Description

The official journal of the Society for Neuroscience, available in full text 1996 forward with plans to archive five years of full text issues. Tables of contents for future issues. Publication precedes receipt of print edition. Available free to Society members and selected librarians for 1997. Available for subscription in 1998. Includes thumbnail expandable graphics.

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Society for Neuroscience

Publications in this journal

• Sex steroids and the organization of the human brain.

  Authors: Jiska S Peper, P Cédric M P Koolschijn

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6745-6.

• Equivalent representation of real and illusory contours in macaque v4.

  Authors: Yanxia Pan, Minggui Chen, Jiapeng Yin, Xu An, Xian Zhang, Yiliang Lu, Hongliang Gong, Wu Li, Wei Wang

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6760-70.

  The cortical processing of illusory contours provides a unique window for exploring the brain mechanisms underlying visual perception. Previous electrophysiological single-cell recordings demonstrateThe cortical processing of illusory contours provides a unique window for exploring the brain mechanisms underlying visual perception. Previous electrophysiological single-cell recordings demonstrate that a subgroup of cells in macaque V1 and V2 signal the presence of illusory contours, whereas recent human brain imaging studies reveal higher-order visual cortices playing a central role in illusory figure processing. It seems that the processing of illusory contours/figures may engage multiple cortical interactions between hierarchically organized processing stages in the ventral visual pathway of primates. However, it is not yet known in which brain areas illusory contours are represented in the same manner as real contours at both the population and single-cell levels. Here, by combining intrinsic optical imaging in anesthetized rhesus macaques with single-cell recordings in awake ones, we found a complete overlap of orientation domains in visual cortical area V4 for processing real and illusory contours. In contrast, the orientation domains mapped in early visual areas V1 and V2 mainly encoded the local physical stimulus features inducing the subjective perception of global illusory contours. Our results indicate that real and illusory contours are encoded equivalently by the same functional domains in V4, suggesting that V4 is a key cortical locus for integration of local features into global contours.

• Calcium-Dependent But Action Potential-Independent BCM-Like Metaplasticity in the Hippocampus.

  Authors: Sarah R Hulme, Owen D Jones, David R Ireland, Wickliffe C Abraham

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6785-94.

  The Bienenstock, Cooper and Munro (BCM) computational model, which incorporates a metaplastic sliding threshold for LTP induction, accounts well for experience-dependent changes in synapticThe Bienenstock, Cooper and Munro (BCM) computational model, which incorporates a metaplastic sliding threshold for LTP induction, accounts well for experience-dependent changes in synaptic plasticity in the visual cortex. BCM-like metaplasticity over a shorter timescale has also been observed in the hippocampus, thus providing a tractable experimental preparation for testing specific predictions of the model. Here, using extracellular and intracellular electrophysiological recordings from acute rat hippocampal slices, we tested the critical BCM predictions (1) that high levels of synaptic activation will induce a metaplastic state that spreads across dendritic compartments, and (2) that postsynaptic cell-firing is the critical trigger for inducing that state. In support of the first premise, high-frequency priming stimulation inhibited subsequent long-term potentiation and facilitated subsequent long-term depression at synapses quiescent during priming, including those located in a dendritic compartment different to that of the primed pathway. These effects were not dependent on changes in synaptic inhibition or NMDA/metabotropic glutamate receptor function. However, in contrast to the BCM prediction, somatic action potentials during priming were neither necessary nor sufficient to induce the metaplasticity effect. Instead, in broad agreement with derivatives of the BCM model, calcium as released from intracellular stores and triggered by M1 muscarinic acetylcholine receptor activation was critical for altering subsequent synaptic plasticity. These results indicate that synaptic plasticity in stratum radiatum of CA1 can be homeostatically regulated by the cell-wide history of synaptic activity through a calcium-dependent but action potential-independent mechanism.

• Egr-1 Induces DARPP-32 Expression in Striatal Medium Spiny Neurons via a Conserved Intragenic Element.

  Authors: Serene Keilani, Samira Chandwani, Georgia Dolios, Alexey Bogush, Heike Beck, Antonis K Hatzopoulos, Gadiparthi N Rao, Elizabeth A Thomas, Rong Wang, Michelle E Ehrlich

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6808-6818.

  DARPP-32 (dopamine and adenosine 3', 5'-cyclic monophosphate cAMP-regulated phosphoprotein, 32 kDa) is a striatal-enriched protein that mediates signaling by dopamine and other first messengers inDARPP-32 (dopamine and adenosine 3', 5'-cyclic monophosphate cAMP-regulated phosphoprotein, 32 kDa) is a striatal-enriched protein that mediates signaling by dopamine and other first messengers in the medium spiny neurons. The transcriptional mechanisms that regulate striatal DARPP-32 expression remain enigmatic and are a subject of much interest in the efforts to induce a striatal phenotype in stem cells. We report the identification and characterization of a conserved region, also known as H10, in intron IV of the gene that codes for DARPP-32 (Ppp1r1b). This DNA sequence forms multiunit complexes with nuclear proteins from adult and embryonic striata of mice and rats. Purification of proteins from these complexes identified early growth response-1 (Egr-1). The interaction between Egr-1 and H10 was confirmed in vitro and in vivo by super-shift and chromatin immunoprecipitation assays, respectively. Importantly, brain-derived neurotrophic factor (BDNF), a known inducer of DARPP-32 and Egr-1 expression, enhanced Egr-1 binding to H10 in vitro. Moreover, overexpression of Egr-1 in primary striatal neurons induced the expression of DARPP-32, whereas a dominant-negative Egr-1 blocked DARPP-32 induction by BDNF. Together, this study identifies Egr-1 as a transcriptional activator of the Ppp1r1b gene and provides insight into the molecular mechanisms that regulate medium spiny neuron maturation.

