-female vulnerability to psychiatric conditions.

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Cytoskeletal changes during development and aging in the cortex of neurofilament light protein knockout mice.

Publication Date: 2013 Jun 1 PMID: 23172043
Authors: Liu, Y. - Staal, J. A. - Canty, A. J. - Kirkcaldie, M. T. - King, A. E. - Bibari, O. - Mitew, S. T. - Dickson, T. C. - Vickers, J. C.
Journal: J Comp Neurol

The neurofilament light (NFL) subunit is considered as an obligate subunit polymer for neuronal intermediate filaments comprising the neurofilament (NF) triplet proteins. We examined cytoskeletal protein levels in the cerebral cortex of NFL knockout (KO) mice at postnatal day 4 (P4), 5 months, and 12 months of age compared with age-matched wild-type (WT) mice of a similar genetic background (C57BL/6). The absence of NFL protein resulted in a significant reduction of phosphorylated and dephosphorylated NFs (NF-P, NF-DP), the medium NF subunit (NFM), and the intermediate filament alpha-internexin (INT) at P4. At 5 months, NF-DP, NFM, and INT remained significantly lower in knockouts. At 12 months, NF-P was again significantly decreased, and INT significantly increased, in KOs compared with wild type. In addition, protein levels of class III neuron-specific beta-tubulin and microtubule-associated protein 2 were significantly increased in NFL KO mice at P4, 5 months, and 12 months, whereas beta-actin levels were significantly decreased at P4. Immunocytochemical studies demonstrated that NF-DP accumulated abnormally in the perikarya of cortical neurons by 5 months of age in NFL KO mice. Neurons that lacked NF triplet proteins, such as calretinin-immunolabeled nonpyramidal cells, showed no alterations in density or cytoarchitectural distribution in NFL KO mice at 5 months relative to WT mice, although calretinin protein levels were decreased significantly after 12 months in NFL KO mice. These findings suggest that a lack of NFL protein alters the expression of cytoskeletal proteins and disrupts other NF subunits, causing intracellular aggregation but not gross structural changes in cortical neurons or cytoarchitecture. The data also indicate that changes in expression of other cytoskeletal proteins may compensate for decreased NFs.

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Basal bodies exhibit polarized positioning in zebrafish cone photoreceptors.

Publication Date: 2013 Jun 1 PMID: 23171982
Authors: Ramsey, M. - Perkins, B. D.
Journal: J Comp Neurol

The asymmetric positioning of basal bodies, and therefore cilia, is often critical for proper cilia function. This planar polarity is critical for motile cilia function but has not been extensively investigated for nonmotile cilia or for sensory cilia such as vertebrate photoreceptors. Zebrafish photoreceptors form an organized mosaic ideal for investigating cilia positioning. We report that, in the adult retina, the basal bodies of red-, green-, and blue-sensitive cone photoreceptors localized asymmetrically on the cell edge nearest the optic nerve. In contrast, no patterning was seen in the basal bodies of ultraviolet-sensitive cones or in rod photoreceptors. The asymmetric localization of basal bodies was consistent in all regions of the adult retina. Basal body patterning was unaffected in the cones of the XOPS-mCFP transgenic line, which lacks rod photoreceptors. Finally, the adult pattern was not seen in 7-days-postfertilization (dpf) larvae; basal bodies were randomly distributed in all the photoreceptor subtypes. These results establish the asymmetrical localization of basal bodies in red-, green-, and blue-sensitive cones in adult zebrafish retinas but not in larvae. This pattern suggests an active cellular mechanism regulated the positioning of basal bodies after the transition to the adult mosaic and that rods do not seem to be necessary for the patterning of cone basal bodies.

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Transgenic labeling of higher order neuronal circuits linked to phospholipase C-beta2-expressing taste bud cells in medaka fish.

Publication Date: 2013 Jun 1 PMID: 23124957
Authors: Ieki, T. - Okada, S. - Aihara, Y. - Ohmoto, M. - Abe, K. - Yasuoka, A. - Misaka, T.
Journal: J Comp Neurol

