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1.  Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice 
Nature neuroscience  2014;17(5):667-669.
Summary
Gene-environment interactions are determining factors for the etiology of psychiatric disorders, diabetes and cancer, and are thought to contribute to disease inheritance across generations. Small non-coding RNAs (sncRNAs) are potential vectors at the interface between genes and environment. Here, we report that environmental conditions involving traumatic stress in early life in mice altered microRNAs (miRNAs) expression, and behavioral and metabolic responses in the progeny. Several miRNAs were affected in the serum and brain of both, the traumatized animals and their progeny when adult, but also in the sperm of traumatized males. Injection of sperm RNAs from these males into fertilized wild-type oocytes reproduced the behavioral and metabolic alterations in the resulting offspring. These results strongly suggest that sncRNAs are sensitive to environmental factors in early life, and contribute to the inheritance of trauma-induced phenotypes across generations. They may offer potential diagnostic markers for associated pathologies in humans.
doi:10.1038/nn.3695
PMCID: PMC4333222  PMID: 24728267
2.  unc-33/CRMP and ankyrin organize microtubules and localize kinesin to polarize axon-dendrite sorting 
Nature neuroscience  2011;15(1):48-56.
The polarized distribution of neuronal proteins to axons and dendrites relies upon microtubule-binding proteins such as CRMP, directed motors such as kinesin UNC-104/Kif1A, and diffusion barriers such as ankyrin. The causative relationships between these molecules are unknown. We show here that Caenorhabditis elegans CRMP (UNC-33) acts early in neuronal development, together with ankyrin (UNC-44), to organize microtubule asymmetry and axon-dendrite sorting. In unc-33 and unc-44 mutants, axonal proteins are present in dendrites and vice versa, suggesting bidirectional failures of axon-dendrite identity. UNC-33 protein is localized to axons by unc-44, and enriched in a region that resembles the axon initial segment. unc-33 and unc-44 establish the asymmetric dynamics of axonal and dendritic microtubules; in their absence, microtubules are disorganized, the axonal kinesin UNC-104 invades dendrites, and inappropriate UNC-104 activity randomizes axonal protein sorting. We suggest that UNC-44 and UNC-33 direct polarized sorting through their global effects on neuronal microtubule organization.
doi:10.1038/nn.2970
PMCID: PMC4328884  PMID: 22101643
3.  Functional organization of glomerular maps in the mouse accessory olfactory bulb 
Nature neuroscience  2014;17(7):953-961.
Summary
The mammalian accessory olfactory system (AOS) extracts information about species, sex, and individual identity from social odors, but its functional organization remains unclear. We imaged presynaptic Ca2+ signals in vomeronasal inputs to the accessory olfactory bulb (AOB) during peripheral stimulation using light sheet microscopy. Urine- and steroid-responsive glomeruli densely innervated the anterior AOB. Glomerular activity maps for sexually mature female mouse urine overlapped maps for juvenile and/or gonadectomized urine of both sexes, whereas maps for sexually mature male urine were highly distinct. Further spatial analysis revealed a complicated organization involving selective juxtaposition and dispersal of functionally-grouped glomerular classes. Glomeruli that were similarly tuned to urines were often closely associated, whereas more disparately tuned glomeruli were selectively dispersed. Maps to a panel of sulfated steroid odorants identified tightly-juxtaposed groups that were disparately tuned and dispersed groups that were similarly tuned. These results reveal a modular, non-chemotopic spatial organization in the AOB.
doi:10.1038/nn.3738
PMCID: PMC4327767  PMID: 24880215
4.  A locus and mechanism of action for associative morphine tolerance 
Nature neuroscience  2000;3(1):47-53.
Repeated administration of an opioid in the presence of specific environmental cues can induce tolerance specific to that setting (associative tolerance). Prolonged or repeated administration of an opioid without consistent contextual pairing yields non-associative tolerance. Here we demonstrate that cholecystokinin acting at the cholecystokinin-B receptor is required for associative but not non-associative morphine tolerance. Morphine given in the morphine-associated context increased Fos-like immunoreactivity in the lateral amygdala and hippocampal area CA1. Microinjection of the cholecystokinin B antagonist L-365,260 into the amygdala blocked associative tolerance. These results indicate that cholecystokinin acting in the amygdala is necessary for associative tolerance to morphine’s analgesic effect.
doi:10.1038/71120
PMCID: PMC4327857  PMID: 10607394
5.  Developmental origins of central norepinephrine neuron diversity 
Nature neuroscience  2013;16(8):1016-1023.
Central norepinephrine producing neurons comprise a diverse population of cells differing in anatomical location, connectivity, function and response to disease and environmental insult. At present, the mechanisms that generate this diversity are unknown. Here we elucidate the lineal relationship between molecularly distinct progenitor populations in the developing mouse hindbrain and mature norepinephrine neuron subtype identity. We have identified four genetically separable subpopulations of mature norepinephrine neurons differing in their anatomical location, axon morphology and efferent projection pattern. One of the subpopulations revealed an unexpected projection to the prefrontal cortex, challenging the long-held belief that the locus coeruleus (LoC) is the sole source of norepinephrine projections to the cortex. These findings reveal the embryonic origins of central norepinephrine neurons and provide for the first time multiple molecular points of entry for future study of individual norepinephrine circuits in complex behavioral and physiological processes including arousal, attention, mood, memory, appetite, and homeostasis.
doi:10.1038/nn.3458
PMCID: PMC4319358  PMID: 23852112
6.  Population coding of affect across stimuli, modalities and individuals 
Nature neuroscience  2014;17(8):1114-1122.
