Nature Neuroscience

Drosophila TRPA channel modulates sugar-stimulated neural excitation, avoidance and social response.

Publication Date: 2008 May 11 PMID: 18469811
Authors: Xu, J. - Sornborger, A. T. - Lee, J. K. - Shen, P.
Journal: Nat Neurosci

Drosophila melanogaster postfeeding larvae show food-averse migration toward food-free habitats before metamorphosis. This developmental switching from food attraction to aversion is regulated by a neuropeptide Y (NPY)-related brain signaling peptide. We used the fly larva model to delineate the neurobiological basis of age-restricted response to environmental stimuli. Here we provide evidence for a fructose-responsive chemosensory pathway that modulates food-averse migratory and social behaviors. We found that fructose potently elicited larval food-averse behaviors, and painless (pain), a transient receptor potential channel that is responsive to noxious stimuli, was required for the fructose response. A subset of pain-expressing sensory neurons have been identified that show pain-dependent excitation by fructose. Although evolutionarily conserved avoidance mechanisms are widely appreciated for their roles in stress coping and survival, their biological importance in animal physiology and development remains unknown. Our findings demonstrate how an avoidance mechanism is recruited to facilitate animal development.

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Activity-dependent site-specific changes of glutamate receptor composition in vivo.

Publication Date: 2008 May 11 PMID: 18469810
Authors: Schmid, A. - Hallermann, S. - Kittel, R. J. - Khorramshahi, O. - Frolich, A. M. - Quentin, C. - Rasse, T. M. - Mertel, S. - Heckmann, M. - Sigrist, S. J.
Journal: Nat Neurosci

The subunit composition of postsynaptic non-NMDA-type glutamate receptors (GluRs) determines the function and trafficking of the receptor. Changes in GluR composition have been implicated in the homeostasis of neuronal excitability and synaptic plasticity underlying learning. Here, we imaged GluRs in vivo during the formation of new postsynaptic densities (PSDs) at Drosophila neuromuscular junctions coexpressing GluRIIA and GluRIIB subunits. GluR composition was independently regulated at directly neighboring PSDs on a submicron scale. Immature PSDs typically had large amounts of GluRIIA and small amounts of GluRIIB. During subsequent PSD maturation, however, the GluRIIA/GluRIIB composition changed and became more balanced. Reducing presynaptic glutamate release increased GluRIIA, but decreased GluRIIB incorporation. Moreover, the maturation of GluR composition correlated in a site-specific manner with the level of Bruchpilot, an active zone protein that is essential for mature glutamate release. Thus, we show that an activity-dependent, site-specific control of GluR composition can contribute to match pre- and postsynaptic assembly.

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MicroRNA-9 directs late organizer activity of the midbrain-hindbrain boundary.

Publication Date: 2008 May 4 PMID: 18454145
Authors: Leucht, C. - Stigloher, C. - Wizenmann, A. - Klafke, R. - Folchert, A. - Bally-Cuif, L.
Journal: Nat Neurosci

The midbrain-hindbrain boundary (MHB) is a long-lasting organizing center in the vertebrate neural tube that is both necessary and sufficient for the ordered development of midbrain and anterior hindbrain (midbrain-hindbrain domain, MH). The MHB also coincides with a pool of progenitor cells that contributes neurons to the entire MH. Here we show that the organizing activity and progenitor state of the MHB are co-regulated by a single microRNA, miR-9, during late embryonic development in zebrafish. Endogenous miR-9 expression, initiated at late stages, selectively spares the MHB. Gain- and loss-of-function studies, in silico predictions and sensor assays in vivo demonstrate that miR-9 targets several components of the Fgf signaling pathway, thereby delimiting the organizing activity of the MHB. In addition, miR-9 promotes progression of neurogenesis in the MH, defining the MHB progenitor pool. Together, these findings highlight a previously unknown mechanism by which a single microRNA fine-tunes late MHB coherence via its co-regulation of patterning activities and neurogenesis.

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Single-neuron labeling with inducible Cre-mediated knockout in transgenic mice.

Publication Date: 2008 May 4 PMID: 18454144
Authors: Young, P. - Qiu, L. - Wang, D. - Zhao, S. - Gross, J. - Feng, G.
Journal: Nat Neurosci

To facilitate a functional analysis of neuronal connectivity in a mammalian nervous system that is tightly packed with billions of cells, we developed a new technique that uses inducible genetic manipulations in fluorescently labeled single neurons in mice. Our technique, single-neuron labeling with inducible Cre-mediated knockout (SLICK), is achieved by coexpressing a drug-inducible form of Cre recombinase and a fluorescent protein in a small subsets of neurons, thus combining the powerful Cre recombinase system for conditional genetic manipulation with fluorescent labeling of single neurons for imaging. Here, we demonstrate efficient inducible genetic manipulation in several types of neurons using SLICK. Furthermore, we applied SLICK to eliminate synaptic transmission in a small subset of neuromuscular junctions. Our results provide evidence for the long-term stability of inactive neuromuscular synapses in adult animals and demonstrate a Cre-loxP compatible system for dissecting gene functions in single identifiable neurons.

