Hot off the presses! Oct 01 Nat Neurosci

The Oct 01 issue of the Nat Neurosci is now up on Pubget (About Nat Neurosci): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Ensuring data integrity
  - Nat Neurosci 12(10):1205 (2009)
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• A neurocomputational jeremiad
  - Nat Neurosci 12(10):1207 (2009)
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• A night vision neuron gets a day job
  - Nat Neurosci 12(10):1209-1211 (2009)
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• Regional control of cortical lamination
  - Nat Neurosci 12(10):1211-1212 (2009)
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• Calcium: an insignificant thing
  - Nat Neurosci 12(10):1213-1214 (2009)
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• TR(I)Pping towards treatment for ischemia
  - Nat Neurosci 12(10):1215-1216 (2009)
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• Six degrees of separation: the amygdala regulates social behavior and perception
  - Nat Neurosci 12(10):1217-1218 (2009)
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• The timing of external input controls the sign of plasticity at local synapses
  - Nat Neurosci 12(10):1219-1221 (2009)
  The method by which local networks in the brain store information from extrinsic afferent inputs is not well understood. We found that the timing of afferent input can bidirectionally control the sign of spike timing–dependent plasticity at local synapses in rat hippocampus. This mechanism provides a means by which temporal information in external input can be encoded in the local matrix of synaptic weights.
• Selective suppression of hippocampal ripples impairs spatial memory
  - Nat Neurosci 12(10):1222-1223 (2009)
  Sharp wave–ripple (SPW-R) complexes in the hippocampus-entorhinal cortex are believed to be important for transferring labile memories from the hippocampus to the neocortex for long-term storage. We found that selective elimination of SPW-Rs during post-training consolidation periods resulted in performance impairment in rats trained on a hippocampus-dependent spatial memory task. Our results provide evidence for a prominent role of hippocampal SPW-Rs in memory consolidation.
• Intact rapid detection of fearful faces in the absence of the amygdala
  - Nat Neurosci 12(10):1224-1225 (2009)
  The amygdala is thought to process fear-related stimuli rapidly and nonconsciously. We found that an individual with complete bilateral amygdala lesions, who cannot recognize fear from faces, nonetheless showed normal rapid detection and nonconscious processing of those same fearful faces. We conclude that the amygdala is not essential for early stages of fear processing but, instead, modulates recognition and social judgment.
• Personal space regulation by the human amygdala
  - Nat Neurosci 12(10):1226-1227 (2009)
  The amygdala plays key roles in emotion and social cognition, but how this translates to face-to-face interactions involving real people remains unknown. We found that an individual with complete amygdala lesions lacked any sense of personal space. Furthermore, healthy individuals showed amygdala activation upon close personal proximity. The amygdala may be required to trigger the strong emotional reactions normally following personal space violations, thus regulating interpersonal distance in humans.
• AP2 regulates basal progenitor fate in a region- and layer-specific manner in the developing cortex
  - Nat Neurosci 12(10):1229-1237 (2009)
  An important feature of the cerebral cortex is its layered organization, which is modulated in an area-specific manner. We found that the transcription factor AP2 regulates laminar fate in a region-specific manner. Deletion of AP2 (also known as Tcfap2c) during development resulted in a specific reduction of upper layer neurons in the occipital cortex, leading to impaired function and enhanced plasticity of the adult visual cortex. AP2 functions in apical progenitors, and its absence resulted in mis-specification of basal progenitors in the occipital cortex at the time at which upper layer neurons were generated. AP2 directly regulated the basal progenitor fate determinants Math3 (also known as Neurod4) and Tbr2, and its overexpression promoted the generation of layer II/III neurons in a time- and region-specific manner. Thus, AP2 acts as a regulator of basal progenitor fate, linking regional and laminar specification in the mouse developing cerebral cortex.
• SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development
  Azim E Jabaudon D Fame RM Macklis JD - Nat Neurosci 12(10):1238-1247 (2009)
  The neuronal diversity of the CNS emerges largely from controlled spatial and temporal segregation of cell type-specific molecular regulators. We found that the transcription factor SOX6 controls the molecular segregation of dorsal (pallial) from ventral (subpallial) telencephalic progenitors and the differentiation of cortical interneurons, regulating forebrain progenitor and interneuron heterogeneity. During corticogenesis in mice, SOX6 and SOX5 were largely mutually exclusively expressed in pallial and subpallial progenitors, respectively, and remained mutually exclusive in a reverse pattern in postmitotic neuronal progeny. Loss of SOX6 from pallial progenitors caused their inappropriate expression of normally subpallium-restricted developmental controls, conferring mixed dorsal-ventral identity. In postmitotic cortical interneurons, loss of SOX6 disrupted the differentiation and diversity of cortical interneuron subtypes, analogous to SOX5 control over cortical pro! jection neuron development. These data indicate that SOX6 is a central regulator of both progenitor and cortical interneuron diversity during neocortical development.
• Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh
  - Nat Neurosci 12(10):1248-1256 (2009)
  Neural stem cells (NSCs) are controlled by diffusible factors. The transcription factor Sox2 is expressed by NSCs and Sox2 mutations in humans cause defects in the brain and, in particular, in the hippocampus. We deleted Sox2 in the mouse embryonic brain. At birth, the mice showed minor brain defects; shortly afterwards, however, NSCs and neurogenesis were completely lost in the hippocampus, leading to dentate gyrus hypoplasia. Deletion of Sox2 in adult mice also caused hippocampal neurogenesis loss. The hippocampal developmental defect resembles that caused by late sonic hedgehog (Shh) loss. In mutant mice, Shh and Wnt3a were absent from the hippocampal primordium. A SHH pharmacological agonist partially rescued the hippocampal defect. Chromatin immunoprecipitation identified Shh as a Sox2 target. Sox2-deleted NSCs did not express Shh in vitro and were rapidly lost. Their replication was partially rescued by the addition of SHH and was almost fully rescued by conditio! ned medium from normal cells. Thus, NSCs control their status, at least partly, through Sox2-dependent autocrine mechanisms.
• Presynaptic CaV2 calcium channel traffic requires CALF-1 and the 2 subunit UNC-36
  - Nat Neurosci 12(10):1257-1265 (2009)
  Presynaptic voltage-gated calcium channels provide calcium for synaptic vesicle exocytosis. We show here that a green fluorescent protein–tagged 1 subunit of the Caenorhabditis elegans CaV2 channel, UNC-2, is localized to presynaptic active zones of sensory and motor neurons. Synaptic localization of CaV2 requires the 2 subunit UNC-36 and CALF-1 (Calcium Channel Localization Factor-1), a neuronal transmembrane protein that localizes to the endoplasmic reticulum. In calf-1 mutants, UNC-2 is retained in the endoplasmic reticulum, but other active-zone components and synaptic vesicles are delivered to synapses. Acute induction of calf-1 mobilizes preexisting UNC-2 for delivery to synapses, consistent with a direct trafficking role. The 2 subunit UNC-36 is likewise required for exit of UNC-2 from endoplasmic reticulum but has additional functions. Genetic and cell biological interactions suggest that CALF-1 couples intracellular traffic to functional maturation of CaV2 p! resynaptic calcium channels.
• EFHC1 interacts with microtubules to regulate cell division and cortical development
  - Nat Neurosci 12(10):1266-1274 (2009)
  Mutations in the EFHC1 gene are linked to juvenile myoclonic epilepsy (JME), one of the most frequent forms of idiopathic generalized epilepsies. JME is associated with subtle alterations of cortical and subcortical architecture, but the underlying pathological mechanism remains unknown. We found that EFHC1 is a microtubule-associated protein involved in the regulation of cell division. In vitro, EFHC1 loss of function disrupted mitotic spindle organization, impaired M phase progression, induced microtubule bundling and increased apoptosis. EFHC1 impairment in the rat developing neocortex by ex vivo and in utero electroporation caused a marked disruption of radial migration. We found that this effect was a result of cortical progenitors failing to exit the cell cycle and defects in the radial glia scaffold organization and in the locomotion of postmitotic neurons. Therefore, we propose that EFHC1 is a regulator of cell division and neuronal migration during cortical de! velopment and that disruption of its functions leads to JME.
• Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines
  - Nat Neurosci 12(10):1275-1284 (2009)
  Dynamic remodeling of spiny synapses is crucial for cortical circuit development, refinement and plasticity, whereas abnormal morphogenesis is associated with neuropsychiatric disorders. We found that activation of Epac2, a PKA-independent cAMP target and Rap guanine-nucleotide exchange factor (GEF), in cultured rat cortical neurons induced spine shrinkage, increased spine motility, removed synaptic GluR2/3-containing AMPA receptors and depressed excitatory transmission, whereas its inhibition promoted spine enlargement and stabilization. Epac2 was required for dopamine D1-like receptor–dependent spine shrinkage and GluR2 removal from spines. Epac2 interaction with neuroligin promoted its membrane recruitment and enhanced its GEF activity. Rare missense mutations in the EPAC2 (also known as RAPGEF4) gene, previously found in individuals with autism, affected basal and neuroligin-stimulated GEF activity, dendritic Rap signaling, synaptic protein distribution and spine! morphology. Thus, we identify a previously unknown mechanism that promotes dynamic remodeling and depression of spiny synapses, disruption of which may contribute to some aspects of disease.
• Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport
  - Nat Neurosci 12(10):1285-1292 (2009)
  Astrocytes are critical participants in synapse development and function, but their role in synaptic plasticity is unclear. Eph receptors and their ephrin ligands have been suggested to regulate neuron-glia interactions, and EphA4-mediated ephrin reverse signaling is required for synaptic plasticity in the hippocampus. Here we show that long-term potentiation (LTP) at the CA3–CA1 synapse is modulated by EphA4 in the postsynaptic CA1 cell and by ephrin-A3, a ligand of EphA4 that is found in astrocytes. Lack of EphA4 increased the abundance of glial glutamate transporters, and ephrin-A3 modulated transporter currents in astrocytes. Pharmacological inhibition of glial glutamate transporters rescued the LTP defects in EphA4 (Epha4) and ephrin-A3 (Efna3) mutant mice. Transgenic overexpression of ephrin-A3 in astrocytes reduces glutamate transporter levels and produces focal dendritic swellings possibly caused by glutamate excitotoxicity. These results suggest that EphA4/e! phrin-A3 signaling is a critical mechanism for astrocytes to regulate synaptic function and plasticity.
• Nicotine activates the chemosensory cation channel TRPA1
  - Nat Neurosci 12(10):1293-1299 (2009)
  Topical application of nicotine, as used in nicotine replacement therapies, causes irritation of the mucosa and skin. This reaction has been attributed to activation of nicotinic acetylcholine receptors (nAChRs) in chemosensory neurons. In contrast with this view, we found that the chemosensory cation channel transient receptor potential A1 (TRPA1) is crucially involved in nicotine-induced irritation. We found that micromolar concentrations of nicotine activated heterologously expressed mouse and human TRPA1. Nicotine acted in a membrane-delimited manner, stabilizing the open state(s) and destabilizing the closed state(s) of the channel. In the presence of the general nAChR blocker hexamethonium, nociceptive neurons showed nicotine-induced responses that were strongly reduced in TRPA1-deficient mice. Finally, TRPA1 mediated the mouse airway constriction reflex to nasal instillation of nicotine. The identification of TRPA1 as a nicotine target suggests that existing mod! els of nicotine-induced irritation should be revised and may facilitate the development of smoking cessation therapies with less adverse effects.
• Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia
  - Nat Neurosci 12(10):1300-1307 (2009)
  Cardiac arrest victims may experience transient brain hypoperfusion leading to delayed death of hippocampal CA1 neurons and cognitive impairment. We prevented this in adult rats by inhibiting the expression of transient receptor potential melastatin 7 (TRPM7), a transient receptor potential channel that is essential for embryonic development, is necessary for cell survival and trace ion homeostasis in vitro, and whose global deletion in mice is lethal. TRPM7 was suppressed in CA1 neurons by intrahippocampal injections of viral vectors bearing shRNA specific for TRPM7. This had no ill effect on animal survival, neuronal and dendritic morphology, neuronal excitability, or synaptic plasticity, as exemplified by robust long-term potentiation (LTP). However, TRPM7 suppression made neurons resistant to ischemic death after brain ischemia and preserved neuronal morphology and function. Also, it prevented ischemia-induced deficits in LTP and preserved performance in fear-assoc! iated and spatial-navigational memory tasks. Thus, regional suppression of TRPM7 is feasible, well tolerated and inhibits delayed neuronal death in vivo.
