Latest Articles Include:
- Mining chemistry for psychiatry
- Nat Neurosci 12(7):809 (2009)
I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Neuroscience Select this option to purchase a personal subscription to Nature Neuroscience. - Working on a Dream
- Nat Neurosci 12(7):811 (2009)
I want to purchase this article Register now Price: US$32 In order to purchase this article you must be a registered user. I want to subscribe to Nature Neuroscience Select this option to purchase a personal subscription to Nature Neuroscience. - A noseful of objects
- Nat Neurosci 12(7):813-814 (2009)
I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Neuroscience Select this option to purchase a personal subscription to Nature Neuroscience. - Genetics meets epigenetics: HDACs and Wnt signaling in myelin development and regeneration
- Nat Neurosci 12(7):815-817 (2009)
I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Neuroscience Select this option to purchase a personal subscription to Nature Neuroscience. - Stop and go GABA
- Nat Neurosci 12(7):817-818 (2009)
I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Neuroscience Select this option to purchase a personal subscription to Nature Neuroscience. - Reactive oxygen species are NOXious for neurons
- Nat Neurosci 12(7):819-820 (2009)
I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Neuroscience Select this option to purchase a personal subscription to Nature Neuroscience. - Prefrontal cortex and cognitive control: motivating functional hierarchies
- Nat Neurosci 12(7):821-822 (2009)
I want to purchase this article Register now Price: US$18 In order to purchase this article you must be a registered user. I want to subscribe to Nature Neuroscience Select this option to purchase a personal subscription to Nature Neuroscience. - CaMKII controls the direction of plasticity at parallel fiber–Purkinje cell synapses
- Nat Neurosci 12(7):823-825 (2009)
We found that CaMKII, the predominant CaMKII isoform of the cerebellum, is important for controlling the direction of plasticity at the parallel fiber–Purkinje cell synapse; a protocol that induced synaptic depression in wild-type mice resulted in synaptic potentiation in Camk2b knockout mice and vice versa. These findings provide us with unique experimental insight into the mechanisms that transduce graded calcium signals into either synaptic depression or potentiation. - Mutant LRRK2R1441G BAC transgenic mice recapitulate cardinal features of Parkinson's disease
- Nat Neurosci 12(7):826-828 (2009)
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. We created a LRRK2 transgenic mouse model that recapitulates cardinal features of the disease: an age-dependent and levodopa-responsive slowness of movement associated with diminished dopamine release and axonal pathology of nigrostriatal dopaminergic projection. These mice provide a valid model of Parkinson's disease and are a resource for the investigation of pathogenesis and therapeutics. - HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the -catenin–TCF interaction
- Nat Neurosci 12(7):829-838 (2009)
Oligodendrocyte development is regulated by the interaction of repressors and activators in a complex transcriptional network. We found that two histone-modifying enzymes, HDAC1 and HDAC2, were required for oligodendrocyte formation. Genetic deletion of both Hdac1 and Hdac2 in oligodendrocyte lineage cells resulted in stabilization and nuclear translocation of -catenin, which negatively regulates oligodendrocyte development by repressing Olig2 expression. We further identified the oligodendrocyte-restricted transcription factor TCF7L2/TCF4 as a bipartite co-effector of -catenin for regulating oligodendrocyte differentiation. Targeted disruption of Tcf7l2 in mice led to severe defects in oligodendrocyte maturation, whereas expression of its dominant-repressive form promoted precocious oligodendrocyte specification in developing chick neural tube. Transcriptional co-repressors HDAC1 and HDAC2 compete with -catenin for TCF7L2 interaction to regulate downstream genes invol! ved in oligodendrocyte differentiation. Thus, crosstalk between HDAC1/2 and the canonical Wnt signaling pathway mediated by TCF7L2 serves as a regulatory mechanism for oligodendrocyte differentiation. - Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity
- Nat Neurosci 12(7):839-847 (2009)
Notch signaling is central to vertebrate development, and analysis of Notch has provided important insights into pathogenetic mechanisms in the CNS and many other tissues. However, surprisingly little is known about the role of Notch in the development and pathology of Schwann cells and peripheral nerves. Using transgenic mice and cell cultures, we found that Notch has complex and extensive regulatory functions in Schwann cells. Notch promoted the generation of Schwann cells from Schwann cell precursors and regulated the size of the Schwann cell pool by controlling proliferation. Notch inhibited myelination, establishing that myelination is subject to negative transcriptional regulation that opposes forward drives such as Krox20. Notably, in the adult, Notch dysregulation resulted in demyelination; this finding identifies a signaling pathway that induces myelin breakdown in vivo. These findings are relevant for understanding the molecular mechanisms that control Schwan! n cell plasticity and underlie nerve pathology, including demyelinating neuropathies and tumorigenesis. - Regulation of acetylcholine receptor clustering by ADF/cofilin-directed vesicular trafficking