The sense of taste plays a pivotal role in the food-selecting behaviors of vertebrates. We have shown that the fish ortholog of the phospholipase C gene (plc-beta2) is expressed in a subpopulation of taste bud cells that transmit taste stimuli to the central nervous system to evoke favorable and aversive behaviors. We generated transgenic medaka expressing wheat germ agglutinin (WGA) under the control of a regulatory region of the medaka plc-beta2 gene to analyze the neuronal circuit connected to these sensory cells. Immunohistochemical analysis of the transgenic fish 12 days post fertilization revealed that the WGA protein was transferred to cranial sensory ganglia and several nuclei in the hindbrain. WGA signals were also detected in the secondary gustatory nucleus in the hindbrain of 3-month-old transgenic fish. WGA signals were observed in several diencephalic and telencephalic regions in 9-month-old transgenic fish. The age-dependent increase in the labeled brain regions strongly suggests that labeling occurred at taste bud cells and progressively extended to cranial nerves and neurons in the central nervous system. These data are the first to demonstrate the tracing of higher order gustatory neuronal circuitry that is associated with a specific subpopulation of taste bud cells. These results provide insight into the basic neuronal architecture of gustatory information processing that is common among vertebrates.

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Anatomical distribution of sex steroid hormone receptors in the brain of female medaka.

Publication Date: 2013 Jun 1 PMID: 23124931
Authors: Zempo, B. - Kanda, S. - Okubo, K. - Akazome, Y. - Oka, Y.
Journal: J Comp Neurol

Estrogen and androgen play crucial roles in coordinating reproductive functions through estrogen receptors (ERs) and androgen receptors (ARs), respectively. These receptors are considered important for regulation of the hypothalamo-pituitary-gonadal (HPG) axis. Despite their biological importance, the distribution of sex steroid receptors has not been fully analyzed anatomically in the teleost brain. The teleosts have many characteristic features, which allow unique approaches toward an understanding of the regulatory mechanisms of reproductive functions. Medaka serves as a good model system for studying the mechanisms by which steroid receptor-mediated systems are regulated, because (1) their breeding conditions can be easily manipulated; (2) we can take advantage of the genome database; and 3) molecular genetic tools, such as transgenic techniques, are applicable. We analyzed the distribution of ERalpha, ERbeta1, ERbeta2, ARalpha, and ARbeta mRNA by in situ hybridization in the brain of female medaka. We found that all subtypes of ERs and ARs were expressed in the following nuclei: the dorsal part of the ventral telencephalic area (Vd), supracommissural part of the ventral telencephalic area (Vs), postcommissural part of the ventral telencephalic area (Vp), preoptic area (POA), and nucleus ventralis tuberis (NVT). These regions are known to be involved in the regulation of sexual behavior (Vd, Vs, Vp, POA) or the HPG axis (NVT). These ER- and/or AR-expressing neurons may regulate sexual behavior or the HPG axis according to their axonal projections. Future analysis should be targeted to the neurons described in the present study to extend our understanding of the central regulatory mechanisms of reproduction.

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Laminar segregation of GABAergic neurons in the avian nucleus isthmi pars magnocellularis: a retrograde tracer and comparative study.

Publication Date: 2013 Jun 1 PMID: 23124899
Authors: Faunes, M. - Fernandez, S. - Gutierrez-Ibanez, C. - Iwaniuk, A. N. - Wylie, D. R. - Mpodozis, J. - Karten, H. J. - Marin, G.
Journal: J Comp Neurol

The isthmic complex is part of a visual midbrain circuit thought to be involved in stimulus selection and spatial attention. In birds, this circuit is composed of the nuclei isthmi pars magnocellularis (Imc), pars parvocellularis (Ipc), and pars semilunaris (SLu), all of them reciprocally connected to the ipsilateral optic tectum (TeO). The Imc conveys heterotopic inhibition to the TeO, Ipc, and SLu via widespread gamma-aminobutyric acid (GABA)ergic axons that allow global competitive interactions among simultaneous sensory inputs. Anatomical studies in the chick have described a cytoarchitectonically uniform Imc nucleus containing two intermingled cell types: one projecting to the Ipc and SLu and the other to the TeO. Here we report that in passerine species, the Imc is segregated into an internal division displaying larger, sparsely distributed cells, and an external division displaying smaller, more densely packed cells. In vivo and in vitro injections of neural tracers in the TeO and the Ipc of the zebra finch demonstrated that neurons from the external and internal subdivisions project to the Ipc and the TeO, respectively, indicating that each Imc subdivision contains one of the two cell types hodologically defined in the chick. In an extensive survey across avian orders, we found that, in addition to passerines, only species of Piciformes and Rallidae exhibited a segregated Imc, whereas all other groups exhibited a uniform Imc. These results offer a comparative basis to investigate the functional role played by each Imc neural type in the competitive interactions mediated by this nucleus.

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