• Approach sensitivity in the retina processed by a multifunctional neural circuit
  Münch TA da Silveira RA Siegert S Viney TJ Awatramani GB Roska B - Nat Neurosci 12(10):1308-1316 (2009)
  The detection of approaching objects, such as looming predators, is necessary for survival. Which neurons and circuits mediate this function? We combined genetic labeling of cell types, two-photon microscopy, electrophysiology and theoretical modeling to address this question. We identify an approach-sensitive ganglion cell type in the mouse retina, resolve elements of its afferent neural circuit, and describe how these confer approach sensitivity on the ganglion cell. The circuit's essential building block is a rapid inhibitory pathway: it selectively suppresses responses to non-approaching objects. This rapid inhibitory pathway, which includes AII amacrine cells connected to bipolar cells through electrical synapses, was previously described in the context of night-time vision. In the daytime conditions of our experiments, the same pathway conveys signals in the reverse direction. The dual use of a neural pathway in different physiological conditions illustrates the ! efficiency with which several functions can be accommodated in a single circuit.
• Coding of stimulus sequences by population responses in visual cortex
  - Nat Neurosci 12(10):1317-1324 (2009)
  Neuronal populations in sensory cortex represent time-changing sensory input through a spatiotemporal code. What are the rules that govern this code? We measured membrane potentials and spikes from neuronal populations in cat visual cortex (V1) using voltage-sensitive dyes and electrode arrays. We first characterized the population response to a single orientation. As response amplitude grew, the population tuning width remained constant for membrane potential responses and became progressively sharper for spike responses. We then asked how these single-orientation responses combine to code for successive orientations. We found that they combined through simple linear summation. Linearity, however, was violated after stimulus offset, when responses exhibited an unexplained persistence. As a result of linearity, the interactions between responses to successive stimuli were minimal. Our results indicate that higher cortical areas may reconstruct the stimulus sequence fro! m V1 population responses through a simple instantaneous decoder. Therefore, spatial and temporal codes in area V1 operate largely independently.
• Fragmentation of grid cell maps in a multicompartment environment
  - Nat Neurosci 12(10):1325-1332 (2009)
  To determine whether entorhinal spatial representations are continuous or fragmented, we recorded neural activity in grid cells while rats ran through a stack of interconnected, zig-zagged compartments of equal shape and orientation (a hairpin maze). The distribution of spatial firing fields was markedly similar across all compartments in which running occurred in the same direction, implying that the grid representation was fragmented into repeating submaps. Activity at neighboring positions was least correlated at the transitions between different arms, indicating that the map split regularly at the turning points. We saw similar discontinuities among place cells in the hippocampus. No fragmentation was observed when the rats followed similar trajectories in the absence of internal walls, implying that stereotypic behavior alone cannot explain the compartmentalization. These results indicate that spatial environments are represented in entorhinal cortex and hippocamp! us as a mosaic of discrete submaps that correspond to the geometric structure of the space.
• Transformation of nonfunctional spinal circuits into functional states after the loss of brain input
  - Nat Neurosci 12(10):1333-1342 (2009)
  After complete spinal cord transections that removed all supraspinal inputs in adult rats, combinations of serotonergic agonists and epidural electrical stimulation were able to acutely transform spinal networks from nonfunctional to highly functional and adaptive states as early as 1 week after injury. Using kinematics, physiological and anatomical analyses, we found that these interventions could recruit specific populations of spinal circuits, refine their control via sensory input and functionally remodel these locomotor pathways when combined with training. The emergence of these new functional states enabled full weight-bearing treadmill locomotion in paralyzed rats that was almost indistinguishable from voluntary stepping. We propose that, in the absence of supraspinal input, spinal locomotion can emerge from a combination of central pattern-generating capability and the ability of these spinal circuits to use sensory afferent input to control stepping. These fi! ndings provide a strategy by which individuals with spinal cord injuries could regain substantial levels of motor control.
• Classical conditioning in the vegetative and minimally conscious state
  - Nat Neurosci 12(10):1343-1349 (2009)
  Pavlovian trace conditioning depends on the temporal gap between the conditioned and unconditioned stimuli. It requires, in mammals, functional medial temporal lobe structures and, in humans, explicit knowledge of the temporal contingency. It is therefore considered to be a plausible objective test to assess awareness without relying on explicit reports. We found that individuals with disorders of consciousness (DOCs), despite being unable to report awareness explicitly, were able to learn this procedure. Learning was specific and showed an anticipatory electromyographic response to the aversive conditioning stimulus, which was substantially stronger than to the control stimulus and was augmented as the aversive stimulus approached. The amount of learning correlated with the degree of cortical atrophy and was a good indicator of recovery. None of these effects were observed in control subjects under the effect of anesthesia (propofol). Our results suggest that individu! als with DOCs might have partially preserved conscious processing, which cannot be mediated by explicit reports and is not detected by behavioral assessment.

