Hot off the presses! Sep 01 Nat Neurosci

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Latest Articles Include:

• Troublesome variability in mouse studies
  - Nat Neurosci 12(9):1075 (2009)
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• Be careful what you train for
  - Nat Neurosci 12(9):1077-1079 (2009)
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• Wnts blow on NeuroD1 to promote adult neuron production and diversity
  - Nat Neurosci 12(9):1079-1081 (2009)
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• Get stoned in GABAergic synapses
  - Nat Neurosci 12(9):1081-1083 (2009)
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• Recognizing Grandmother
  - Nat Neurosci 12(9):1083-1085 (2009)
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• Reconnecting injured nerves
  - Nat Neurosci 12(9):1085 (2009)
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• Midline crossing and Slit responsiveness of commissural axons require USP33
  - Nat Neurosci 12(9):1087-1089 (2009)
  Commissural axons cross the ventral midline of the neural tube in a Slit-dependent manner. The underlying molecular mechanisms remain unclear. We found that the deubiquitinating enzyme USP33 interacts with the Robo1 receptor. USP33 was essential for midline crossing by commissural axons and for their response to Slit. Our results reveal a previously unknown role for USP33 in vertebrate commissural axon guidance and in Slit signaling.
• Neurod1 is essential for the survival and maturation of adult-born neurons
  - Nat Neurosci 12(9):1090-1092 (2009)
  The transcriptional program that controls adult neurogenesis is unknown. We generated mice with an inducible stem cell–specific deletion of Neurod1, resulting in substantially fewer newborn neurons in the hippocampus and olfactory bulb. Thus, Neurod1 is cell-intrinsically required for the survival and maturation of adult-born neurons.
• L-type voltage-dependent Ca2+ channels mediate expression of presynaptic LTP in amygdala
  Fourcaudot E Gambino F Casassus G Poulain B Humeau Y Lüthi A - Nat Neurosci 12(9):1093-1095 (2009)
  The molecular mechanisms underlying the expression of postsynaptic long-term potentiation (LTP) at glutamatergic synapses are well understood. However, little is known about those that mediate the expression of presynaptic LTP. We found that presynaptic LTP at cortical inputs to the mouse lateral amygdala was blocked and reversed by L-type voltage-dependent Ca2+ channel (L-VDCC) blockers. Thus, a persistent increase in L-VDCC–mediated glutamate release underlies the expression of presynaptic LTP in the amygdala.
• Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis
  - Nat Neurosci 12(9):1097-1105 (2009)
  In adult hippocampus, new neurons are continuously generated from neural stem cells (NSCs), but the molecular mechanisms regulating adult neurogenesis remain elusive. We found that Wnt signaling, together with the removal of Sox2, triggered the expression of NeuroD1 in mice. This transcriptional regulatory mechanism was dependent on a DNA element containing overlapping Sox2 and T-cell factor/lymphoid enhancer factor (TCF/LEF)-binding sites (Sox/LEF) in the promoter. Notably, Sox/LEF sites were also found in long interspersed nuclear element 1 (LINE-1) elements, consistent with their critical roles in the transition of NSCs to proliferating neuronal progenitors. Our results describe a previously unknown Wnt-mediated regulatory mechanism that simultaneously coordinates activation of NeuroD1 and LINE-1, which is important for adult neurogenesis and survival of neuronal progenitors. Moreover, the discovery that LINE-1 retro-elements embedded in the mammalian genome can fun! ction as bi-directional promoters suggests that Sox/LEF regulatory sites may represent a general mechanism, at least in part, for relaying environmental signals to other nearby loci to promote adult hippocampal neurogenesis.
• Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury
  Alto LT Havton LA Conner JM Hollis Ii ER Blesch A Tuszynski MH - Nat Neurosci 12(9):1106-1113 (2009)
  A principal objective of spinal cord injury (SCI) research is the restoration of axonal connectivity to denervated targets. We tested the hypothesis that chemotropic mechanisms would guide regenerating spinal cord axons to appropriate brainstem targets. We subjected rats to cervical level 1 (C1) lesions and combinatorial treatments to elicit axonal bridging into and beyond lesion sites. Lentiviral vectors expressing neurotrophin-3 (NT-3) were then injected into an appropriate brainstem target, the nucleus gracilis, and an inappropriate target, the reticular formation. NT-3 expression in the correct target led to reinnervation of the nucleus gracilis in a dose-related fashion, whereas NT-3 expression in the reticular formation led to mistargeting of regenerating axons. Axons regenerating into the nucleus gracilis formed axodendritic synapses containing rounded vesicles, reflective of pre-injury synaptic architecture. Thus, we report for the first time, to the best of ou! r knowledge, the reinnervation of brainstem targets after SCI and an essential role for chemotropic axon guidance in target selection.
• Kinetic basis of partial agonism at NMDA receptors
  Kussius CL Popescu GK - Nat Neurosci 12(9):1114-1120 (2009)
  Activation of ligand-gated channels is initiated by the binding of small molecules at extracellular sites and culminates with the opening of a membrane-embedded pore. To investigate how perturbations at ligand-binding domains influence the gating reaction, we examined current traces recorded from individual NMDA receptors in the presence of several subunit-specific partial agonists. We found that low-efficacy agonists acting at either the glycine-binding or the glutamate-binding NMDA receptor subunits had very similar effects on the receptor's activation reaction, possibly reflecting a high degree of coupling between the two subunit types during gating. In addition, we found that partial agonists increased the height of all energy barriers encountered by NMDA receptors during activation. This result stands in sharp contrast to the localized effects that have been observed for pentameric ligand-gated channels and may represent a previously unknown mechanism by which par! tial agonists reduce receptor activity.
• Cholinergic modulation of multivesicular release regulates striatal synaptic potency and integration
  - Nat Neurosci 12(9):1121-1128 (2009)
  The pleiotropic actions of neuromodulators on pre- and postsynaptic targets make disentangling the mechanisms underlying regulation of synaptic transmission challenging. In the striatum, acetylcholine modulates glutamate release via activation of muscarinic receptors (mAchRs), although the consequences for postsynaptic signaling are unclear. Using two-photon microscopy and glutamate uncaging to examine individual synapses in the rat striatum, we found that glutamatergic afferents have a high degree of multivesicular release (MVR) in the absence of postsynaptic receptor saturation. We found that mAchR activation decreased both the probability of release and the concentration of glutamate in the synaptic cleft. The corresponding decrease in synaptic potency reduced the duration of synaptic potentials and limited temporal summation of afferent inputs. These findings reveal a mechanism by which a combination of basal MVR and low receptor saturation allow the presynaptic ac! tions of a neuromodulator to control the engagement of postsynaptic nonlinearities and regulate synaptic integration.
• Rapamycin activation of 4E-BP prevents parkinsonian dopaminergic neuron loss
  - Nat Neurosci 12(9):1129-1135 (2009)
  Mutations in PINK1 and PARK2 cause autosomal recessive parkinsonism, a neurodegenerative disorder that is characterized by the loss of dopaminergic neurons. To discover potential therapeutic pathways, we identified factors that genetically interact with Drosophila park and Pink1. We found that overexpression of the translation inhibitor Thor (4E-BP) can suppress all of the pathologic phenotypes, including degeneration of dopaminergic neurons in Drosophila. 4E-BP is activated in vivo by the TOR inhibitor rapamycin, which could potently suppress pathology in Pink1 and park mutants. Rapamycin also ameliorated mitochondrial defects in cells from individuals with PARK2 mutations. Recently, 4E-BP was shown to be inhibited by the most common cause of parkinsonism, dominant mutations in LRRK2. We also found that loss of the Drosophila LRRK2 homolog activated 4E-BP and was also able to suppress Pink1 and park pathology. Thus, in conjunction with recent findings, our results sug! gest that pharmacologic stimulation of 4E-BP activity may represent a viable therapeutic approach for multiple forms of parkinsonism.
