Hot off the presses! Jun 01 Nat Neurosci

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Latest Articles Include:

• Encouraging science outreach
  - Nat Neurosci 12(6):665 (2009)
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• The motor cortex re-imagined
  - Nat Neurosci 12(6):667 (2009)
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• Neurogenesis in G minor
  - Nat Neurosci 12(6):669-671 (2009)
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• Pool rules
  - Nat Neurosci 12(6):671-673 (2009)
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• How serotonin gates olfactory information flow
  - Nat Neurosci 12(6):673-675 (2009)
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• The rhythms of learning
  - Nat Neurosci 12(6):675-676 (2009)
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• Focus on hearing
  - Nat Neurosci 12(6):677 (2009)
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• Quo vadis, hair cell regeneration?
  - Nat Neurosci 12(6):679-685 (2009)
  Hearing loss is a global health problem with profound socioeconomic impact. We contend that acquired hearing loss is mainly a modern disorder caused by man-made noise and modern drugs, among other causes. These factors, combined with increasing lifespan, have exposed a deficit in cochlear self-regeneration that was irrelevant for most of mammalian evolution. Nevertheless, the mammalian cochlea has evolved from phylogenetically older structures, which do have the capacity for self-repair. Moreover, nonmammalian vertebrates can regenerate auditory hair cells that restore sensory function. We will offer a critical perspective on recent advances in stem cell biology, gene therapy, cell cycle regulation and pharmacotherapeutics to define and validate regenerative medical interventions for mammalian hair cell loss. Although these advances are promising, we are only beginning to fully appreciate the complexity of the many challenges that lie ahead.
• Beyond cochlear implants: awakening the deafened brain
  - Nat Neurosci 12(6):686-691 (2009)
  Cochlear implants have provided hearing to more than 120,000 deaf people. Recent surgical developments include direct electrical stimulation of the brain, bilateral implants and implantation in children less than 1 year old. However, research is beginning to refocus on the role of the brain in providing benefits to implant users. The auditory system is able to use the highly impoverished input provided by implants to interpret speech, but this only works well in those who have developed language before their deafness or in those who receive their implant at a very young age. We discuss recent evidence suggesting that developing the ability of the brain to learn how to use an implant may be as important as further improvements of the implant technology.
• On hearing with more than one ear: lessons from evolution
  - Nat Neurosci 12(6):692-697 (2009)
  Although ears capable of detecting airborne sound have arisen repeatedly and independently in different species, most animals that are capable of hearing have a pair of ears. We review the advantages that arise from having two ears and discuss recent research on the similarities and differences in the binaural processing strategies adopted by birds and mammals. We also ask how these different adaptations for binaural and spatial hearing might inform and inspire the development of techniques for future auditory prosthetic devices.
• Unraveling the principles of auditory cortical processing: can we learn from the visual system?
  - Nat Neurosci 12(6):698-701 (2009)
  Studies of auditory cortex are often driven by the assumption, derived from our better understanding of visual cortex, that basic physical properties of sounds are represented there before being used by higher-level areas for determining sound-source identity and location. However, we only have a limited appreciation of what the cortex adds to the extensive subcortical processing of auditory information, which can account for many perceptual abilities. This is partly because of the approaches that have dominated the study of auditory cortical processing to date, and future progress will unquestionably profit from the adoption of methods that have provided valuable insights into the neural basis of visual perception. At the same time, we propose that there are unique operating principles employed by the auditory cortex that relate largely to the simultaneous and sequential processing of previously derived features and that therefore need to be studied and understood in ! their own right.
• Linking genes underlying deafness to hair-bundle development and function
  - Nat Neurosci 12(6):703-710 (2009)
  The identification of mutations underlying monogenic, early-onset forms of deafness in humans has provided unprecedented insight into the molecular mechanisms of hearing in the peripheral auditory system. The molecules involved in the development and function of the cochlea eluded characterization until recently owing to the scarcity of the principal cell types present. The genetic approach has circumvented this problem and succeeded in identifying proteins and deciphering some of the molecular complexes that operate in these cells. In combination with mouse models, the genetic approach is now revealing some of the principles underlying the development and physiology of the cochlea. Focusing on the hair bundle, the mechanosensory device of the sensory hair cell, we highlight recent advances in understanding the way in which the hair bundle is formed, how it operates as a mechanotransducer and how it processes sound. In particular, we discuss how these findings confer a! central role on the various hair-bundle links in these processes.