Hot off the presses! Jul 01 Nat Neurosci

The Jul 01 issue of the Nat Neurosci is now up on Pubget (About Nat Neurosci): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Mining chemistry for psychiatry
  - Nat Neurosci 12(7):809 (2009)
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• Working on a Dream
  - Nat Neurosci 12(7):811 (2009)
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• A noseful of objects
  - Nat Neurosci 12(7):813-814 (2009)
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• Genetics meets epigenetics: HDACs and Wnt signaling in myelin development and regeneration
  - Nat Neurosci 12(7):815-817 (2009)
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• Stop and go GABA
  - Nat Neurosci 12(7):817-818 (2009)
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• Reactive oxygen species are NOXious for neurons
  - Nat Neurosci 12(7):819-820 (2009)
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• Prefrontal cortex and cognitive control: motivating functional hierarchies
  - Nat Neurosci 12(7):821-822 (2009)
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• 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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Latest Articles Include:

• Changes in house rules
  - Nat Neurosci 12(8):955 (2009)
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• PDLIM5 is not a neuronal CaV2.2 adaptor protein
  - Nat Neurosci 12(8):957-958 (2009)
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• Reply to "PDLIM5 is not a neuronal CaV2.2 adaptor protein"
  - Nat Neurosci 12(8):958 (2009)
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• Who let the spikes out?
  - Nat Neurosci 12(8):959-960 (2009)
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• Practice makes perfect, even for breathing
  - Nat Neurosci 12(8):961-963 (2009)
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• Should I stay or should I go: genetic bases for uncertainty-driven exploration
  - Nat Neurosci 12(8):963-965 (2009)
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• Inactivating the activated: identifying functions of specific neural networks
  - Nat Neurosci 12(8):965-966 (2009)
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• Resolving single cone inputs to visual receptive fields
  - Nat Neurosci 12(8):967-969 (2009)
  With the current techniques available for mapping receptive fields, it is impossible to resolve the contribution of single cone photoreceptors to the response of central visual neurons. Using adaptive optics to correct for ocular aberrations, we delivered micron-scale spots of light to the receptive field centers of neurons in the macaque lateral geniculate nucleus. Parvocellular LGN neurons mapped in this manner responded with high reliability to stimulation of single cones.
• Representation of internal models of action in the autistic brain
  - Nat Neurosci 12(8):970-972 (2009)
  Children with autism spectrum disorder (ASD) have deficits in motor control, imitation and social function. Does a dysfunction in the neural basis of representing internal models of action contribute to these problems? We measured patterns of generalization as children learned to control a novel tool and found that the autistic brain built a stronger than normal association between self-generated motor commands and proprioceptive feedback; furthermore, the greater the reliance on proprioception, the greater the child's impairments in social function and imitation.
• The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1
  - Nat Neurosci 12(8):973-980 (2009)
  Defective responses to DNA single strand breaks underlie various neurodegenerative diseases. However, the exact role of this repair pathway during the development and maintenance of the nervous system is unclear. Using murine neural-specific inactivation of Xrcc1, a factor that is critical for the repair of DNA single strand breaks, we found a profound neuropathology that is characterized by the loss of cerebellar interneurons. This cell loss was linked to p53-dependent cell cycle arrest and occurred as interneuron progenitors commenced differentiation. Loss of Xrcc1 also led to the persistence of DNA strand breaks throughout the nervous system and abnormal hippocampal function. Collectively, these data detail the in vivo link between DNA single strand break repair and neurogenesis and highlight the diverse consequences of specific types of genotoxic stress in the nervous system.
• A trophic role for Wnt-Ror kinase signaling during developmental pruning in Caenorhabditis elegans
  - Nat Neurosci 12(8):981-987 (2009)
  The molecular mechanism by which neurites are selected for elimination or incorporation into the mature circuit during developmental pruning remains unknown. The trophic theory postulates that local cues provided by target or surrounding cells act to inhibit neurite elimination. However, no widely conserved factor mediating this trophic function has been identified. We found that the developmental survival of specific neurites in Caenorhabditis elegans largely depends on detection of the morphogen Wnt by the Ror kinase CAM-1, which is a transmembrane tyrosine kinase with a Frizzled domain. Mutations in Wnt genes or in cam-1 enhanced neurite elimination, whereas overexpression of cam-1 inhibited neurite elimination in a Wnt-dependent manner. Moreover, mutations in these genes counteracted the effect of a mutation in mbr-1, which encodes a transcription factor that promotes neurite elimination. These results reveal the trophic role of an atypical Wnt pathway and reinforc! e the classical model of developmental pruning.