• Origins of correlated activity in an olfactory circuit
  - Nat Neurosci 12(9):1136-1144 (2009)
  Multineuronal recordings often reveal synchronized spikes in different neurons. The manner in which correlated spike timing affects neural codes depends on the statistics of correlations, which in turn reflects the connectivity that gives rise to correlations. However, determining the connectivity of neurons recorded in vivo can be difficult. We investigated the origins of correlated activity in genetically labeled neurons of the Drosophila antennal lobe. Dual recordings showed synchronized spontaneous spikes in projection neurons (PNs) postsynaptic to the same type of olfactory receptor neuron (ORN). Odors increased these correlations. The primary origin of correlations lies in the divergence of each ORN onto every PN in its glomerulus. Reciprocal PN–PN connections make a smaller contribution to correlations and PN spike trains in different glomeruli were only weakly correlated. PN axons from the same glomerulus reconverge in the lateral horn, where pooling redundan! t signals may allow lateral horn neurons to average out noise that arises independently in these PNs.
• Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation
  - Nat Neurosci 12(9):1145-1151 (2009)
  Chondroitinase ABC treatment promotes spinal cord plasticity. We investigated whether chondroitinase-induced plasticity combined with physical rehabilitation promotes recovery of manual dexterity in rats with cervical spinal cord injuries. Rats received a C4 dorsal funiculus cut followed by chondroitinase ABC or penicillinase as a control. They were assigned to two alternative rehabilitation procedures, the first reinforcing skilled reaching and the second reinforcing general locomotion. Chondroitinase treatment enhanced sprouting of corticospinal axons independently of the rehabilitation regime. Only the rats receiving the combination of chondroitinase and specific rehabilitation showed improved manual dexterity. Rats that received general locomotor rehabilitation were better at ladder walking, but had worse skilled-reaching abilities than rats that received no treatment. Our results indicate that chondroitinase treatment opens a window during which rehabilitation can! promote recovery. However, only the trained skills are improved and other functions may be negatively affected.
• Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling
  Puighermanal E Marsicano G Busquets-Garcia A Lutz B Maldonado R Ozaita A - Nat Neurosci 12(9):1152-1158 (2009)
  Cognitive impairment is one of the most important negative consequences associated with cannabis consumption. We found that CB1 cannabinoid receptor (CB1R) activation transiently modulated the mammalian target of rapamycin (mTOR)/p70S6K pathway and the protein synthesis machinery in the mouse hippocampus, which correlated with the amnesic properties of delta9-tetrahydrocannabinol (THC). In addition, non-amnesic doses of either the mTOR blocker rapamycin or the protein synthesis inhibitor anisomycin abrogated the amnesic-like effects of THC, pointing to a mechanism involving new protein synthesis. Moreover, using pharmacological and genetic tools, we found that THC long-term memory deficits were mediated by CB1Rs expressed on GABAergic interneurons through a glutamatergic mechanism, as both the amnesic-like effects and p70S6K phosphorylation were reduced in GABA-CB1R knockout mice and by NMDA blockade.
• High-sensitivity rod photoreceptor input to the blue-yellow color opponent pathway in macaque retina
  - Nat Neurosci 12(9):1159-1164 (2009)
  Small bistratified cells (SBCs) in the primate retina carry a major blue-yellow opponent signal to the brain. We found that SBCs also carry signals from rod photoreceptors, with the same sign as S cone input. SBCs exhibited robust responses under low scotopic conditions. Physiological and anatomical experiments indicated that this rod input arose from the AII amacrine cell–mediated rod pathway. Rod and cone signals were both present in SBCs at mesopic light levels. These findings have three implications. First, more retinal circuits may multiplex rod and cone signals than were previously thought to, efficiently exploiting the limited number of optic nerve fibers. Second, signals from AII amacrine cells may diverge to most or all of the 20 retinal ganglion cell types in the peripheral primate retina. Third, rod input to SBCs may be the substrate for behavioral biases toward perception of blue at mesopic light levels.
