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1.  Multiplexed memories: a view from human cortex 
Nature neuroscience  2013;16(3):257-258.
A study recording directly from the human brain shows that connectivity between the prefrontal cortex, parietal cortex and the medial temporal lobe across different frequency bands underlies successful memory retrieval.
doi:10.1038/nn.3341
PMCID: PMC4090684  PMID: 23434977
2.  Retooling Spare Parts: Gene Duplication And Vertebrate Cognitive Complexity 
Nature neuroscience  2013;16(1):6-8.
Two new studies experimentally demonstrate how ancient genomic duplications of synaptic genes provided the substrate for diversification that ultimately expanded vertebrate cognitive complexity.
doi:10.1038/nn.3292
PMCID: PMC4090687  PMID: 23257927
3.  Convergent cortical innervation of striatal projection neurons 
Nature neuroscience  2013;16(6):665-667.
Anatomical studies have led to the assertion that intratelencephalic (IT) and pyramidal tract (PT) cortical neurons innervate different striatal projection neurons. To test this hypothesis, the responses of mouse striatal neurons to optogenetic activation of IT and PT axons were measured. Contrary to expectation, direct and indirect pathway striatal spiny projection neurons (SPNs) responded to both IT and PT activation, arguing that these cortical networks innervate both striatal projection neurons.
doi:10.1038/nn.3397
PMCID: PMC4085670  PMID: 23666180
4.  Engaging in an auditory task suppresses responses in auditory cortex 
Nature neuroscience  2009;12(5):646-654.
Although systems involved in attentional selection have been studied extensively, much less is known about non-selective systems. To study these preparatory mechanisms, we compared activity in auditory cortex elicited by sounds while rats performed an auditory task (“engaged”) with activity elicited by identical stimuli while subjects were awake but not performing a task (“passive”). Surprisingly, we found that engagement suppressed responses, an effect opposite in sign to that elicited by selective attention. In the auditory thalamus, however, engagement enhanced spontaneous firing rates but did not affect evoked responses. These results demonstrate that in auditory cortex, neural activity cannot be viewed simply as a limited resource allocated in greater measure as the state of the animal passes from somnolent to passively listening to engaged and attentive. Instead the engaged condition possesses a characteristic and distinct neural signature in which sound-evoked responses are paradoxically suppressed.
doi:10.1038/nn.2306
PMCID: PMC4084972  PMID: 19363491
5.  Memory, navigation and theta rhythm in the hippocampal-entorhinal system 
Nature neuroscience  2013;16(2):130-138.
Theories on the functions of the hippocampal system are based largely on two fundamental discoveries: the amnestic consequences of removing the hippocampus and associated structures in the famous patient H.M. and the observation that spiking activity of hippocampal neurons is associated with the spatial position of the rat. In the footsteps of these discoveries, many attempts were made to reconcile these seemingly disparate functions. Here we propose that mechanisms of memory and planning have evolved from mechanisms of navigation in the physical world and hypothesize that the neuronal algorithms underlying navigation in real and mental space are fundamentally the same. We review experimental data in support of this hypothesis and discuss how specific firing patterns and oscillatory dynamics in the entorhinal cortex and hippocampus can support both navigation and memory.
doi:10.1038/nn.3304
PMCID: PMC4079500  PMID: 23354386
6.  Parental olfactory experience influences behavior and neural structure in subsequent generations 
Nature neuroscience  2013;17(1):89-96.
Using olfactory molecular specificity, we examined the inheritance of parental traumatic exposure, a phenomenon that has been frequently observed, but not understood. We subjected F0 mice to odor fear conditioning before conception and found that subsequently conceived F1 and F2 generations had an increased behavioral sensitivity to the F0-conditioned odor, but not to other odors. When an odor (acetophenone) that activates a known odorant receptor (Olfr151) was used to condition F0 mice, the behavioral sensitivity of the F1 and F2 generations to acetophenone was complemented by an enhanced neuroanatomical representation of the Olfr151 pathway. Bisulfite sequencing of sperm DNA from conditioned F0 males and F1 naive offspring revealed CpG hypomethylation in the Olfr151 gene. In addition, in vitro fertilization, F2 inheritance and cross-fostering revealed that these transgenerational effects are inherited via parental gametes. Our findings provide a framework for addressing how environmental information may be inherited transgenerationally at behavioral, neuroanatomical and epigenetic levels.
doi:10.1038/nn.3594
PMCID: PMC3923835  PMID: 24292232
7.  Coronin-1 is a neurotrophin endosomal effector required for developmental competition for survival 
Nature neuroscience  2013;17(1):36-45.