• Dopaminergic modulation of mitral cells and odor responses in the zebrafish olfactory bulb.

  Authors: Sebastian T Bundschuh, Peixin Zhu, Yan-Ping Zhang Schärer, Rainer W Friedrich

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6830-40.

  In the olfactory bulb, the modulatory neurotransmitter dopamine (DA) is coexpressed with GABA by local interneurons, but its role in odor processing remains obscure. We examined functions of DAIn the olfactory bulb, the modulatory neurotransmitter dopamine (DA) is coexpressed with GABA by local interneurons, but its role in odor processing remains obscure. We examined functions of DA mediated by D(2)-like receptors in the olfactory bulb of adult zebrafish by pharmacology, whole-cell recordings, calcium imaging, and optogenetics. Bath application of DA had no detectable effect on odorant-evoked sensory input. DA directly hyperpolarized mitral cells (MCs) via D(2)-like receptors and slightly increased their response gain. Consistent with this effect on input-output functions of MCs, small odorant responses were suppressed, whereas strong responses were enhanced in the presence of DA. These effects increased the root-mean-square contrast of population activity patterns but did not reduce their correlations. Optical stimulation of interneurons expressing channelrhodopsin-2 evoked fast GABAergic inhibitory currents in mitral cells but failed to activate D(2) receptor-mediated currents when stimuli were short. Prolonged stimulus trains, however, activated a slow hyperpolarizing current that was blocked by an antagonist of D(2)-like receptors. GABA and DA are therefore both released from interneurons by electrical activity and hyperpolarize MCs, but D(2)-dependent dopaminergic effects occur on slower timescales. Additional effects of DA may be mediated by D(1)-like receptors. These results indicate that DA acts on D(2)-like receptors via asynchronous release and/or volume transmission and implicate DA in the slow adaptation of circuit function. The shift of the membrane potential away from spike threshold could adapt mitral cells to background input without compromising their sensitivity.

• Segregated Pathways Carrying Frontally Derived Top-Down Signals to Visual Areas MT and V4 in Macaques.

  Authors: Taihei Ninomiya, Hiromasa Sawamura, Ken-Ichi Inoue, Masahiko Takada

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6851-8.

  The bottom-up processing of visual information is strongly influenced by top-down signals, at least part of which is thought to be conveyed from the frontal cortex through the frontal eye field (FEF)The bottom-up processing of visual information is strongly influenced by top-down signals, at least part of which is thought to be conveyed from the frontal cortex through the frontal eye field (FEF) and the lateral intraparietal area (LIP). Here we investigated the architecture of multisynaptic pathways from the frontal cortex to the middle temporal area (MT) of the dorsal visual stream and visual area 4 (V4) of the ventral visual stream in macaques. In the first series of experiments, the retrograde trans-synaptic tracer, rabies virus, was injected into MT or V4. Three days after rabies injections, the second-order (disynaptically connected) neuron labeling appeared in the ventral part of area 46 (area 46v), along with the first-order (monosynaptically connected) neuron labeling in FEF and LIP. In the MT-injection case, second-order neurons were also observed in the supplementary eye field (SEF). In the next series of experiments, double injections of two fluorescent dyes, fast blue and diamidino yellow, were made into MT and V4 to examine whether the frontal inputs are mediated by distinct or common neuronal populations. Virtually no double-labeled neurons were observed in FEF or LIP, indicating that separate neuronal populations mediate the frontal inputs to MT and V4. The present results define that the multisynaptic frontal input to V4 arises primarily from area 46v, whereas the input to MT arises from not only area 46v but also SEF, through distinct FEF and LIP neurons. Segregated pathways from the frontal cortex possibly carry the functionally diverse top-down signals to each visual stream.

• Intersection of reward and memory in monkey rhinal cortex.

  Authors: Andrew M Clark, Sebastien Bouret, Adrienne M Young, Barry J Richmond

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6869-77.

  In humans and other animals, the vigor with which a reward is pursued depends on its desirability, that is, on the reward's predicted value. Predicted value is generally context-dependent, varyingIn humans and other animals, the vigor with which a reward is pursued depends on its desirability, that is, on the reward's predicted value. Predicted value is generally context-dependent, varying according to the value of rewards obtained in the recent and distant past. Signals related to reward prediction and valuation are believed to be encoded in a circuit centered around midbrain dopamine neurons and their targets in the prefrontal cortex and basal ganglia. Notably absent from this hypothesized reward pathway are dopaminergic targets in the medial temporal lobe. Here we show that a key part of the medial temporal lobe memory system previously reported to be important for sensory mnemonic and perceptual processing, the rhinal cortex (Rh), is required for using memories of previous reward values to predict the value of forthcoming rewards. We tested monkeys with bilateral Rh lesions on a task in which reward size varied across blocks of uncued trials. In this experiment, the only cues for predicting current reward value are the sizes of rewards delivered in previous blocks. Unexpectedly, monkeys with Rh ablations, but not intact controls, were insensitive to differences in predicted reward, responding as if they expected all rewards to be of equal magnitude. Thus, it appears that Rh is critical for using memory of previous rewards to predict the value of forthcoming rewards. These results are in agreement with accumulating evidence that Rh is critical for establishing the relationships between temporally interleaved events, which is a key element of episodic memory.