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Corrigendum: CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking.

Publication Date: 2008 May PMID: 18437193
Authors: Anderson, S. M. - Famous, K. R. - Sadri-Vakili, G. - Kumaresan, V. - Schmidt, H. D. - Bass, C. E. - Terwilliger, E. F. - Cha, J. H. - Pierce, R. C.
Journal: Nat Neurosci

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Learning outside the song system.

Publication Date: 2008 May PMID: 18437192
Authors: Gray, N.
Journal: Nat Neurosci

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A volume control for the sense of smell.

Publication Date: 2008 May PMID: 18437191
Authors: Strowbridge, B. W.
Journal: Nat Neurosci

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The need for a cool head: reversible inactivation reveals functional segregation in auditory cortex.

Publication Date: 2008 May PMID: 18437190
Authors: Sumner, C. J. - Palmer, A. R. - Moore, D. R.
Journal: Nat Neurosci

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Fire in the hole: pore dilation of the capsaicin receptor TRPV1.

Publication Date: 2008 May PMID: 18437189
Authors: Bautista, D. - Julius, D.
Journal: Nat Neurosci

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How I learned to stop worrying and love calcineurin.

Publication Date: 2008 May PMID: 18437188
Authors: Sindreu, C. B. - Storm, D. R.
Journal: Nat Neurosci

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Fraternizing with gender differences.

Publication Date: 2008 May PMID: 18437187
Authors: Durazzo, A. - Breedlove, S. M.
Journal: Nat Neurosci

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Reply to "BOLD and spiking activity".

Publication Date: 2008 May PMID: 18437186
Authors: Viswanathan, A. - Freeman, R. D.
Journal: Nat Neurosci

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BOLD and spiking activity.

Publication Date: 2008 May PMID: 18437185
Authors: Nir, Y. - Dinstein, I. - Malach, R. - Heeger, D. J.
Journal: Nat Neurosci

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Nature Neuroscience turns 10.

Publication Date: 2008 May PMID: 18437184
Authors:
Journal: Nat Neurosci

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Three-dimensional random access multiphoton microscopy for functional imaging of neuronal activity.

Publication Date: 2008 Apr 27 PMID: 18432198
Authors: Duemani Reddy, G. - Kelleher, K. - Fink, R. - Saggau, P.
Journal: Nat Neurosci

The dynamic ability of neuronal dendrites to shape and integrate synaptic responses is the hallmark of information processing in the brain. Effectively studying this phenomenon requires concurrent measurements at multiple sites on live neurons. Substantial progress has been made by optical imaging systems that combine confocal and multiphoton microscopy with inertia-free laser scanning. However, all of the systems developed so far restrict fast imaging to two dimensions. This severely limits the extent to which neurons can be studied, as they represent complex three-dimensional structures. Here we present a new imaging system that utilizes a unique arrangement of acousto-optic deflectors to steer a focused, ultra-fast laser beam to arbitrary locations in three-dimensional space without moving the objective lens. As we demonstrate, this highly versatile random-access multiphoton microscope supports functional imaging of complex three-dimensional cellular structures such as neuronal dendrites or neural populations at acquisition rates on the order of tens of kilohertz.

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Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration.

Publication Date: 2008 Apr 27 PMID: 18432197
Authors: Lagali, P. S. - Balya, D. - Awatramani, G. B. - Munch, T. A. - Kim, D. S. - Busskamp, V. - Cepko, C. L. - Roska, B.
Journal: Nat Neurosci

Genetically encoded optical neuromodulators create an opportunity for circuit-specific intervention in neurological diseases. One of the diseases most amenable to this approach is retinal degeneration, where the loss of photoreceptors leads to complete blindness. To restore photosensitivity, we genetically targeted a light-activated cation channel, channelrhodopsin-2, to second-order neurons, ON bipolar cells, of degenerated retinas in vivo in the Pde6b(rd1) (also known as rd1) mouse model. In the absence of 'classical' photoreceptors, we found that ON bipolar cells that were engineered to be photosensitive induced light-evoked spiking activity in ganglion cells. The rescue of light sensitivity was selective to the ON circuits that would naturally respond to increases in brightness. Despite degeneration of the outer retina, our intervention restored transient responses and center-surround organization of ganglion cells. The resulting signals were relayed to the visual cortex and were sufficient for the animals to successfully perform optomotor behavioral tasks.