Retrograde communication from axonal targets to neuronal cell bodies is critical for both development and function of the nervous system. Much progress has been made in recent years linking long-distance, retrograde signaling to a signaling endosome, yet the mechanisms governing the trafficking and signaling of these endosomes remain mainly uncharacterized. Here we report that in mouse sympathetic neurons the target-derived NGF-TrkA signaling endosome, upon arrival at the cell body, induces the expression and recruitment of a novel effector protein known as Coronin-1. In the absence of Coronin-1, the NGF-TrkA signaling endosome fuses to lysosomes 6–10 fold faster than when Coronin-1 is intact. We also define a novel Coronin-1-dependent trafficking event where signaling endosomes recycle and re-internalize upon arrival at the cell body. Beyond influencing endosomal trafficking, Coronin-1 is also required for several NGF-TrkA dependent-signaling events including calcium release, calcineurin activation, and CREB phosphorylation. These results establish Coronin-1 as an essential component of a novel feedback loop mediating NGF-TrkA endosome stability, recycling, and signaling as a critical mechanism governing developmental competition for survival.
doi:10.1038/nn.3593
PMCID: PMC3962792  PMID: 24270184
8.  Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving 
Nature neuroscience  2013;17(1):73-80.
Cue-induced cocaine craving is a major cause of relapse in abstinent addicts. In rats, cue-induced craving progressively intensifies (incubates) during withdrawal from extended-access cocaine self-administration. After ~1 month of withdrawal, incubated craving is mediated by Ca2+-permeable AMPARs (CP-AMPARs) that accumulate in the nucleus accumbens (NAc). We found that decreased mGluR1 surface expression in the NAc precedes and enables CP-AMPAR accumulation. Thus, restoring mGluR1 tone by administering repeated injections of an mGluR1 positive allosteric modulator (PAM) prevented CP-AMPAR accumulation and incubation, whereas blocking mGluR1 transmission at even earlier withdrawal times accelerated CP-AMPAR accumulation. In studies conducted after prolonged withdrawal, when CP-AMPAR levels and cue-induced craving are high, we found that systemic administration of an mGluR1 PAM attenuated the expression of incubated craving by reducing CP-AMPAR transmission in the NAc to control levels. These results demonstrate a strategy whereby recovering addicts could use a systemically active compound to protect against cue-induced relapse.
doi:10.1038/nn.3590
PMCID: PMC3971923  PMID: 24270186
9.  Female contact modulates male aggression via a sexually dimorphic GABAergic circuit in Drosophila 
Nature neuroscience  2013;17(1):81-88.
Intraspecific male-male aggression, important for sexual selection, is regulated by environment, experience and internal states through largely undefined molecular and cellular mechanisms. To understand the basic neural pathway underlying the modulation of this innate behavior, we established a behavioral paradigm in Drosophila melanogaster and investigated the relationship between sexual experience and aggression. In the presence of mating partners, adult male flies exhibited elevated levels of aggression, which was largely suppressed by prior exposure to females via a sexually dimorphic neural mechanism. The suppression involved the ability of male flies to detect females by contact chemosensation through the pheromone-sensing ion channel, ppk29, and was mediated by male specific GABAergic neurons acting upon GABA-a receptor RDL in target cells. Silencing or activation of this circuit led to dis-inhibition or elimination of sex-related aggression, respectively. We propose that the GABAergic inhibition represents a critical cellular mechanism that enables prior experience to modulate aggression.
doi:10.1038/nn.3581
PMCID: PMC3995170  PMID: 24241395
10.  The Missense of Smell: Functional Variability in the Human Odorant Receptor Repertoire 
Nature neuroscience  2013;17(1):114-120.