• PMCA2 via PSD-95 Controls Calcium Signaling by α7-Containing Nicotinic Acetylcholine Receptors on Aspiny Interneurons.

  Authors: David Gómez-Varela, Manuela Schmidt, Jeff Schoellerman, Eric C Peters, Darwin K Berg

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6894-905.

  Local control of calcium concentration within neurons is critical for signaling and regulation of synaptic communication in neural circuits. How local control can be achieved in the absence ofLocal control of calcium concentration within neurons is critical for signaling and regulation of synaptic communication in neural circuits. How local control can be achieved in the absence of physical compartmentalization is poorly understood. Challenging examples are provided by nicotinic acetylcholine receptors that contain α7 nicotinic receptor subunits (α7-nAChRs). These receptors are highly permeable to calcium and are concentrated on aspiny dendrites of interneurons, which lack obvious physical compartments for constraining calcium diffusion. Using functional proteomics on rat brain, we show that α7-nAChRs are associated with plasma membrane calcium-ATPase pump isoform 2 (PMCA2). Analysis of α7-nAChR function in hippocampal interneurons in culture shows that PMCA2 activity limits the duration of calcium elevations produced by the receptors. Unexpectedly, PMCA2 inhibition triggers rapid calcium-dependent loss of α7-nAChR clusters. This extreme regulatory response is mediated by CaMKII, involves proteasome activity, depends on the second intracellular loop of α7-nAChR subunits, and is specific in that it does not alter two other classes of calcium-permeable ionotropic receptors on the same neurons. A critical link is provided by the scaffold protein PSD-95 (postsynaptic density-95), which is associated with α7-nAChRs and constrains their mobility as revealed by single-particle tracking on neurons. The PSD-95 link is required for PMCA2-mediated removal of α7-nAChR clusters. This three-component combination of PMCA2, PSD-95, and α7-nAChR offers a novel mechanism for tight control of calcium dynamics in neurons.

• Rewiring of Afferent Fibers in the Somatosensory Thalamus of Mice Caused by Peripheral Sensory Nerve Transection.

  Authors: Yuichi Takeuchi, Miwako Yamasaki, Yasuyuki Nagumo, Keiji Imoto, Masahiko Watanabe, Mariko Miyata

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6917-6930.

  The remodeling of neural circuitry and changes in synaptic efficacy after peripheral sensory nerve injury are considered the basis for functional reorganization in the brain, including changes inThe remodeling of neural circuitry and changes in synaptic efficacy after peripheral sensory nerve injury are considered the basis for functional reorganization in the brain, including changes in receptive fields. However, when or how the remodeling occurs is largely unknown. Here we show the rapid rewiring of afferent fibers in the mature ventral posteromedial thalamic nucleus of mice after transection of the peripheral whisker sensory nerve, using the whole-cell voltage-clamp technique. Transection induced the recruitment of afferent fibers to a thalamic relay neuron within 5-6 d of injury. The rewiring was pathway specific, but not sensory experience dependent or peripheral nerve activity dependent. The newly recruited fibers mediated small EPSCs, and postsynaptic GluA2-containing AMPA receptors were selectively upregulated at the new synapses. This rapid and pathway-specific remodeling of thalamic circuitry may be an initial step in the massive axonal reorganization at supraspinal levels, which occurs months or years after peripheral sensory nerve injury.

• Sleep Deprivation Is Associated with Attenuated Parametric Valuation and Control Signals in the Midbrain during Value-Based Decision Making.

  Authors: Mareike M Menz, Christian Büchel, Jan Peters

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6937-46.

  Sleep deprivation (SD) has detrimental effects on cognition, but the affected psychological processes and underlying neural mechanisms are still essentially unclear. Here we combined functionalSleep deprivation (SD) has detrimental effects on cognition, but the affected psychological processes and underlying neural mechanisms are still essentially unclear. Here we combined functional magnetic resonance imaging and computational modeling to examine how SD alters neural representation of specific choice variables (subjective value and decision conflict) during reward-related decision making. Twenty-two human subjects underwent two functional neuroimaging sessions in counterbalanced order, once during rested wakefulness and once after 24 h of SD. Behaviorally, SD attenuated conflict-dependent slowing of response times, which was reflected in an attenuated conflict-induced decrease in drift rates in the drift diffusion model. Furthermore, SD increased overall choice stochasticity during risky choice. Model-based functional neuroimaging revealed attenuated parametric subjective value signals in the midbrain, parietal cortex, and ventromedial prefrontal cortex after SD. Conflict-related midbrain signals showed a similar downregulation. Findings are discussed with respect to changes in dopaminergic signaling associated with the sleep-deprived state.