• Tonotopic reorganization of developing auditory brainstem circuits
  - Nat Neurosci 12(6):711-717 (2009)
  A fundamental organizing principle of auditory brain circuits is tonotopy, the orderly representation of the sound frequency to which neurons are most sensitive. Tonotopy arises from the coding of frequency along the cochlea and the topographic organization of auditory pathways. The mechanisms that underlie the establishment of tonotopy are poorly understood. In auditory brainstem pathways, topographic precision is present at very early stages in development, which may suggest that synaptic reorganization contributes little to the construction of precise tonotopic maps. Accumulating evidence from several brainstem nuclei, however, is now changing this view by demonstrating that developing auditory brainstem circuits undergo a marked degree of refinement on both a subcellular and circuit level.
• Maps and streams in the auditory cortex: nonhuman primates illuminate human speech processing
  - Nat Neurosci 12(6):718-724 (2009)
  Speech and language are considered uniquely human abilities: animals have communication systems, but they do not match human linguistic skills in terms of recursive structure and combinatorial power. Yet, in evolution, spoken language must have emerged from neural mechanisms at least partially available in animals. In this paper, we will demonstrate how our understanding of speech perception, one important facet of language, has profited from findings and theory in nonhuman primate studies. Chief among these are physiological and anatomical studies showing that primate auditory cortex, across species, shows patterns of hierarchical structure, topographic mapping and streams of functional processing. We will identify roles for different cortical areas in the perceptual processing of speech and review functional imaging work in humans that bears on our understanding of how the brain decodes and monitors speech. A new model connects structures in the temporal, frontal and! parietal lobes linking speech perception and production.
• Intracellular zinc inhibits KCC2 transporter activity
  - Nat Neurosci 12(6):725-727 (2009)
  We found that K+/Cl- co-transporter 2 (KCC2) activity, monitored with wide-field fluorescence, was inhibited by intracellular Zn2+, a major component of neuronal injury. Zn2+-mediated KCC2 inhibition produced a depolarizing shift of GABAA reversal potentials in rat cortical neurons. Moreover, oxygen-glucose deprivation attenuated KCC2 activity in a Zn2+-dependent manner. The link between Zn2+ and KCC2 activity provides a previously unknown target for neuroprotection and may be important in activity-dependent regulation of inhibitory synaptic transmission.
• Adult neurogenesis promotes synaptic plasticity in the olfactory bulb
  - Nat Neurosci 12(6):728-730 (2009)
  To explore the functional consequences of adult neurogenesis in the mouse olfactory bulb, we investigated plasticity at glutamatergic synapses onto GABAergic interneurons. We found that one subset of excitatory synapses onto adult-born granule cells showed long-term potentiation shortly after their arrival in the bulb. This property faded as the newborn neurons matured. These results indicate that recently generated adult-born olfactory interneurons undergo different experience-dependent synaptic modifications compared with their pre-existing mature neighbors and provide a possible substrate for adult neurogenesis–dependent olfactory learning.
• Long-term plasticity of excitatory inputs to granule cells in the rat olfactory bulb
  - Nat Neurosci 12(6):731-733 (2009)
  Using two photon–guided focal stimulation, we found spike timing–dependent plasticity of proximal excitatory inputs to olfactory bulb granule cells that originated, in part, from cortical feedback projections. The protocol that potentiated proximal inputs depressed distal, dendrodendritic inputs to granule cells. Granule cell excitatory postsynaptic potentials and mitral cell inhibition were also potentiated by theta-burst stimulation. Plasticity of cortical feedback inputs to interneurons provides a mechanism for encoding information by modulating bulbar inhibition.