Humans have approximately 400 intact odorant receptors, but each individual has a unique set of genetic variations that lead to variation in olfactory perception. We used a heterologous assay to determine how often genetic polymorphisms in odorant receptors alter receptor function. We identified agonists for 18 odorant receptors and found that 63% of the odorant receptors we examined had polymorphisms that altered in vitro function. On average, two individuals differ functionally at over 30% of their odorant receptor alleles. To show that these in vitro results are relevant to olfactory perception, we verified that variations in OR10G4 genotype explain over 15% of the observed variation in perceived intensity and over 10% of the observed variation in perceived valence for the high affinity in vitro agonist guaiacol, but do not explain phenotypic variation for the lower affinity agonists vanillin and ethyl vanillin.
doi:10.1038/nn.3598
PMCID: PMC3990440  PMID: 24316890
11.  Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety 
Nature neuroscience  2013;17(1):106-113.
Successfully differentiating safety from danger is an essential skill for survival. While decreased activity in the medial prefrontal cortex (mPFC) is associated with fear generalization in animals and humans, the circuit level mechanisms used by the mPFC to discern safety are not clear. To answer this question, we recorded activity in the mPFC, basolateral amygdala (BLA), and dorsal (dHPC) and ventral hippocampus (vHPC) in mice during exposure to learned (differential fear conditioning) and innate (open field) anxiety. We found increased synchrony between the mPFC and BLA in the theta frequency range (4–12 Hz) only in animals that differentiate between averseness and safety. Moreover, during recognized safety across learned and innate paradigms, BLA firing becomes entrained to theta input from the mPFC. These data suggest that selective tuning of BLA firing to mPFC input provides a safety-signaling mechanism whereby the mPFC taps into the microcircuitry of the amygdala to diminish fear.
doi:10.1038/nn.3582
PMCID: PMC4035371  PMID: 24241397
12.  Identification of a Unique TGF-β Dependent Molecular and Functional Signature in Microglia 
Nature neuroscience  2013;17(1):131-143.
Microglia are myeloid cells of the central nervous system (CNS) that participate both in normal CNS function and disease. We investigated the molecular signature of microglia and identified 239 genes and 8 microRNAs that were uniquely or highly expressed in microglia vs. myeloid and other immune cells. Out of 239 genes, 106 were enriched in microglia as compared to astrocytes, oligodendrocytes and neurons. This microglia signature was not observed in microglial lines or in monocytes recruited to the CNS and was also observed in human microglia. Based on this signature, we found a crucial role for TGF-β in microglial biology that included: 1) the requirement of TGF-β for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia; and 2) the absence of microglia in CNS TGF-β1 deficient mice. Our results identify a unique microglial signature that is dependent on TGF-β signaling which provides insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease.
doi:10.1038/nn.3599
PMCID: PMC4066672  PMID: 24316888
13.  Plasticity and Specificity of the Circadian Epigenome 
Nature neuroscience  2010;13(11):1324-1329.
Circadian clocks control a variety of neuronal, behavioral and physiological responses, via transcriptional regulation of a significant portion of the genome. We describe the complex communication network between the brain-specific central clock and the tissue-specific peripheral clocks that serve to synchronize the organism to both external and internal demands. In addition, we discuss and speculate how epigenetic processes are involved in creating transcriptional environments that are permissive to tissue-specific gene expression programs, which work in concert with the circadian machinery. Accumulating data shows that chromatin remodeling events may be critical for providing specificity and plasticity in circadian regulation, and metabolic cues may be involved in directing such epigenetic events. A detailed understanding of the communication cues between the central and peripheral clocks is crucial for a more complete understanding of the circadian system and the multiple levels of control that are implicated in maintaining biological timekeeping.
doi:10.1038/nn.2668
PMCID: PMC4071955  PMID: 20975756
14.  Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease 
Nature neuroscience  2010;13(4):411-413.
Microglia, the immune cells of the brain, can have a beneficial effect in Alzheimer’s disease by phagocytosing amyloid-β. Two-photon in vivo imaging of neuron loss in the intact brain of living Alzheimer’s disease mice revealed an involvement of microglia in neuron elimination, indicated by locally increased number and migration velocity of microglia around lost neurons. Knockout of the microglial chemokine receptor Cx3cr1, which is critical in neuron-microglia communication, prevented neuron loss.
doi:10.1038/nn.2511
PMCID: PMC4072212  PMID: 20305648
15.  Insulin induces long-term depression of VTA dopamine neurons via an endocannabinoid-mediated mechanism 
Nature neuroscience  2013;16(3):300-308.