• Subregional, dendritic compartment, and spine subtype specificity in cocaine regulation of dendritic spines in the nucleus accumbens.

  Authors: Dani Dumitriu, Quincey Laplant, Yael S Grossman, Caroline Dias, William G Janssen, Scott J Russo, John H Morrison, Eric J Nestler

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6957-66.

  Numerous studies have found that chronic cocaine increases dendritic spine density of medium spiny neurons in the nucleus accumbens (NAc). Here, we used single-cell microinjections and advanced 3DNumerous studies have found that chronic cocaine increases dendritic spine density of medium spiny neurons in the nucleus accumbens (NAc). Here, we used single-cell microinjections and advanced 3D imaging and analysis techniques to extend these findings in several important ways: by assessing cocaine regulation of dendritic spines in the core versus shell subregions of NAc in the mouse, over a broad time course (4 h, 24 h, or 28 d) of withdrawal from chronic cocaine, and with a particular focus on proximal versus distal dendrites. Our data demonstrate subregion-specific, and in some cases opposite, regulation of spines by cocaine on proximal but not distal dendrites. Notably, all observed density changes were attributable to selective regulation of thin spines. At 4 h after injection, the proximal spine density is unchanged in the core but significantly increased in the shell. At 24 h, the density of proximal dendritic spines is reduced in the core but increased in the shell. Such downregulation of thin spines in the core persists through 28 d of withdrawal, whereas the spine density in the shell returns to baseline levels. Consistent with previous results, dendritic tips exhibited upregulation of dendritic spines after 24 h of withdrawal, an effect localized to the shell. The divergence in regulation of proximal spine density in NAc core versus shell by cocaine correlates with recently reported electrophysiological data from a similar drug administration regimen and might represent a key mediator of changes in the reward circuit that drive aspects of addiction.

• Light-driven calcium signals in mouse cone photoreceptors.

  Authors: Tao Wei, Timm Schubert, François Paquet-Durand, Naoyuki Tanimoto, Le Chang, Katja Koeppen, Thomas Ott, Oliver Griesbeck, Mathias W Seeliger, Thomas Euler, Bernd Wissinger

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6981-94.

  Calcium mediates various neuronal functions. The complexity of neuronal Ca(2+) signaling is well exemplified by retinal cone photoreceptors, which, with their distinct compartmentalization, offerCalcium mediates various neuronal functions. The complexity of neuronal Ca(2+) signaling is well exemplified by retinal cone photoreceptors, which, with their distinct compartmentalization, offer unique possibilities for studying the diversity of Ca(2+) functions in a single cell. Measuring subcellular Ca(2+) signals in cones under physiological conditions is not only fundamental for understanding cone function, it also bears important insights into pathophysiological processes governing retinal neurodegeneration. However, due to the proximity of light-sensitive outer segments to other cellular compartments, optical measurements of light-evoked Ca(2+) responses in cones are challenging. We addressed this problem by generating a transgenic mouse (HR2.1:TN-XL) in which both short- and middle-wavelength-sensitive cones selectively express the genetically encoded ratiometric Ca(2+) biosensor TN-XL. We show that HR2.1:TN-XL allows recording of light-evoked Ca(2+) responses using two-photon imaging in individual cone photoreceptor terminals and to probe phototransduction and its diverse regulatory mechanisms with pharmacology at subcellular resolution. To further test this system, we asked whether the classical, nitric oxide (NO)-soluble guanylyl-cyclase (sGC)-cGMP pathway could modulate Ca(2+) in cone terminals. Surprisingly, NO reduced Ca(2+) resting levels in mouse cones, without evidence for direct sGC involvement. In conclusion, HR2.1:TN-XL mice offer unprecedented opportunities to elucidate light-driven Ca(2+) dynamics and their (dys)regulation in cone photoreceptors.

• Visual attentional load influences plasticity in the human motor cortex.

  Authors: Marc R Kamke, Michelle G Hall, Hayley F Lye, Martin V Sale, Laura R Fenlon, Timothy J Carroll, Stephan Riek, Jason B Mattingley

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):7001-8.

  Neural plasticity plays a critical role in learning, memory, and recovery from injury to the nervous system. Although much is known about the physical and physiological determinants of plasticity,Neural plasticity plays a critical role in learning, memory, and recovery from injury to the nervous system. Although much is known about the physical and physiological determinants of plasticity, little is known about the influence of cognitive factors. In this study, we investigated whether selective attention plays a role in modifying changes in neural excitability reflecting long-term potentiation (LTP)-like plasticity. We induced LTP-like effects in the hand area of the human motor cortex using transcranial magnetic stimulation (TMS). During the induction of plasticity, participants engaged in a visual detection task with either low or high attentional demands. Changes in neural excitability were assessed by measuring motor-evoked potentials in a small hand muscle before and after the TMS procedures. In separate experiments plasticity was induced either by paired associative stimulation (PAS) or intermittent theta-burst stimulation (iTBS). Because these procedures induce different forms of LTP-like effects, they allowed us to investigate the generality of any attentional influence on plasticity. In both experiments reliable changes in motor cortex excitability were evident under low-load conditions, but this effect was eliminated under high-attentional load. In a third experiment we investigated whether the attentional task was associated with ongoing changes in the excitability of motor cortex, but found no difference in evoked potentials across the levels of attentional load. Our findings indicate that in addition to their role in modifying sensory processing, mechanisms of attention can also be a potent modulator of cortical plasticity.