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Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri.

Publication Date: 2008 Apr 23 PMID: 18432196
Authors: Zhang, F. - Prigge, M. - Beyriere, F. - Tsunoda, S. P. - Mattis, J. - Yizhar, O. - Hegemann, P. - Deisseroth, K.
Journal: Nat Neurosci

The introduction of two microbial opsin-based tools, channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), to neuroscience has generated interest in fast, multimodal, cell type-specific neural circuit control. Here we describe a cation-conducting channelrhodopsin (VChR1) from Volvox carteri that can drive spiking at 589 nm, with excitation maximum red-shifted approximately 70 nm compared with ChR2. These results demonstrate fast photostimulation with yellow light, thereby defining a functionally distinct third category of microbial rhodopsin proteins.

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Theta phase-specific codes for two-dimensional position, trajectory and heading in the hippocampus.

Publication Date: 2008 May PMID: 18425124
Authors: Huxter, J. R. - Senior, T. J. - Allen, K. - Csicsvari, J.
Journal: Nat Neurosci

Temporal coding is a means of representing information by the time, as opposed to the rate, at which neurons fire. Evidence of temporal coding in the hippocampus comes from place cells, whose spike times relative to theta oscillations reflect a rat's position while running along stereotyped trajectories. This arises from the backwards shift in cell firing relative to local theta oscillations (phase precession). Here we demonstrate phase precession during place-field crossings in an open-field foraging task. This produced spike sequences in each theta cycle that disambiguate the rat's trajectory through two-dimensional space and can be used to predict movement direction. Furthermore, position and movement direction were maximally predicted from firing in the early and late portions of the theta cycle, respectively. This represents the first direct evidence of a combined representation of position, trajectory and heading in the hippocampus, organized on a fine temporal scale by theta oscillations.

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Cortical activity patterns predict speech discrimination ability.

Publication Date: 2008 May PMID: 18425123
Authors: Engineer, C. T. - Perez, C. A. - Chen, Y. H. - Carraway, R. S. - Reed, A. C. - Shetake, J. A. - Jakkamsetti, V. - Chang, K. Q. - Kilgard, M. P.
Journal: Nat Neurosci

Neural activity in the cerebral cortex can explain many aspects of sensory perception. Extensive psychophysical and neurophysiological studies of visual motion and vibrotactile processing show that the firing rate of cortical neurons averaged across 50-500 ms is well correlated with discrimination ability. In this study, we tested the hypothesis that primary auditory cortex (A1) neurons use temporal precision on the order of 1-10 ms to represent speech sounds shifted into the rat hearing range. Neural discrimination was highly correlated with behavioral performance on 11 consonant-discrimination tasks when spike timing was preserved and was not correlated when spike timing was eliminated. This result suggests that spike timing contributes to the auditory cortex representation of consonant sounds.

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Quantal noise from human red cone pigment.

Publication Date: 2008 May PMID: 18425122
Authors: Fu, Y. - Kefalov, V. - Luo, D. G. - Xue, T. - Yau, K. W.
Journal: Nat Neurosci

The rod pigment, rhodopsin, shows spontaneous isomerization activity. This quantal noise produces a dark light of approximately 0.01 photons s(-1) rod(-1) in human, setting the threshold for rod vision. The spontaneous isomerization activity of human cone pigments has long remained a mystery because the effect of a single isomerized pigment molecule in cones, unlike that in rods, is small and beyond measurement. We have now overcome this problem by expressing human red cone pigment transgenically in mouse rods in order to exploit their large single-photon response, especially after genetic removal of a key negative-feedback regulation. Extrapolating the measured quantal noise of transgenic cone pigment to native human red cones, we obtained a dark rate of approximately 10 false events s(-1) cone(-1), almost 10(3)-fold lower than the overall dark transduction noise previously reported in primate cones. Our measurements provide a rationale for why mammalian red, green and blue cones have comparable sensitivities, unlike their amphibian counterparts.

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Control of the establishment of aversive memory by calcineurin and Zif268.