The prevalence of obesity has drastically increased over the last few decades. Exploration into how hunger and satiety signals influence the reward system can help us to understand non-homeostatic mechanisms of feeding. Evidence suggests that insulin may act in the ventral tegmental area (VTA), a critical site for reward-seeking behavior, to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA remain unknown. We demonstrate that insulin, a circulating catabolic peptide that inhibits feeding, can induce a long-term depression (LTD) of excitatory synapses onto VTA dopamine neurons. This effect requires endocannabinoid-mediated presynaptic inhibition of glutamate release. Furthermore, after a sweetened high fat meal, which elevates endogenous insulin levels, insulin-induced LTD is occluded. Finally, insulin in the VTA reduces food anticipatory behavior and conditioned place preference for food. Taken together, these results suggest that insulin in the VTA suppresses excitatory synaptic transmission and reduces salience of food-related cues.
doi:10.1038/nn.3321
PMCID: PMC4072656  PMID: 23354329 CAMSID: cams3903
Insulin; Ventral Tegmental Area; Dopamine; LTD; AMPA receptors; obesity; CB1 receptor; endocannabinoid; conditioned place preference; incentive salience
16.  A genomic atlas of mouse hypothalamic development 
Nature neuroscience  2010;13(6):767-775.
The hypothalamus is a central regulator of many behaviors that are essential for survival, such as temperature regulation, food intake and circadian rhythms. However, the molecular pathways that mediate hypothalamic development are largely unknown. To identify genes expressed in developing mouse hypothalamus, we performed microarray analysis at 12 different developmental time points. We then conducted developmental in situ hybridization for 1,045 genes that were dynamically expressed over the course of hypothalamic neurogenesis. We identified markers that stably labeled each major hypothalamic nucleus over the entire course of neurogenesis and constructed a detailed molecular atlas of the developing hypothalamus. As a proof of concept of the utility of these data, we used these markers to analyze the phenotype of mice in which Sonic Hedgehog (Shh) was selectively deleted from hypothalamic neuroepithelium and found that Shh is essential for anterior hypothalamic patterning. Our results serve as a resource for functional investigations of hypothalamic development, connectivity, physiology and dysfunction.
doi:10.1038/nn.2545
PMCID: PMC4067769  PMID: 20436479
17.  Flipping the switch from electrical to chemical communication 
Nature neuroscience  2005;8(12):1633-1634.
Immature neurons in many brain regions are electrically coupled through gap junctions, which are lost as chemical synaptic transmission matures. This developmental uncoupling is now shown to require NMDA receptor activation.
doi:10.1038/nn1205-1633
PMCID: PMC4067002  PMID: 16306887
18.  Adaptive regulation of sparseness by feedforward inhibition 
Nature neuroscience  2007;10(9):1176-1184.
In the mushroom body of insects, odors are represented by very few spikes in a small number of neurons, a highly efficient strategy known as sparse coding. Physiological studies of these neurons have shown that sparseness is maintained across thousand-fold changes in odor concentration. Using a realistic computational model, we propose that sparseness in the olfactory system is regulated by adaptive feedforward inhibition. When odor concentration changes, feedforward inhibition modulates the duration of the temporal window over which the mushroom body neurons may integrate excitatory presynaptic input. This simple adaptive mechanism could maintain the sparseness of sensory representations across wide ranges of stimulus conditions.
doi:10.1038/nn1947
PMCID: PMC4061731  PMID: 17660812
19.  Millisecond-scale differences in neural activity in auditory cortex can drive decisions 
Nature neuroscience  2008;11(11):1262-1263.
Neurons in the auditory cortex can lock with millisecond precision to the fine timing of acoustic stimuli, but it is not known whether this precise spike timing can be used to guide decisions. We used chronically implanted microelectrode pairs to stimulate neurons in the rat auditory cortex directly. Here we demonstrate that rats can exploit differences in the timing of cortical activity as short as three milliseconds to guide decisions.
doi:10.1038/nn.2211
PMCID: PMC4062077  PMID: 18849984
20.  Chordin-induced lineage plasticity of adult SVZ neuroblasts after demyelination 
Nature neuroscience  2010;13(5):541-550.