• Laminarly orthogonal excitation of fast-spiking and low-threshold-spiking interneurons in mouse motor cortex.

  Authors: Alfonso J Apicella, Ian R Wickersham, H Sebastian Seung, Gordon M G Shepherd

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):7021-33.

  In motor cortex, long-range output to subcortical motor circuits depends on excitatory and inhibitory inputs converging on projection neurons in layers 5A/B. How interneurons interconnect with theseIn motor cortex, long-range output to subcortical motor circuits depends on excitatory and inhibitory inputs converging on projection neurons in layers 5A/B. How interneurons interconnect with these projection neurons, and whether these microcircuits are interneuron and/or projection specific, is unclear. We found that fast-spiking interneurons received strong intralaminar (horizontal) excitation from pyramidal neurons in layers 5A/B including corticostriatal and corticospinal neurons, implicating them in mediating disynaptic recurrent, feedforward, and feedback inhibition within and across the two projection classes. Low-threshold-spiking (LTS) interneurons were instead strongly excited by descending interlaminar (vertical) input from layer 2/3 pyramidal neurons, implicating them in mediating disynaptic feedforward inhibition to both projection classes. Furthermore, in a novel pattern, lower layer 2/3 preferentially excited interneurons in one layer (5A/LTS) and excitatory neurons in another (5B/corticospinal). Thus, these inhibitory microcircuits in mouse motor cortex follow an orderly arrangement that is laminarly orthogonalized by interneuron-specific, projection-nonspecific connectivity.

• PKC-2 Phosphorylation of UNC-18 Ser322 in AFD Neurons Regulates Temperature Dependency of Locomotion.

  Authors: Mark R Edwards, James R Johnson, Kimberley Rankin, Rosalind E Jenkins, Carl Maguire, Alan Morgan, Robert D Burgoyne, Jeff W Barclay

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):7042-51.

  Diacylglycerol (DAG)/protein kinase C (PKC) signaling plays an integral role in the regulation of neuronal function. This is certainly true in Caenorhabditis elegans and in particular forDiacylglycerol (DAG)/protein kinase C (PKC) signaling plays an integral role in the regulation of neuronal function. This is certainly true in Caenorhabditis elegans and in particular for thermosensory signaling and behavior. Downstream molecular targets for transduction of this signaling cascade remain, however, virtually uncharacterized. We investigated whether PKC phosphorylation of Munc18-1, an essential protein in vesicle trafficking and exocytosis, was the downstream effector for DAG regulation of thermosensory behavior. We demonstrate here that the C. elegans ortholog of Munc18-1, UNC-18, was phosphorylated in vitro at Ser322. Transgenic rescue of unc-18-null worms with Ser322 phosphomutants displayed altered thermosensitivity. C. elegans expresses three DAG-regulated PKCs, and blocking UNC-18 Ser322 phosphorylation was phenocopied only by deletion of calcium-activated PKC-2. Expression of nonphosphorylatable UNC-18 S322A, either pan-neuronally or specifically in AFD thermosensory neurons, converted wild-type worms to a pkc-2-null phenotype. These data demonstrate that an individual DAG-dependent thermosensory behavior of an organism is effected specifically by the downstream PKC-2 phosphorylation of UNC-18 on Ser322 in AFD neurons.

• Regulation of Fasciclin II and Synaptic Terminal Development by the Splicing Factor Beag.

  Authors: Erin S Beck, Gabriel Gasque, Wendy L Imlach, Wei Jiao, Ben Jiwon Choi, Pao-Shu Wu, Matthew L Kraushar, Brian D McCabe

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):7058-73.

  Pre-mRNA alternative splicing is an important mechanism for the generation of synaptic protein diversity, but few factors governing this process have been identified. From a screen for DrosophilaPre-mRNA alternative splicing is an important mechanism for the generation of synaptic protein diversity, but few factors governing this process have been identified. From a screen for Drosophila mutants with aberrant synaptic development, we identified beag, a mutant with fewer synaptic boutons and decreased neurotransmitter release. Beag encodes a spliceosomal protein similar to splicing factors in humans and Caenorhabditis elegans. We find that both beag mutants and mutants of an interacting gene dsmu1 have changes in the synaptic levels of specific splice isoforms of Fasciclin II (FasII), the Drosophila ortholog of neural cell adhesion molecule. We show that restoration of one splice isoform of FasII can rescue synaptic morphology in beag mutants while expression of other isoforms cannot. We further demonstrate that this FasII isoform has unique functions in synaptic development independent of transsynaptic adhesion. beag and dsmu1 mutants demonstrate an essential role for these previously uncharacterized splicing factors in the regulation of synapse development and function.

• Connectivity Changes Underlying Spectral EEG Changes during Propofol-Induced Loss of Consciousness.