Publication Date: 2008 May PMID: 18425121
Authors: Baumgartel, K. - Genoux, D. - Welzl, H. - Tweedie-Cullen, R. Y. - Koshibu, K. - Livingstone-Zatchej, M. - Mamie, C. - Mansuy, I. M.
Journal: Nat Neurosci

Emotional memory is a rapidly acquired and persistent form of memory, and its robustness is in part determined by the initial strength of the memory. Here, we provide new evidence that the protein phosphatase calcineurin (CaN), a potent negative regulator of neuronal signaling that is known to constrain learning and memory, critically regulates the establishment of emotional memory through mechanisms involving the immediate early gene Zif268 (also known as Egr1). We found that CaN is inhibited in the amygdala during the establishment of aversive memory, but Zif268 is activated. Using inducible transgenesis in mice, we further saw that CaN inhibition and Zif268 overexpression during memory establishment strengthen the memory trace and enhance its resistance to extinction. We found that CaN inhibition correlates with increased Zif268 expression and that a common pool of proteins is regulated in the amygdala after CaN inhibition and Zif268 overexpression. Together, these findings reveal a previously unknown mechanism for the control of emotional memory that depends on CaN and Zif268.

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Double dissociation of 'what' and 'where' processing in auditory cortex.

Publication Date: 2008 May PMID: 18408717
Authors: Lomber, S. G. - Malhotra, S.
Journal: Nat Neurosci

Studies of cortical connections or neuronal function in different cerebral areas support the hypothesis that parallel cortical processing streams, similar to those identified in visual cortex, may exist in the auditory system. However, this model has not yet been behaviorally tested. We used reversible cooling deactivation to investigate whether the individual regions in cat nonprimary auditory cortex that are responsible for processing the pattern of an acoustic stimulus or localizing a sound in space could be doubly dissociated in the same animal. We found that bilateral deactivation of the posterior auditory field resulted in deficits in a sound-localization task, whereas bilateral deactivation of the anterior auditory field resulted in deficits in a pattern-discrimination task, but not vice versa. These findings support a model of cortical organization that proposes that identifying an acoustic stimulus ('what') and its spatial location ('where') are processed in separate streams in auditory cortex.

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Reduction of stimulus visibility compresses apparent time intervals.

Publication Date: 2008 May PMID: 18408716
Authors: Terao, M. - Watanabe, J. - Yagi, A. - Nishida, S.
Journal: Nat Neurosci

The neural mechanisms underlying visual estimation of subsecond durations remain unknown, but perisaccadic underestimation of interflash intervals may provide a clue as to the nature of these mechanisms. Here we found that simply reducing the flash visibility, particularly the visibility of transient signals, induced similar time underestimation by human observers. Our results suggest that weak transient responses fail to trigger the proper detection of temporal asynchrony, leading to increased perception of simultaneity and apparent time compression.

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Unconscious determinants of free decisions in the human brain.

Publication Date: 2008 May PMID: 18408715
Authors: Soon, C. S. - Brass, M. - Heinze, H. J. - Haynes, J. D.
Journal: Nat Neurosci

There has been a long controversy as to whether subjectively 'free' decisions are determined by brain activity ahead of time. We found that the outcome of a decision can be encoded in brain activity of prefrontal and parietal cortex up to 10 s before it enters awareness. This delay presumably reflects the operation of a network of high-level control areas that begin to prepare an upcoming decision long before it enters awareness.

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Oligomeric amyloid-beta peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism.

Publication Date: 2008 May PMID: 18391946
Authors: Berman, D. E. - Dall'armi, C. - Voronov, S. V. - McIntire, L. B. - Zhang, H. - Moore, A. Z. - Staniszewski, A. - Arancio, O. - Kim, T. W. - Di Paolo, G.
Journal: Nat Neurosci

Synaptic dysfunction caused by oligomeric assemblies of amyloid-beta peptide (Abeta) has been linked to cognitive deficits in Alzheimer's disease. Here we found that incubation of primary cortical neurons with oligomeric Abeta decreases the level of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)), a phospholipid that regulates key aspects of neuronal function. The destabilizing effect of Abeta on PtdIns(4,5)P(2) metabolism was Ca(2+)-dependent and was not observed in neurons that were derived from mice that are haploinsufficient for Synj1. This gene encodes synaptojanin 1, the main PtdIns(4,5)P(2) phosphatase in the brain and at the synapses. We also found that the inhibitory effect of Abeta on hippocampal long-term potentiation was strongly suppressed in slices from Synj1(+/-) mice, suggesting that Abeta-induced synaptic dysfunction can be ameliorated by treatments that maintain the normal PtdIns(4,5)P(2) balance in the brain.

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TRPV1 shows dynamic ionic selectivity during agonist stimulation.