- Nat Neurosci 12(7):848-856 (2009)
Postsynaptic receptor localization is crucial for synapse development and function, but the underlying cytoskeletal mechanisms remain elusive. Using Xenopus neuromuscular junctions as a model, we found that actin depolymerizing factor (ADF)/cofilin regulated actin-dependent vesicular trafficking of acetylcholine receptors (AChRs) to the postsynaptic membrane. Active ADF/cofilin was concentrated in small puncta adjacent to AChR clusters and was spatiotemporally correlated with the formation and maintenance of surface AChR clusters. Notably, increased actin dynamics, vesicular markers and intracellular AChRs were all enriched at the sites of ADF/cofilin localization. Furthermore, a substantial amount of new AChRs was detected at these ADF/cofilin-enriched sites. Manipulation of either ADF/cofilin activity through its serine-3 phosphorylation or ADF/cofilin localization via 14-3-3 proteins markedly attenuated AChR insertion and clustering. These results suggest that spati! otemporally restricted ADF/cofilin-mediated actin dynamics regulate AChR trafficking during the development of neuromuscular synapses. - NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation
- Nat Neurosci 12(7):857-863 (2009)
Neuronal NMDA receptor (NMDAR) activation leads to the formation of superoxide, which normally acts in cell signaling. With extensive NMDAR activation, the resulting superoxide production leads to neuronal death. It is widely held that NMDA-induced superoxide production originates from the mitochondria, but definitive evidence for this is lacking. We evaluated the role of the cytoplasmic enzyme NADPH oxidase in NMDA-induced superoxide production. Neurons in culture and in mouse hippocampus responded to NMDA with a rapid increase in superoxide production, followed by neuronal death. These events were blocked by the NADPH oxidase inhibitor apocynin and in neurons lacking the p47phox subunit, which is required for NADPH oxidase assembly. Superoxide production was also blocked by inhibiting the hexose monophosphate shunt, which regenerates the NADPH substrate, and by inhibiting protein kinase C zeta, which activates the NADPH oxidase complex. These findings identify NADPH ! oxidase as the primary source of NMDA-induced superoxide production. - Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin
- Nat Neurosci 12(7):864-871 (2009)
Selected vulnerability of neurons in Huntington's disease suggests that alterations occur in a cellular process that is particularly critical for neuronal function. Supporting this idea, pathogenic Htt (polyQ-Htt) inhibits fast axonal transport (FAT) in various cellular and animal models of Huntington's disease (mouse and squid), but the molecular basis of this effect remains unknown. We found that polyQ-Htt inhibited FAT through a mechanism involving activation of axonal cJun N-terminal kinase (JNK). Accordingly, we observed increased activation of JNK in vivo in cellular and mouse models of Huntington's disease. Additional experiments indicated that the effects of polyQ-Htt on FAT were mediated by neuron-specific JNK3 and not by ubiquitously expressed JNK1, providing a molecular basis for neuron-specific pathology in Huntington's disease. Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced! kinesin-1 binding to microtubules. These data identify JNK3 as a critical mediator of polyQ-Htt toxicity and provide a molecular basis for polyQ-Htt–induced inhibition of FAT. - Adenosine A2A receptor mediates microglial process retraction
- Nat Neurosci 12(7):872-878 (2009)
Cell motility drives many biological processes, including immune responses and embryonic development. In the brain, microglia are immune cells that survey and scavenge brain tissue using elaborate and motile cell processes. The motility of these processes is guided by the local release of chemoattractants. However, most microglial processes retract during prolonged brain injury or disease. This hallmark of brain inflammation remains unexplained. We identified a molecular pathway in mouse and human microglia that converted ATP-driven process extension into process retraction during inflammation. This chemotactic reversal was driven by upregulation of the A2A adenosine receptor coincident with P2Y12 downregulation. Thus, A2A receptor stimulation by adenosine, a breakdown product of extracellular ATP, caused activated microglia to assume their characteristic amoeboid morphology during brain inflammation. Our results indicate that purine nucleotides provide an opportunity ! for context-dependent shifts in receptor signaling. Thus, we reveal an unexpected chemotactic switch that generates a hallmark feature of CNS inflammation. - Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation
- Nat Neurosci 12(7):879-887 (2009)