  Authors: Mélanie Boly, Rosalyn Moran, Michael Murphy, Pierre Boveroux, Marie-Aurélie Bruno, Quentin Noirhomme, Didier Ledoux, Vincent Bonhomme, Jean-François Brichant, Giulio Tononi, Steven Laureys, Karl Friston

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):7082-7090.

  The mechanisms underlying anesthesia-induced loss of consciousness remain a matter of debate. Recent electrophysiological reports suggest that while initial propofol infusion provokes an increase inThe mechanisms underlying anesthesia-induced loss of consciousness remain a matter of debate. Recent electrophysiological reports suggest that while initial propofol infusion provokes an increase in fast rhythms (from beta to gamma range), slow activity (from delta to alpha range) rises selectively during loss of consciousness. Dynamic causal modeling was used to investigate the neural mechanisms mediating these changes in spectral power in humans. We analyzed source-reconstructed data from frontal and parietal cortices during normal wakefulness, propofol-induced mild sedation, and loss of consciousness. Bayesian model selection revealed that the best model for explaining spectral changes across the three states involved changes in corticothalamic interactions. Compared with wakefulness, mild sedation was accounted for by an increase in thalamic excitability, which did not further increase during loss of consciousness. In contrast, loss of consciousness per se was accompanied by a decrease in backward corticocortical connectivity from frontal to parietal cortices, while thalamocortical connectivity remained unchanged. These results emphasize the importance of recurrent corticocortical communication in the maintenance of consciousness and suggest a direct effect of propofol on cortical dynamics.

• Nonsynaptic NMDA Receptors Mediate Activity-Dependent Plasticity of Gap Junctional Coupling in the AII Amacrine Cell Network.

  Authors: W Wade Kothmann, E Brady Trexler, Christopher M Whitaker, Wei Li, Stephen C Massey, John O'Brien

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6747-59.

  Many neurons are coupled by electrical synapses into networks that have emergent properties. In the retina, coupling in these networks is dynamically regulated by changes in background illumination,Many neurons are coupled by electrical synapses into networks that have emergent properties. In the retina, coupling in these networks is dynamically regulated by changes in background illumination, optimizing signal integration for the visual environment. However, the mechanisms that control this plasticity are poorly understood. We have investigated these mechanisms in the rabbit AII amacrine cell, a multifunctional retinal neuron that forms an electrically coupled network via connexin 36 (Cx36) gap junctions. We find that presynaptic activity of glutamatergic ON bipolar cells drives increased phosphorylation of Cx36, indicative of increased coupling in the AII network. The phosphorylation is dependent on activation of nonsynaptic NMDA receptors that colocalize with Cx36 on AII amacrine cells, and is mediated by CaMKII. This activity-dependent increase in Cx36 phosphorylation works in opposition to dopamine-driven reduction of phosphorylation, establishing a local dynamic regulatory mechanism, and accounting for the nonlinear control of AII coupling by background illumination.

• κ-Opioid Receptors within the Nucleus Accumbens Shell Mediate Pair Bond Maintenance.

  Authors: Shanna L Resendez, Morgan Kuhnmuench, Tarin Krzywosinski, Brandon J Aragona

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6771-84.

  The prairie vole is a socially monogamous species in which breeder pairs typically show strong and selective pair bonds. The establishment of a pair bond is associated with a behavioral transitionThe prairie vole is a socially monogamous species in which breeder pairs typically show strong and selective pair bonds. The establishment of a pair bond is associated with a behavioral transition from general affiliation to aggressive rejection of novel conspecifics. This "selective aggression" is indicative of mate guarding that is necessary to maintain the initial pair bond. In the laboratory, the neurobiology of this behavior is studied using resident-intruder testing. Although it is well established that social behaviors in other species are mediated by endogenous opioid systems, opiate regulation of pair bond maintenance has never been studied. Here, we used resident-intruder testing to determine whether endogenous opioids within brain motivational circuitry mediate selective aggression in prairie voles. We first show that peripheral blockade of κ-opioid receptors with the antagonist norbinaltorphimine (nor-BNI; 100 mg/kg), but not with the preferential μ-opioid receptor antagonist naloxone (1, 10, or 30 mg/kg), decreased selective aggression in males. We then provide the first comprehensive characterization of κ- and μ-opioid receptors in the prairie vole brain. Finally, we demonstrate that blockade of κ-opioid receptors (500 ng nor-BNI) within the nucleus accumbens (NAc) shell abolishes selective aggression in both sexes, but blockade of these receptors within the NAc core enhances this behavior specifically in females. Blockade of κ-opioid receptors within the ventral pallidum or μ-opioid receptors with the specific μ-opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-PenThr-NH2 (1 ng CTAP) within the NAc shell had no effect in either sex. Thus, κ-opioid receptors within the NAc shell mediate aversive social motivation that is critical for pair bond maintenance.

• Maladaptive dendritic spine remodeling contributes to diabetic neuropathic pain.

  Authors: Andrew M Tan, Omar A Samad, Tanya Z Fischer, Peng Zhao, Anna-Karin Persson, Stephen G Waxman

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6795-807.