• Lfc and Tctex-1 regulate the genesis of neurons from cortical precursor cells
  - Nat Neurosci 12(6):735-744 (2009)
  The mechanisms that regulate symmetric, proliferative divisions versus asymmetric, neurogenic divisions of mammalian neural precursors are still not well understood. We found that Lfc (Arhgef2), a Rho-specific guanine nucleotide exchange factor that interacts with spindle microtubules, and its negative regulator Tctex-1 (Dynlt1) determine the genesis of neurons from precursors in the embryonic murine cortex. Specifically, genetic knockdown of Arhgef2 in cortical precursors either in culture or in vivo inhibited neurogenesis and maintained cells as cycling radial precursors. Conversely, genetic knockdown of Dynlt1 in radial precursors promoted neurogenesis and depleted cycling cortical precursors. Coincident silencing of these two genes indicated that Tctex-1 normally inhibits the genesis of neurons from radial precursors by antagonizing the proneurogenic actions of Lfc. Moreover, Lfc and Tctex-1 were required to determine the orientation of mitotic precursor cell divis! ions in vivo. Thus, Lfc and Tctex-1 interact to regulate cortical neurogenesis, potentially by regulating mitotic spindle orientation.
• Na+-activated K+ channels express a large delayed outward current in neurons during normal physiology
  - Nat Neurosci 12(6):745-750 (2009)
  One of the largest components of the delayed outward current that is active under physiological conditions in many mammalian neurons, such as medium spiny neurons of the striatum and tufted-mitral cells of the olfactory bulb, has gone unnoticed and is the result of a Na+-activated K+ current. Previous studies of K+ currents in mammalian neurons may have overlooked this large outward component because the sodium channel blocker tetrodotoxin (TTX) is typically used in such studies. We found that TTX also eliminated this delayed outward component in rat neurons as a secondary consequence. Unexpectedly, we found that the activity of a persistent inward sodium current (persistent INa) is highly effective at activating this large Na+-dependent (TTX sensitive) delayed outward current. Using siRNA techniques, we identified SLO2.2 channels as being carriers of this delayed outward current. These findings have far reaching implications for many aspects of cellular and systems ne! uroscience, as well as clinical neurology and pharmacology.
• A resting pool of vesicles is responsible for spontaneous vesicle fusion at the synapse
  - Nat Neurosci 12(6):751-758 (2009)
  Synapses relay information through the release of neurotransmitters stored in presynaptic vesicles. The identity, kinetics and location of the vesicle pools that are mobilized by neuronal activity have been studied using a variety of techniques. We created a genetically encoded probe, biosyn, which consists of a biotinylated VAMP2 expressed at presynaptic terminals. We exploited the high-affinity interaction between streptavidin and biotin to label biosyn with fluorescent streptavidin during vesicle fusion. This approach allowed us to tag vesicles sequentially to visualize and establish the identity of presynaptic pools. Using this technique, we were able to distinguish between two different pools of vesicles in rat hippocampal neurons: one that was released in response to presynaptic activity and another, distinct vesicle pool that spontaneously fused with the plasma membrane. We found that the spontaneous vesicles belonged to a 'resting pool' that is normally not mob! ilized by neuronal activity and whose function was previously unknown.
• Synaptotagmin-1 functions as a Ca2+ sensor for spontaneous release
  - Nat Neurosci 12(6):759-766 (2009)
  Spontaneous 'mini' release occurs at all synapses, but its nature remains enigmatic. We found that >95% of spontaneous release in murine cortical neurons was induced by Ca2+-binding to synaptotagmin-1 (Syt1), the Ca2+ sensor for fast synchronous neurotransmitter release. Thus, spontaneous and evoked release used the same Ca2+-dependent release mechanism. As a consequence, Syt1 mutations that altered its Ca2+ affinity altered spontaneous and evoked release correspondingly. Paradoxically, Syt1 deletions (as opposed to point mutations) massively increased spontaneous release. This increased spontaneous release remained Ca2+ dependent but was activated at lower Ca2+ concentrations and with a lower Ca2+ cooperativity than synaptotagmin-driven spontaneous release. Thus, in addition to serving as a Ca2+ sensor for spontaneous and evoked release, Syt1 clamped a second, more sensitive Ca2+ sensor for spontaneous release that resembles the Ca2+ sensor for evoked asynchronous rel! ease. These data suggest that Syt1 controls both evoked and spontaneous release at a synapse as a simultaneous Ca2+-dependent activator and clamp of exocytosis.