• A discrete alcohol pocket involved in GIRK channel activation
  - Nat Neurosci 12(8):988-995 (2009)
  Ethanol modifies neural activity in the brain by modulating ion channels. Ethanol activates G protein–gated inwardly rectifying K+ channels, but the molecular mechanism is not well understood. Here, we used a crystal structure of a mouse inward rectifier containing a bound alcohol and structure-based mutagenesis to probe a putative alcohol-binding pocket located in the cytoplasmic domains of GIRK channels. Substitutions with bulkier side-chains in the alcohol-binding pocket reduced or eliminated activation by alcohols. By contrast, alcohols inhibited constitutively open channels, such as IRK1 or GIRK2 engineered to strongly bind PIP2. Mutations in the hydrophobic alcohol-binding pocket of these channels had no effect on alcohol-dependent inhibition, suggesting an alternate site is involved in inhibition. Comparison of high-resolution structures of inwardly rectifying K+ channels suggests a model for activation of GIRK channels using this hydrophobic alcohol-binding p! ocket. These results provide a tool for developing therapeutic compounds that could mitigate the effects of alcohol.
• Distinct contributions of Nav1.6 and Nav1.2 in action potential initiation and backpropagation
  - Nat Neurosci 12(8):996-1002 (2009)
  The distal end of the axon initial segment (AIS) is the preferred site for action potential initiation in cortical pyramidal neurons because of its high Na+ channel density. However, it is not clear why action potentials are not initiated at the proximal AIS, which has a similarly high Na+ channel density. We found that low-threshold Nav1.6 and high-threshold Nav1.2 channels preferentially accumulate at the distal and proximal AIS, respectively, and have distinct functions in action potential initiation and backpropagation. Patch-clamp recording from the axon cut end of pyramidal neurons in the rat prefrontal cortex revealed a high density of Na+ current and a progressive reduction in the half-activation voltage (up to 14 mV) with increasing distance from the soma at the AIS. Further modeling studies and simultaneous somatic and axonal recordings showed that distal Nav1.6 promotes action potential initiation, whereas proximal Nav1.2 promotes its backpropagation to the ! soma.
• Ca2+ and calmodulin initiate all forms of endocytosis during depolarization at a nerve terminal
  - Nat Neurosci 12(8):1003-1010 (2009)
  Although endocytosis maintains synaptic transmission, how endocytosis is initiated is unclear. We found that calcium influx initiated all forms of endocytosis at a single nerve terminal in rodents, including clathrin-dependent slow endocytosis, bulk endocytosis, rapid endocytosis and endocytosis overshoot (excess endocytosis), with each being evoked with a correspondingly higher calcium threshold. As calcium influx increased, endocytosis gradually switched from very slow endocytosis to slow endocytosis to bulk endocytosis to rapid endocytosis and to endocytosis overshoot. The calcium-induced endocytosis rate increase was a result of the speeding up of membrane invagination and fission. Pharmacological experiments suggested that the calcium sensor mediating these forms of endocytosis is calmodulin. In addition to its role in recycling vesicles, calcium/calmodulin-initiated endocytosis facilitated vesicle mobilization to the readily releasable pool, probably by clearing ! fused vesicle membrane at release sites. Our findings provide a unifying mechanism for the initiation of various forms of endocytosis that are critical in maintaining exocytosis.
• SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway
  - Nat Neurosci 12(8):1011-1019 (2009)
  Synaptic plasticity is dependent on the differential sorting, delivery and retention of neurotransmitter receptors, but the mechanisms underlying these processes are poorly understood. We found that differential sorting of glutamate receptor subtypes began in the endoplasmic reticulum of rat hippocampal neurons. As AMPA receptors (AMPARs) were trafficked to the plasma membrane via the conventional somatic Golgi network, NMDA receptors (NMDARs) were diverted from the somatic endoplasmic reticulum into a specialized endoplasmic reticulum subcompartment that bypasses somatic Golgi, merging instead with dendritic Golgi outposts. This endoplasmic reticulum subcompartment was composed of highly mobile vesicles containing the NMDAR subunits NR1 and NR2B, the microtubule-dependent motor protein KIF17, and the postsynaptic adaptor proteins CASK and SAP97. Our data demonstrate that the retention and trafficking of NMDARs in this endoplasmic reticulum subcompartment requires both! CASK and SAP97. These findings indicate that NMDARs are sorted away from AMPARs via a non-conventional secretory pathway that utilizes dendritic Golgi outposts.
• Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry
  - Nat Neurosci 12(8):1020-1027 (2009)
  Genomic studies demonstrate that, although the majority of the mammalian genome is transcribed, only about 2% of these transcripts are code for proteins. We investigated how the long, polyadenylated Evf2 noncoding RNA regulates transcription of the homeodomain transcription factors DLX5 and DLX6 in the developing mouse forebrain. We found that, in developing ventral forebrain, Evf2 recruited DLX and MECP2 transcription factors to important DNA regulatory elements in the Dlx5/6 intergenic region and controlled Dlx5, Dlx6 and Gad1 expression through trans and cis-acting mechanisms. Evf2 mouse mutants had reduced numbers of GABAergic interneurons in early postnatal hippocampus and dentate gyrus. Although the numbers of GABAergic interneurons and Gad1 RNA levels returned to normal in Evf2 mutant adult hippocampus, reduced synaptic inhibition occurred. These results suggest that noncoding RNA–dependent balanced gene regulation in embryonic brain is critical for proper for! mation of GABA-dependent neuronal circuitry in adult brain.
• Genetic identification of an embryonic parafacial oscillator coupling to the preBötzinger complex
  - Nat Neurosci 12(8):1028-1035 (2009)
  The hindbrain transcription factors Phox2b and Egr2 (also known as Krox20) are linked to the development of the autonomic nervous system and rhombomere-related regulation of breathing, respectively. Mutations in these proteins can lead to abnormal breathing behavior as a result of an alteration in an unidentified neuronal system. We characterized a bilateral embryonic parafacial (e-pF) population of rhythmically bursting neurons at embryonic day (E) 14.5 in mice. These cells expressed Phox2b, were derived from Egr2-expressing precursors and their development was dependent on the integrity of the Egr2 gene. Silencing or eliminating the e-pF oscillator, but not the putative inspiratory oscillator (preBötzinger complex, preBötC), led to an abnormally slow rhythm, demonstrating that the e-pF controls the respiratory rhythm. The e-pF oscillator, the only one active at E14.5, entrained and then coupled with the preBötC, which emerged independently at E15.5. These data est! ablish the dual organization of the respiratory rhythm generator at the time of its inception, when it begins to drive fetal breathing.
• Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc
  - Nat Neurosci 12(8):1036-1041 (2009)
  Addictive drugs hijack mechanisms of learning and memory that normally underlie reinforcement of natural rewards and induce synaptic plasticity of glutamatergic transmission in the mesolimbic dopamine (DA) system. In the ventral tegmental area (VTA), a single exposure to cocaine efficiently triggers NMDA receptor–dependent synaptic plasticity in DA neurons, whereas plasticity in the nucleus accumbens (NAc) occurs only after repeated injections. Whether these two forms of plasticity are independent or hierarchically organized remains unknown. We combined ex vivo electrophysiology in acute brain slices with behavioral assays modeling drug relapse in mice and found that the duration of the cocaine-evoked synaptic plasticity in the VTA is gated by mGluR1. Overriding mGluR1 in vivo made the potentiation in the VTA persistent. This led to synaptic plasticity in the NAc, which contributes to cocaine-seeking behavior after protracted withdrawal. Impaired mGluR1 function in v! ulnerable individuals could represent a first step in the recruitment of the neuronal network that underlies drug addiction.