  Diabetic neuropathic pain imposes a huge burden on individuals and society, and represents a major public health problem. Despite aggressive efforts, diabetic neuropathic pain is generally refractoryDiabetic neuropathic pain imposes a huge burden on individuals and society, and represents a major public health problem. Despite aggressive efforts, diabetic neuropathic pain is generally refractory to available clinical treatments. A structure-function link between maladaptive dendritic spine plasticity and pain has been demonstrated previously in CNS and PNS injury models of neuropathic pain. Here, we reasoned that if dendritic spine remodeling contributes to diabetic neuropathic pain, then (1) the presence of malformed spines should coincide with the development of pain, and (2) disrupting maladaptive spine structure should reduce chronic pain. To determine whether dendritic spine remodeling contributes to neuropathic pain in streptozotocin (STZ)-induced diabetic rats, we analyzed dendritic spine morphology and electrophysiological and behavioral signs of neuropathic pain. Our results show changes in dendritic spine shape, distribution, and shape on wide-dynamic-range (WDR) neurons within lamina IV-V of the dorsal horn in diabetes. These diabetes-induced changes were accompanied by WDR neuron hyperexcitability and decreased pain thresholds at 4 weeks. Treatment with NSC23766 (N(6)-[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine trihydrochloride), a Rac1-specific inhibitor known to interfere with spine plasticity, decreased the presence of malformed spines in diabetes, attenuated neuronal hyperresponsiveness to peripheral stimuli, reduced spontaneous firing activity from WDR neurons, and improved nociceptive mechanical pain thresholds. At 1 week after STZ injection, animals with hyperglycemia with no evidence of pain had few or no changes in spine morphology. These results demonstrate that diabetes-induced maladaptive dendritic spine remodeling has a mechanistic role in neuropathic pain. Molecular pathways that control spine morphogenesis and plasticity may be promising future targets for treatment.

• Genetic analysis of ecdysis behavior in Drosophila reveals partially overlapping functions of two unrelated neuropeptides.

  Authors: Eleanor C Lahr, Derek Dean, John Ewer

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6819-29.

  Ecdysis behavior allows insects to shed their old exoskeleton at the end of every molt. It is controlled by a suite of interacting hormones and neuropeptides, and has served as a useful behavior forEcdysis behavior allows insects to shed their old exoskeleton at the end of every molt. It is controlled by a suite of interacting hormones and neuropeptides, and has served as a useful behavior for understanding how bioactive peptides regulate CNS function. Previous findings suggest that crustacean cardioactive peptide (CCAP) activates the ecdysis motor program; the hormone bursicon is believed to then act downstream of CCAP to inflate, pigment, and harden the exoskeleton of the next stage. However, the exact roles of these signaling molecules in regulating ecdysis remain unclear. Here we use a genetic approach to investigate the functions of CCAP and bursicon in Drosophila ecdysis. We show that null mutants in CCAP express no apparent defects in ecdysis and postecdysis, producing normal adults. By contrast, a substantial fraction of flies genetically null for one of the two subunits of bursicon [encoded by the partner of bursicon gene (pburs)] show severe defects in ecdysis, with escaper adults exhibiting the expected failures in wing expansion and exoskeleton pigmentation and hardening. Furthermore, flies lacking both CCAP and bursicon show much more severe defects at ecdysis than do animals null for either neuropeptide alone. Our results show that the functions thought to be subserved by CCAP are partially effected by bursicon, and that bursicon plays an important and heretofore undescribed role in ecdysis behavior itself. These findings have important implications for understanding the regulation of this vital insect behavior and the mechanisms by which hormones and neuropeptides control the physiology and behavior of animals.

• Developmental changes in medial auditory thalamic contributions to associative motor learning.

  Authors: Ka H Ng, John H Freeman

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6841-50.

  Eyeblink conditioning (EBC) was used in the current study to examine the mechanisms underlying the ontogeny of associative motor learning in rats. Eyeblink conditioning emerges ontogeneticallyEyeblink conditioning (EBC) was used in the current study to examine the mechanisms underlying the ontogeny of associative motor learning in rats. Eyeblink conditioning emerges ontogenetically between postnatal day 17 (P17) and P24 in rats. Previous studies used electrical stimulation to show that the ontogeny of EBC is influenced by developmental changes in input from the medial auditory thalamus to the pontine nuclei, which in turn affects input to the cerebellum. The current study used tetrode recordings to examine the ontogeny of medial auditory thalamic sensory responses to the conditioned stimulus (CS) and learning-related activity during EBC. Rat pups were implanted with multiple tetrodes in the medial nucleus of the medial geniculate (MGm) and suprageniculate (SG) and trained on delay EBC on P17-P19, P24-P26, or P31-P33 while recording spike activity. Developmental changes in MGm and SG sensory-related activity were found during a pretraining session with unpaired presentations of the auditory CS and periorbital stimulation unconditioned stimulus (US). Substantial developmental changes were observed in learning-related activity in the MGm and SG during CS-US paired training. The ontogenetic changes in learning-related activity may be related to developmental changes in input to the medial auditory thalamus from the amygdala and cerebellum. The findings suggest that the ontogeny of associative motor learning involves developmental changes in sensory input to the thalamus, amygdala input to the thalamus, thalamic input to the pontine nuclei, and cerebellar feedback to the thalamus.