The insertion of AMPA receptors (AMPARs) into the plasma membrane is an important step in the synaptic delivery of AMPARs during the expression of synaptic plasticity. However, the molecular mechanisms regulating AMPAR insertion remain elusive. By directly visualizing individual insertion events of the AMPAR subunit GluR1 in rodents, we found that the protein 4.1N was required for activity-dependent GluR1 insertion. Protein kinase C (PKC) phosphorylation of the serine 816 (S816) and S818 residues of GluR1 enhanced 4.1N binding to GluR1 and facilitated GluR1 insertion. In addition, palmitoylation of GluR1 C811 residue modulated PKC phosphorylation and GluR1 insertion. Finally, disrupting 4.1N-dependent GluR1 insertion decreased surface expression of GluR1 and the expression of long-term potentiation. Our study uncovers a previously unknown mechanism that governs activity-dependent GluR1 trafficking, reveals an interaction between AMPAR palmitoylation and phosphorylation! , and underscores the functional importance of 4.1N in AMPAR trafficking and synaptic plasticity. - Roles of stargazin and phosphorylation in the control of AMPA receptor subcellular distribution
- Nat Neurosci 12(7):888-896 (2009)
Understanding how the subcellular fate of newly synthesized AMPA receptors (AMPARs) is controlled is important for elucidating the mechanisms of neuronal function. We examined the effect of increased synthesis of AMPAR subunits on their subcellular distribution in rat hippocampal neurons. Virally expressed AMPAR subunits (GluR1 or GluR2) accumulated in cell bodies and replaced endogenous dendritic AMPAR with little effect on total dendritic amounts and caused no change in synaptic transmission. Coexpressing stargazin (STG) or mimicking GluR1 phosphorylation enhanced dendritic GluR1 levels by protecting GluR1 from lysosomal degradation. However, STG interaction or GluR1 phosphorylation did not increase surface or synaptic GluR1 levels. Unlike GluR1, STG did not protect GluR2 from lysosomal degradation or increase dendritic GluR2 levels. In general, AMPAR surface levels, and not intracellular amounts, correlated strongly with synaptic levels. Our results suggest that AMP! AR surface expression, but not its intracellular production or accumulation, is critical for regulating synaptic transmission. - Brain extracellular matrix affects AMPA receptor lateral mobility and short-term synaptic plasticity
- Nat Neurosci 12(7):897-904 (2009)
Many synapses in the mature CNS are wrapped by a dense extracellular matrix (ECM). Using single-particle tracking and fluorescence recovery after photobleaching, we found that this net-like ECM formed surface compartments on rat primary neurons that acted as lateral diffusion barriers for AMPA-type glutamate receptors. Enzymatic removal of the ECM increased extrasynaptic receptor diffusion and the exchange of synaptic AMPA receptors. Whole-cell patch-clamp recording revealed an increased paired-pulse ratio as a functional consequence of ECM removal. These results suggest that the surface compartments formed by the ECM hinder lateral diffusion of AMPA receptors and may therefore modulate short-term synaptic plasticity. - Cellular and systems mechanisms of memory strength as a constraint on auditory fear reconsolidation
- Nat Neurosci 12(7):905-912 (2009)
Memory reconsolidation has been demonstrated in various tasks and species, suggesting it is a fundamental process. However, there are experimental parameters that can inhibit reconsolidation from occurring (boundary conditions). These conditions and their mechanisms remain poorly defined. Here, we characterize the ability of strong training to inhibit reconsolidation at the behavioral, systems and molecular levels. We demonstrate that strong memories in rats initially are resistant to reconsolidation, but after sufficient time will undergo reconsolidation, suggesting that boundary conditions can be transient. At the systems level, we show that the hippocampus is necessary for inhibiting reconsolidation in the amygdala. At the molecular level, we demonstrate that NR2B NMDA-receptor subunits which are critical for the induction of reconsolidation of auditory memories in the amygdala, are downregulated only under conditions when strong memories do not undergo reconsolidat! ion. This suggests that one molecular mechanism for mediating boundary conditions is through downregulation of reconsolidation induction mechanisms. - Awake replay of remote experiences in the hippocampus
- Nat Neurosci 12(7):913-918 (2009)
Hippocampal replay is thought to be essential for the consolidation of event memories in hippocampal-neocortical networks. Replay is present during both sleep and waking behavior, but although sleep replay involves the reactivation of stored representations in the absence of specific sensory inputs, awake replay is thought to depend on sensory input from the current environment. Here, we show that stored representations are reactivated during both waking and sleep replay. We found frequent awake replay of sequences of rat hippocampal place cells from a previous experience. This spatially remote replay was as common as local replay of the current environment and was more robust when the rat had recently been in motion than during extended periods of quiescence. Our results indicate that the hippocampus consistently replays past experiences during brief pauses in waking behavior, suggesting a role for waking replay in memory consolidation and retrieval. - Replay of rule-learning related neural patterns in the prefrontal cortex during sleep
- Nat Neurosci 12(7):919-926 (2009)