The mechanisms that regulate the developmental potential of adult neural progenitor populations under physiological and pathological conditions remain poorly defined. Glutamic acid decarboxylase 65 (GAD65)- and Doublecortin (Dcx)-expressing cells constitute major progenitor populations in the adult mouse subventricular zone (SVZ). Under normal physiological conditions, SVZ-derived GAD65-positive and Dcx-positive cells expressed the transcription factor Pax6 and migrated along the rostral migratory stream to the olfactory bulb to generate interneurons. After lysolecithin-induced demyelination of corpus callosum, however, these cells altered their molecular and cellular properties and migratory path. Demyelination upregulated chordin in the SVZ, which redirected GAD65-positive and Dcx-positive progenitors from neuronal to glial fates, generating new oligodendrocytes in the corpus callosum. Our findings suggest that the lineage plasticity of SVZ progenitor cells could be a potential therapeutic strategy for diseased or injured brain.
doi:10.1038/nn.2536
PMCID: PMC4059417  PMID: 20418875
21.  Regulation of dietary choice by the decision-making circuitry 
Nature neuroscience  2013;16(12):1717-1724.
To advance our understanding of how the brain makes food decisions, it is essential to combine knowledge from two fields that have not yet been well integrated: the neuro-computational basis of decision-making and the homeostatic regulators of feeding. This Review integrates these two literatures from a neuro-computational perspective, with an emphasis in describing the variables computed by different neural systems and how they affect dietary choice. We highlight what is unique about feeding decisions, the mechanisms through which metabolic and endocrine factors affect the decision-making circuitry, why making healthy food choices is difficult for many people, and key processes at work in the obesity epidemic.
doi:10.1038/nn.3561
PMCID: PMC4053793  PMID: 24270272
22.  Recognition memory: opposite effects of hippocampal damage on recollection and familiarity 
Nature neuroscience  2007;11(1):16-18.
A major controversy in memory research concerns whether recognition is subdivided into distinct cognitive mechanisms of recollection and familiarity that are supported by different neural substrates. Here we developed a new associative recognition protocol for rats that enabled us to show that recollection is reduced, whereas familiarity is increased following hippocampal damage. These results provide strong evidence that these processes are qualitatively different and that the hippocampus supports recollection and not familiarity.
doi:10.1038/nn2016
PMCID: PMC4053160  PMID: 18037884
23.  Critical role of the hippocampus in memory for sequences of events 
Nature neuroscience  2002;5(5):458-462.
Recent models of hippocampal function emphasize the potential role of this brain structure in encoding and retrieving sequences of events that compose episodic memories. Here we show that hippocampal lesions produce a severe and selective impairment in the capacity of rats to remember the sequential ordering of a series of odors, despite an intact capacity to recognize odors that recently occurred. These findings support the hypothesis that hippocampal networks mediate associations between sequential events that constitute elements of an episodic memory.
doi:10.1038/nn834
PMCID: PMC4053170  PMID: 11976705
24.  A mechanism for value-guided choice based on the excitation-inhibition balance in prefrontal cortex 
Nature neuroscience  2012;15(7):960-961.
Although the ventromedial prefrontal cortex (vmPFC) has long been implicated in reward-guided decision making, its exact role in this process has remained an unresolved issue. Here, we show that vmPFC levels of GABA and glutamate in human volunteers are predictive of both behavioural performance and the dynamics of a neural value comparison signal in a manner as predicted by models of decision-making. These data provide evidence for a neural competition mechanism in vmPFC supporting value-guided choice.
doi:10.1038/nn.3140
PMCID: PMC4050076  PMID: 22706268
25.  Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer’s disease 
Nature neuroscience  2013;17(2):304-311.
The entorhinal cortex has been implicated in the early stages of Alzheimer’s disease, which is characterized by changes in the tau protein and in the cleaved fragments of the amyloid precursor protein (APP). We used a high-resolution functional magnetic resonance imaging (fMRI) variant that can map metabolic defects in patients and mouse models to address basic questions about entorhinal cortex pathophysiology. The entorhinal cortex is divided into functionally distinct regions, the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), and we exploited the high-resolution capabilities of the fMRI variant to ask whether either of them was affected in patients with preclinical Alzheimer’s disease. Next, we imaged three mouse models of disease to clarify how tau and APP relate to entorhinal cortex dysfunction and to determine whether the entorhinal cortex can act as a source of dysfunction observed in other cortical areas. We found that the LEC was affected in preclinical disease, that LEC dysfunction could spread to the parietal cortex during preclinical disease and that APP expression potentiated tau toxicity in driving LEC dysfunction, thereby helping to explain regional vulnerability in the disease.
doi:10.1038/nn.3606
PMCID: PMC4044925  PMID: 24362760

Results 1-25 (1000)