• Guidance-Cue Control of Horizontal Cell Morphology, Lamination, and Synapse Formation in the Mammalian Outer Retina.

  Authors: Ryota L Matsuoka, Zheng Jiang, Ivy S Samuels, Kim T Nguyen-Ba-Charvet, Lu O Sun, Neal S Peachey, Alain Chédotal, King-Wai Yau, Alex L Kolodkin

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6859-6868.

  In the vertebrate retina, neuronal circuitry required for visual perception is organized within specific laminae. Photoreceptors convey external visual information to bipolar and horizontal cells atIn the vertebrate retina, neuronal circuitry required for visual perception is organized within specific laminae. Photoreceptors convey external visual information to bipolar and horizontal cells at triad ribbon synapses established within the outer plexiform layer (OPL), initiating retinal visual processing. However, the molecular mechanisms that organize these three classes of neuronal processes within the OPL, thereby ensuring appropriate ribbon synapse formation, remain largely unknown. Here we show that mice with null mutations in Sema6A or PlexinA4 (PlexA4) exhibit a pronounced defect in OPL stratification of horizontal cell axons without any apparent deficits in bipolar cell dendrite or photoreceptor axon targeting. Furthermore, these mutant horizontal cells exhibit aberrant dendritic arborization and reduced dendritic self-avoidance within the OPL. Ultrastructural analysis shows that the horizontal cell contribution to rod ribbon synapse formation in PlexA4(-/-) retinas is disrupted. These findings define molecular components required for outer retina lamination and ribbon synapse formation.

• NMDA Receptors with Incomplete Mg2+ Block Enable Low-Frequency Transmission through the Cerebellar Cortex.

  Authors: Eric J Schwartz, Jason S Rothman, Guillaume P Dugué, Marco Diana, Charly Rousseau, R Angus Silver, Stéphane Dieudonné

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6878-93.

  The cerebellar cortex coordinates movements and maintains balance by modifying motor commands as a function of sensory-motor context, which is encoded by mossy fiber (MF) activity. MFs exhibit a wideThe cerebellar cortex coordinates movements and maintains balance by modifying motor commands as a function of sensory-motor context, which is encoded by mossy fiber (MF) activity. MFs exhibit a wide range of activity, from brief precisely timed high-frequency bursts, which encode discrete variables such as whisker stimulation, to low-frequency sustained rate-coded modulation, which encodes continuous variables such as head velocity. While high-frequency MF inputs have been shown to activate granule cells (GCs) effectively, much less is known about sustained low-frequency signaling through the GC layer, which is impeded by a hyperpolarized resting potential and strong GABA(A)-mediated tonic inhibition of GCs. Here we have exploited the intrinsic MF network of unipolar brush cells to activate GCs with sustained low-frequency asynchronous MF inputs in rat cerebellar slices. We find that low-frequency MF input modulates the intrinsic firing of Purkinje cells, and that this signal transmission through the GC layer requires synaptic activation of Mg(2+)-block-resistant NMDA receptors (NMDARs) that are likely to contain the GluN2C subunit. Slow NMDAR conductances sum temporally to contribute approximately half the MF-GC synaptic charge at hyperpolarized potentials. Simulations of synaptic integration in GCs show that the NMDAR and slow spillover-activated AMPA receptor (AMPAR) components depolarize GCs to a similar extent. Moreover, their combined depolarizing effect enables the fast quantal AMPAR component to trigger action potentials at low MF input frequencies. Our results suggest that the weak Mg(2+) block of GluN2C-containing NMDARs enables transmission of low-frequency MF signals through the input layer of the cerebellar cortex.

• Susceptibility to PTSD-Like Behavior Is Mediated by Corticotropin-Releasing Factor Receptor Type 2 Levels in the Bed Nucleus of the Stria Terminalis.

  Authors: Maya Lebow, Adi Neufeld-Cohen, Yael Kuperman, Michael Tsoory, Shosh Gil, Alon Chen

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(20):6906-16.

  Posttraumatic stress disorder (PTSD) is a debilitating disease, which affects 8-10% of the population exposed to traumatic events. The factors that make certain individuals susceptible to PTSD andPosttraumatic stress disorder (PTSD) is a debilitating disease, which affects 8-10% of the population exposed to traumatic events. The factors that make certain individuals susceptible to PTSD and others resilient are currently unknown. Corticotropin-releasing factor receptor type 2 (CRFR2) has been implicated in mediating stress coping mechanisms. Here, we use a physiological PTSD-like animal model and an in-depth battery of tests that reflect the symptomology of PTSD to separate mice into subpopulations of "PTSD-like" and "Resilient" phenotypes. PTSD-like mice are hypervigilant, hyperalert, insomniac, have impaired attention and risk assessment, as well as accompanying attenuated corticosterone levels. Intriguingly, PTSD-like mice show long-term robust upregulation of BNST-CRFR2 mRNA levels, and BNST-CRFR2-specific lentiviral knockdown reduces susceptibility to PTSD-like behavior. Additionally, using a BNST mRNA expression array, PTSD-like mice exhibit a general transcriptional attenuation profile, which was associated with upregulation of the BNST-deacetylation enzyme, HDAC5. We suggest PTSD to be a disease of maladaptive coping.

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