Publication Date: 2008 May PMID: 18391945
Authors: Chung, M. K. - Guler, A. D. - Caterina, M. J.
Journal: Nat Neurosci

Transient receptor potential vanilloid 1 (TRPV1) is an ion channel that is gated by noxious heat, capsaicin and other diverse stimuli. It is a nonselective cation channel that prefers Ca(2+) over Na(+). These permeability characteristics, as in most channels, are widely presumed to be static. On the contrary, we found that activation of native or recombinant rat TRPV1 leads to time- and agonist concentration-dependent increases in relative permeability to large cations and changes in Ca(2+) permeability. Using the substituted cysteine accessibility method, we saw that these changes were attributable to alterations in the TRPV1 selectivity filter. TRPV1 agonists showed different capabilities for evoking ionic selectivity changes. Furthermore, protein kinase C-dependent phosphorylation of Ser800 in the TRPV1 C terminus potentiated agonist-evoked ionic selectivity changes. Thus, the qualitative signaling properties of TRPV1 are dynamically modulated during channel activation, a process that probably shapes TRPV1 participation in pain, cytotoxicity and neurotransmitter release.

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Functional identification of sensory mechanisms required for developmental song learning.

Publication Date: 2008 May PMID: 18391944
Authors: London, S. E. - Clayton, D. F.
Journal: Nat Neurosci

A young male zebra finch (Taeniopygia guttata) learns to sing by copying the vocalizations of an older tutor in a process that parallels human speech acquisition. Brain pathways that control song production are well defined, but little is known about the sites and mechanisms of tutor song memorization. Here we test the hypothesis that molecular signaling in a sensory brain area outside of the song system is required for developmental song learning. Using controlled tutoring and a pharmacological inhibitor, we transiently suppressed the extracellular signal-regulated kinase signaling pathway in a portion of the auditory forebrain specifically during tutor song exposure. On maturation, treated birds produced poor copies of tutor song, whereas controls copied the tutor song effectively. Thus the foundation of normal song learning, the formation of a sensory memory of tutor song, requires a conserved molecular pathway in a brain area that is distinct from the circuit for song motor control.

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Silencing preBotzinger Complex somatostatin-expressing neurons induces persistent apnea in awake rat.

Publication Date: 2008 May PMID: 18391943
Authors: Tan, W. - Janczewski, W. A. - Yang, P. - Shao, X. M. - Callaway, E. M. - Feldman, J. L.
Journal: Nat Neurosci

Delineating neurons that underlie complex behaviors is of fundamental interest. Using adeno-associated virus 2, we expressed the Drosophila allatostatin receptor in somatostatin (Sst)-expressing neurons in the preBotzinger Complex (preBotC). Rapid silencing of these neurons in awake rats induced a persistent apnea without any respiratory movements to rescue their breathing. We hypothesize that breathing requires preBotC Sst neurons and that their sudden depression can lead to serious, even fatal, respiratory failure.

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Corollary discharge circuits for saccadic modulation of the pigeon visual system.

Publication Date: 2008 May PMID: 18391942
Authors: Yang, Y. - Cao, P. - Yang, Y. - Wang, S. R.
Journal: Nat Neurosci

A saccadic eye movement causes a variety of transient perceptual sequelae that might be the results of corollary discharge. Here we describe the neural circuits for saccadic corollary discharge that modulates activity throughout the pigeon visual system. Saccades in pigeons caused inhibition that was mediated by corollary discharge followed by enhancement of firing activity in the telencephalic hyperpallium, visual thalamus and pretectal nucleus lentiformis mesencephali (nLM) with opposite responses in the accessory optic nucleus (nBOR). Inactivation of thalamic neurons eliminated saccadic responses in telencephalic neurons, and inactivation of both the nLM and the nBOR abolished saccadic responses in thalamic neurons. Saccade-related omnipause neurons in the brainstem raphe complex inhibited the nBOR and excited the nLM, whereas inactivation of raphe neurons eliminated saccadic responses in both optokinetic and thalamic neurons. It seems that saccadic responses in telencephalic neurons are generated by corollary discharge signals from brainstem neurons that are transmitted through optokinetic and thalamic neurons. These signals might have important roles in visual perception.

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Instantaneous correlation of excitation and inhibition during ongoing and sensory-evoked activities.

Publication Date: 2008 May PMID: 18376400
Authors: Okun, M. - Lampl, I.
Journal: Nat Neurosci

Temporal and quantitative relations between excitatory and inhibitory inputs in the cortex are central to its activity, yet they remain poorly understood. In particular, a controversy exists regarding the extent of correlation between cortical excitation and inhibition. Using simultaneous intracellular recordings in pairs of nearby neurons in vivo, we found that excitatory and inhibitory inputs are continuously synchronized and correlated in strength during spontaneous and sensory-evoked activities in the rat somatosensory cortex.

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