Slow-wave sleep (SWS) is important for memory consolidation. During sleep, neural patterns reflecting previously acquired information are replayed. One possible reason for this is that such replay exchanges information between hippocampus and neocortex, supporting consolidation. We recorded neuron ensembles in the rat medial prefrontal cortex (mPFC) to study memory trace reactivation during SWS following learning and execution of cross-modal strategy shifts. In general, reactivation of learning-related patterns occurred in distinct, highly synchronized transient bouts, mostly simultaneous with hippocampal sharp wave/ripple complexes (SPWRs), when hippocampal ensemble reactivation and cortico-hippocampal interaction is enhanced. During sleep following learning of a new rule, mPFC neural patterns that appeared during response selection replayed prominently, coincident with hippocampal SPWRs. This was learning dependent, as the patterns appeared only after rule acquisitio! n. Therefore, learning, or the resulting reliable reward, influenced which patterns were most strongly encoded and successively reactivated in the hippocampal/prefrontal network. - Adult birdsong is actively maintained by error correction
- Nat Neurosci 12(7):927-931 (2009)
Humans learn to speak by a process of vocal imitation that requires the availability of auditory feedback. Similarly, young birds rely on auditory feedback when learning to imitate the songs of adult birds, providing one of the few examples of nonhuman vocal learning. However, although humans continue to use auditory feedback to correct vocal errors in adulthood, the mechanisms underlying the stability of adult birdsong are unknown. We found that, similar to human speech, adult birdsong is maintained by error correction. We perturbed the pitch (fundamental frequency) of auditory feedback in adult Bengalese finches using custom-designed headphones. Birds compensated for the imposed auditory error by adjusting the pitch of song. When the perturbation was removed, pitch returned to baseline. Our results indicate that adult birds correct vocal errors by comparing auditory feedback to a sensory target and suggest that lifelong error correction is a general principle of lear! ned vocal behavior. - Odor quality coding and categorization in human posterior piriform cortex
- Nat Neurosci 12(7):932-938 (2009)
Efficient recognition of odorous objects universally shapes animal behavior and is crucial for survival. To distinguish kin from nonkin, mate from nonmate and food from nonfood, organisms must be able to create meaningful perceptual representations of odor qualities and categories. It is currently unknown where and in what form the brain encodes information about odor quality. By combining functional magnetic resonance imaging (fMRI) with multivariate (pattern-based) techniques, we found that spatially distributed ensemble activity in human posterior piriform cortex (PPC) coincides with perceptual ratings of odor quality, such that odorants with more (or less) similar fMRI patterns were perceived as more (or less) alike. We did not observe these effects in anterior piriform cortex, amygdala or orbitofrontal cortex, indicating that ensemble coding of odor categorical perception is regionally specific for PPC. These findings substantiate theoretical models emphasizing th! e importance of distributed piriform templates for the perceptual reconstruction of odor object quality. - Motivation and cognitive control in the human prefrontal cortex
- Nat Neurosci 12(7):939-945 (2009)
The prefrontal cortex (PFC) subserves cognitive control, that is, the ability to select thoughts or actions in relation to internal goals. Little is known, however, about how the PFC combines motivation and the selection processes underlying cognitive control. We used functional magnetic resonance imaging in humans and found that the medial and lateral PFC have a parallel hierarchical organization from posterior to anterior regions for motivating and selecting behaviors, respectively. Moreover, using functional connectivity analyses, we found that functional interactions in this parallel system from medial to lateral PFC regions convey motivational incentives on the basis of rewards/penalties regulating the differential engagement of lateral PFC regions in top-down selection. Our results indicate that motivation is a dissociable function, reveal how the PFC integrates motivation and cognitive control in the service of decision-making, and have major implications for cu! rrent theories of prefrontal executive function. - Twin-spot MARCM to reveal the developmental origin and identity of neurons
- Nat Neurosci 12(7):947-953 (2009)
A comprehensive understanding of the brain requires the analysis of individual neurons. We used twin-spot mosaic analysis with repressible cell markers (twin-spot MARCM) to trace cell lineages at high resolution by independently labeling paired sister clones. We determined patterns of neurogenesis and the influences of lineage on neuron-type specification. Notably, neural progenitors were able to yield intermediate precursors that create one, two or more neurons. Furthermore, neurons acquired stereotyped projections according to their temporal position in various brain sublineages. Twin-spot MARCM also permitted birth dating of mutant clones, enabling us to detect a single temporal fate that required chinmo in a sublineage of six Drosophila central complex neurons. In sum, twin-spot MARCM can reveal the developmental origins of neurons and the mechanisms that underlie cell fate.
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