• Synaptotagmin-IV modulates synaptic function and long-term potentiation by regulating BDNF release
  - Nat Neurosci 12(6):767-776 (2009)
  Synaptotagmin-IV (syt-IV) is a membrane trafficking protein that influences learning and memory, but its localization and role in synaptic function remain unclear. We found that syt-IV localized to brain-derived neurotrophic factor (BDNF)-containing vesicles in hippocampal neurons. Syt-IV/BDNF–harboring vesicles underwent exocytosis in both axons and dendrites, and syt-IV inhibited BDNF release at both sites. Knockout of syt-IV increased, and overexpression decreased, the rate of synaptic vesicle exocytosis from presynaptic terminals indirectly via changes in postsynaptic release of BDNF. Thus, postsynaptic syt-IV regulates the trans-synaptic action of BDNF to control presynaptic vesicle dynamics. Furthermore, selective loss of presynaptic syt-IV increased spontaneous quantal release, whereas a loss of postsynaptic syt-IV increased quantal amplitude. Finally, syt-IV knockout mice showed enhanced long-term potentiation (LTP), which depended entirely on disinhibition o! f BDNF release. Thus, regulation of BDNF secretion by syt-IV emerges as a mechanism for maintaining synaptic strength in a useful range during LTP.
• Ube3a is required for experience-dependent maturation of the neocortex
  - Nat Neurosci 12(6):777-783 (2009)
  Experience-dependent maturation of neocortical circuits is required for normal sensory and cognitive abilities, which are distorted in neurodevelopmental disorders. We tested whether experience-dependent neocortical modifications require Ube3a, an E3 ubiquitin ligase whose dysregulation has been implicated in autism and Angelman syndrome. Using visual cortex as a model, we found that experience-dependent maturation of excitatory cortical circuits was severely impaired in Angelman syndrome model mice deficient in Ube3a. This developmental defect was associated with profound impairments in neocortical plasticity. Normal plasticity was preserved under conditions of sensory deprivation, but was rapidly lost by sensory experiences. The loss of neocortical plasticity is reversible, as late-onset visual deprivation restored normal synaptic plasticity. Furthermore, Ube3a-deficient mice lacked ocular dominance plasticity in vivo when challenged with monocular deprivation. We co! nclude that Ube3a is necessary for maintaining plasticity during experience-dependent neocortical development and suggest that the loss of neocortical plasticity contributes to deficits associated with Angelman syndrome.
• Serotonergic modulation of odor input to the mammalian olfactory bulb
  - Nat Neurosci 12(6):784-791 (2009)
  Centrifugal serotonergic fibers innervate the olfactory bulb, but the importance of these projections for olfactory processing is unclear. We examined serotonergic modulation of sensory input to olfactory glomeruli using mice that express synaptopHluorin in olfactory receptor neurons (ORN). Odor-evoked synaptic input to glomeruli was attenuated by increased serotonin signaling through serotonin 2C (5-HT2C) receptors and amplified by decreased serotonergic activity. Intravital multiphoton calcium imaging revealed that 5-HT2C receptor activation amplified odor-evoked activity in a subset of juxtaglomerular cells and attenuated glutamate release from ORN terminals via GABAB receptors. Endogenous serotonin released by electrical stimulation of the dorsal raphe nucleus attenuated odor-evoked responses without detectable bias in glomerular position or odor identity. Weaker glomerular responses, however, were less sensitive to raphe stimulation than strong responses. Our data! indicate that the serotonergic system regulates odor inputs in the olfactory bulb and suggest that behavioral states may alter odor processing at the earliest stages.
• Sparse temporal coding of elementary tactile features during active whisker sensation
  - Nat Neurosci 12(6):792-800 (2009)
  How the brain encodes relevant sensory stimuli in the context of active, natural sensation is not known. During active tactile sensation by rodents, whisker movement across surfaces generates complex whisker micro-motion, including discrete, transient slip-stick events, which carry information about surface properties. We simultaneously measured whisker motion and neural activity in somatosensory cortex (S1) in rats whisking across surfaces. Slip-stick motion events were prominently encoded by one or two low-probability, precisely timed spikes in S1 neurons, resulting in a probabilistically sparse ensemble code. Slips could be efficiently decoded from transient, correlated spiking (approx20-ms time scale) in small (approx100 neuron) populations. Slip responses contributed substantially to increased firing rate and transient firing synchrony on surfaces, and firing synchrony was an important cue for surface texture. Slips are thus a fundamental encoded tactile feature i! n natural whisker input streams and are represented by sparse, temporally precise, synchronous spiking in S1.