• Synaptic inhibition of Purkinje cells mediates consolidation of vestibulo-cerebellar motor learning
  - Nat Neurosci 12(8):1042-1049 (2009)
  Although feedforward inhibition onto Purkinje cells was first documented 40 years ago, we understand little of how inhibitory interneurons contribute to cerebellar function in behaving animals. Using a mouse line (PC-2) in which GABAA receptor–mediated synaptic inhibition is selectively removed from Purkinje cells, we examined how feedforward inhibition from molecular layer interneurons regulates adaptation of the vestibulo-ocular reflex. Although impairment of baseline motor performance was relatively mild, the ability to adapt the phase of the vestibulo-ocular reflex and to consolidate gain adaptations was strongly compromised. Purkinje cells showed abnormal patterns of simple spikes, both during and in the absence of evoked compensatory eye movements. On the basis of modeling our experimental data, we propose that feedforward inhibition, by controlling the fine-scale patterns of Purkinje cell activity, enables the induction of plasticity in neurons of the cerebell! ar and vestibular nuclei.
• Disparity- and velocity-based signals for three-dimensional motion perception in human MT+
  - Nat Neurosci 12(8):1050-1055 (2009)
  How does the primate visual system encode three-dimensional motion? The macaque middle temporal area (MT) and the human MT complex (MT+) have well-established sensitivity to two-dimensional frontoparallel motion and static disparity. However, evidence for sensitivity to three-dimensional motion has remained elusive. We found that human MT+ encodes two binocular cues to three-dimensional motion: changing disparities over time and interocular comparisons of retinal velocities. By varying important properties of moving dot displays, we distinguished these three-dimensional motion signals from their constituents, instantaneous binocular disparity and monocular retinal motion. An adaptation experiment confirmed direction selectivity for three-dimensional motion. Our results indicate that MT+ carries critical binocular signals for three-dimensional motion processing, revealing an important and previously overlooked role for this well-studied brain area.
• Sensory transformations and the use of multiple reference frames for reach planning
  - Nat Neurosci 12(8):1056-1061 (2009)
  The sensory signals that drive movement planning arrive in a variety of 'reference frames', and integrating or comparing them requires sensory transformations. We propose a model in which the statistical properties of sensory signals and their transformations determine how these signals are used. This model incorporates the patterns of gaze-dependent errors that we found in our human psychophysics experiment when the sensory signals available for reach planning were varied. These results challenge the widely held ideas that error patterns directly reflect the reference frame of the underlying neural representation and that it is preferable to use a single common reference frame for movement planning. We found that gaze-dependent error patterns, often cited as evidence for retinotopic reach planning, can be explained by a transformation bias and are not exclusively linked to retinotopic representations. Furthermore, the presence of multiple reference frames allows for o! ptimal use of available sensory information and explains task-dependent reweighting of sensory signals.
• Prefrontal and striatal dopaminergic genes predict individual differences in exploration and exploitation
  - Nat Neurosci 12(8):1062-1068 (2009)
  The basal ganglia support learning to exploit decisions that have yielded positive outcomes in the past. In contrast, limited evidence implicates the prefrontal cortex in the process of making strategic exploratory decisions when the magnitude of potential outcomes is unknown. Here we examine neurogenetic contributions to individual differences in these distinct aspects of motivated human behavior, using a temporal decision-making task and computational analysis. We show that two genes controlling striatal dopamine function, DARPP-32 (also called PPP1R1B) and DRD2, are associated with exploitative learning to adjust response times incrementally as a function of positive and negative decision outcomes. In contrast, a gene primarily controlling prefrontal dopamine function (COMT) is associated with a particular type of 'directed exploration', in which exploratory decisions are made in proportion to Bayesian uncertainty about whether other choices might produce outcomes t! hat are better than the status quo. Quantitative model fits reveal that genetic factors modulate independent parameters of a reinforcement learning system.
• Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization
  - Nat Neurosci 12(8):1069-1073 (2009)
  Learned associations between effects of abused drugs and the drug administration environment are important in drug addiction. Histochemical and electrophysiological studies suggest that these associations are encoded in sparsely distributed nucleus accumbens neurons that are selectively activated by drugs and drug-associated cues. Although correlations have been observed between nucleus accumbens neuronal activity and responsivity to drugs and drug cues, no technique exists for selectively manipulating these activated neurons and establishing their causal role in behavioral effects of drugs and drug cues. Here we describe a new approach, which we term the 'Daun02 inactivation method', that selectively inactivates a minority of neurons previously activated by cocaine in an environment repeatedly paired with cocaine to demonstrate a causal role for these activated neurons in context-specific cocaine-induced psychomotor sensitization in rats. This method provides a new to! ol for studying the causal roles of selectively activated neurons in behavioral effects of drugs and drug cues and in other learned behaviors.