• Change detection by thalamic reticular neurons
  - Nat Neurosci 12(9):1165-1170 (2009)
  The thalamic reticular nucleus (TRN) is thought to function in the attentional searchlight. We analyzed the detection of deviant acoustic stimuli by TRN neurons and the consequences of deviance detection on the TRN target, the medial geniculate body (MGB) of the rat. TRN neurons responded more strongly to pure-tone stimuli presented as deviant stimuli (low appearance probability) than those presented as standard stimuli (high probability) (deviance-detection index = 0.321). MGB neurons also showed deviance detection in this procedure, albeit to a smaller extent (deviance-detection index = 0.154). TRN neuron deviance detection either enhanced (14 neurons) or suppressed (27 neurons) MGB neuronal responses to a probe stimulus. Both effects were neutralized by inactivation of the auditory TRN. Deviance modulation effects were cross-modal. Deviance detection probably causes TRN neurons to transiently deactivate surrounding TRN neurons in response to a fresh stimulus, alteri! ng auditory thalamus responses and inducing attention shift.
• Elimination of climbing fiber instructive signals during motor learning
  - Nat Neurosci 12(9):1171-1179 (2009)
  The climbing fiber input to the cerebellum from the inferior olive is thought to act as a teacher whose activity controls the induction of motor learning. We designed training conditions that did not elicit instructive signals in the climbing fibers, but nevertheless induced robust and consistent motor learning in the vestibulo-ocular reflex of rhesus monkeys. Our results indicate that instructive signals in the climbing fibers are not necessary for cerebellum-dependent learning. Instead, instructive signals carried by either the climbing fibers or Purkinje cell simple spikes may be sufficient to induce motor learning, with additive effects occurring when both instructive signals are present during training.
• Stress, genotype and norepinephrine in the prediction of mouse behavior using reinforcement learning
  - Nat Neurosci 12(9):1180-1186 (2009)
  Individual behavioral performance during learning is known to be affected by modulatory factors, such as stress and motivation, and by genetic predispositions that influence sensitivity to these factors. Despite numerous studies, no integrative framework is available that could predict how a given animal would perform a certain learning task in a realistic situation. We found that a simple reinforcement learning model can predict mouse behavior in a hole-box conditioning task if model metaparameters are dynamically controlled on the basis of the mouse's genotype and phenotype, stress conditions, recent performance feedback and pharmacological manipulations of adrenergic alpha-2 receptors. We find that stress and motivation affect behavioral performance by altering the exploration-exploitation balance in a genotype-dependent manner. Our results also provide computational insights into how an inverted U–shape relation between stress/arousal/norepinephrine levels and be! havioral performance could be explained through changes in task performance accuracy and future reward discounting.
• A face feature space in the macaque temporal lobe
  - Nat Neurosci 12(9):1187-1196 (2009)
  The ability of primates to effortlessly recognize faces has been attributed to the existence of specialized face areas. One such area, the macaque middle face patch, consists almost entirely of cells that are selective for faces, but the principles by which these cells analyze faces are unknown. We found that middle face patch neurons detect and differentiate faces using a strategy that is both part based and holistic. Cells detected distinct constellations of face parts. Furthermore, cells were tuned to the geometry of facial features. Tuning was most often ramp-shaped, with a one-to-one mapping of feature magnitude to firing rate. Tuning amplitude depended on the presence of a whole, upright face and features were interpreted according to their position in a whole, upright face. Thus, cells in the middle face patch encode axes of a face space specialized for whole, upright faces.
• Genetic address book for retinal cell types
  Siegert S Scherf BG Del Punta K Didkovsky N Heintz N Roska B - Nat Neurosci 12(9):1197-1204 (2009)
  The mammalian brain is assembled from thousands of neuronal cell types that are organized in distinct circuits to perform behaviorally relevant computations. Transgenic mouse lines with selectively marked cell types would facilitate our ability to dissect functional components of complex circuits. We carried out a screen for cell type–specific green fluorescent protein expression in the retina using BAC transgenic mice from the GENSAT project. Among others, we identified mouse lines in which the inhibitory cell types of the night vision and directional selective circuit were selectively labeled. We quantified the stratification patterns to predict potential synaptic connectivity between marked cells of different lines and found that some of the lines enabled targeted recordings and imaging of cell types from developing or mature retinal circuits. Our results suggest the potential use of a stratification-based screening approach for characterizing neuronal circuitry i! n other layered brain structures, such as the neocortex.