• Coherent gamma oscillations couple the amygdala and striatum during learning
  - Nat Neurosci 12(6):801-807 (2009)
  The basolateral amygdala (BLA) mediates the facilitating effects of emotions on memory. The BLA's enhancing influence extends to various types of memories, including striatal-dependent habit formation. To shed light on the underlying mechanisms, we carried out unit and local field potential (LFP) recordings in BLA, striatum, auditory cortex and intralaminar thalamus in cats trained on a stimulus-response task in which the presentation of one of two tones predicted reward delivery. The coherence of BLA, but not of cortical or thalamic, LFPs was highest with striatal gamma activity, and intra-BLA muscimol infusions selectively reduced striatal gamma power. Moreover, coupling of BLA-striatal unit activity increased when LFP gamma power was augmented. Early in training, the rewarded and unrewarded tones elicited a modest increase in coherent BLA-striatal gamma. As learning progressed, this gamma coupling selectively increased in relation to the rewarded tone. Thus, coheren! t gamma oscillations coordinate amygdalostriatal interactions during learning and might facilitate synaptic plasticity.
• Erratum: A dual leucine kinase–dependent axon self-destruction program promotes Wallerian degeneration
  - Nat Neurosci 12(6):808 (2009)
  Introduction Nat. Neurosci. 12, 387–389 (2008); published online 15 March 2009; corrected after print 15 May 2009 In the version of this article initially published, the abbreviation DLK was omitted from the abstract. The second sentence of the abstract should be "We found that dual leucine kinase (DLK) promoted degeneration of severed axons in Drosophila and mice, and that its target, c-Jun N-terminal kinase, promoted degeneration locally in axons as they committed to degenerate". The error has been corrected in the HTML and PDF versions of the article.
• Erratum: A precise form of divisive suppression supports population coding in the primary visual cortex
  - Nat Neurosci 12(6):808 (2009)
  Introduction Nat. Neurosci. 12, 637–645 (2009); published online 26 April 2009; corrected after print 6 May 2009 In the version of this article initially published, the gray curve in Figure 1j was shifted to the left. The corrected figure is shown below. The error has been corrected in the HTML and PDF versions of the article.
• Erratum: Selective regulation of long-form calcium-permeable AMPA receptors by an atypical TARP, bold gamma-5
  - Nat Neurosci 12(6):808 (2009)
  Introduction Nat. Neurosci. 12, 277–285 (2009); published online 22 February 2009; corrected after print 16 March 2009 In the version of this article initially published, the bar graphs in Figure 7c and 7d were misaligned. The error has been corrected in the HTML and PDF versions of the article.
• Corrigendum: Links from complex spikes to local plasticity and motor learning in the cerebellum of awake-behaving monkeys
  - Nat Neurosci 12(6):808 (2009)
  Introduction Nat. Neurosci. 11, 1185–1192 (2008); published online 21 September 2008; corrected after print 15 January and 30 April 2009 In the version of this article initially published, two citations were inadvertently omitted. To correct this, the following two sentences were added to the second paragraph of the introduction, following the sixth sentence. "One line of work has supported the theory by demonstrating that arm movement errors evoke complex spikes51, 52 and that subsequent learned changes in motor behavior are associated with suitable changes in simple spike responses51. This work demonstrates a strong correlation, but stops short of showing cause-and-effect links between individual complex spikes, changes in simple spikes and behavioral learning." Two references were also added to the reference list as follows: In addition, the second sentence of the abstract should read "Many elements of this hypothesis have been supported by prior experiments, and correlations have been found between complex spikes, simple-spike plasticity and behavior during the learning process." The errors have been corrected in the HTML and PDF versions of the article.