It remains unclear how the brain represents external objective sensory events alongside our internal subjective impressions of them—affect. Representational mapping of population level activity evoked by complex scenes and basic tastes uncovered a neural code supporting a continuous axis of pleasant-to-unpleasant valence. This valence code was distinct from low-level physical and high-level object properties. While ventral temporal and anterior insular cortices supported valence codes specific to vision and taste, both the medial and lateral orbitofrontal cortices (OFC), maintained a valence code independent of sensory origin. Further only the OFC code could classify experienced affect across participants. The entire valence spectrum is represented as a collective pattern in regional neural activity as sensory-specific and abstract codes, whereby the subjective quality of affect can be objectively quantified across stimuli, modalities, and people.
doi:10.1038/nn.3749
PMCID: PMC4317366  PMID: 24952643 CAMSID: cams4454
7.  [No title available] 
PMCID: PMC3992254  PMID: 24362761
8.  [No title available] 
PMCID: PMC4019963  PMID: 24390226
9.  [No title available] 
PMCID: PMC4020413  PMID: 24473264
10.  [No title available] 
PMCID: PMC4115017  PMID: 24952642
11.  [No title available] 
PMCID: PMC4115015  PMID: 24974797
12.  [No title available] 
PMCID: PMC4115047  PMID: 24952644
13.  Orbitofrontal activation restores insight lost after cocaine use 
Nature neuroscience  2014;17(8):1092-1099.
Addiction is characterized by a lack of insight into the likely outcomes of one’s behavior. Insight or the ability to imagine outcomes is evident when outcomes have not been directly experienced. Using this concept, work in both rats and humans has recently identified neural correlates of insight in the medial and orbital prefrontal cortices. Here we show that these correlates are selectively abolished in rats by cocaine self-administration. Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, reversal of which by optogenetic activation restored normal behavior. These results provide a link between cocaine use and problems with insight. Deficits in these functions are likely to be particularly important for problems such as drug relapse, in which behavior fails to account for likely adverse outcomes. As such, these data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.
doi:10.1038/nn.3763
PMCID: PMC4120653  PMID: 25042581
14.  Gene co-regulation by Fezf2 selects neurotransmitter identity and connectivity of corticospinal neurons 
Nature neuroscience  2014;17(8):1046-1054.
The neocortex contains an unparalleled diversity of neuronal subtypes, each defined by distinct traits that are developmentally acquired under the control of subtype-specific and pan-neuronal genes. The regulatory logic that orchestrates the expression of these unique combinations of genes is unknown for any class of cortical neuron. Here, we report that Fezf2 is a selector gene able to regulate the expression of gene sets that collectively define mouse corticospinal motor neurons (CSMN). We find that Fezf2 directly induces the glutamatergic identity of CSMN via activation of Vglut1 (Scl17a7) and inhibits a GABAergic fate by repressing transcription of Gad1. In addition, we identify the axon guidance receptor Ephb1 as a target of Fezf2 necessary to execute the ipsilateral extension of the corticospinal tract. Our data indicate that co-regulated expression of neuron subtype–specific and pan-neuronal gene batteries by a single transcription factor is one component of the regulatory logic responsible for the establishment of CSMN identity.
doi:10.1038/nn.3757
PMCID: PMC4188416  PMID: 24997765
15.  Genome-wide identification and characterization of functional neuronal activity-dependent enhancers 
Nature neuroscience  2014;17(10):1330-1339.
SUMMARY
Experience-dependent gene transcription is required for nervous system development and function. However, the DNA regulatory elements that control this program of gene expression are not well defined. Here we characterize the enhancers that function across the genome to mediate activity-dependent transcription in mouse cortical neurons. We find that the subset of enhancers enriched for monomethylation of histone H3 lysine 4 (H3K4me1) and binding of the transcriptional co-activator CREBBP (CBP) that shows increased acetylation of histone H3 lysine 27 (H3K27ac) upon membrane depolarization of cortical neurons functions to regulate activity-dependent transcription. A subset of these enhancers appears to require binding of FOS, which previously was thought to bind primarily to promoters. These findings suggest that FOS functions at enhancers to control activity-dependent gene programs that are critical for nervous system function and provide a resource of functional cis-regulatory elements that may give insight into the genetic variants that contribute to brain development and disease.
doi:10.1038/nn.3808
PMCID: PMC4297619  PMID: 25195102
16.  A supercritical density of fast Na+ channels ensures rapid propagation of action potentials in GABAergic interneuron axons 
Nature neuroscience  2014;17(5):686-693.
Fast-spiking, parvalbumin-expressing GABAergic interneurons/basket cells (BCs) play a key role in feedforward and feedback inhibition, gamma oscillations, and complex information processing. For these functions, fast propagation of action potentials (APs) from the soma to the presynaptic terminals is important. However, the functional properties of interneuron axons remain elusive. Here, we examined interneuron axons by confocally targeted subcellular patch-clamp recording in rat hippocampal slices. APs were initiated in the proximal axon ~20 μm from the soma, and propagated to the distal axon with high reliability and speed. Subcellular mapping revealed a stepwise increase of Na+ conductance density from the soma to the proximal axon, followed by a further gradual increase in the distal axon. Active cable modeling and experiments with partial channel block indicated that low axonal Na+ conductance density was sufficient for reliability, but high Na+ density was necessary for both speed of propagation and fast-spiking AP phenotype. Our results suggest that a supercritical density of Na+ channels compensates for the morphological properties of interneuron axons (small segmental diameter, extensive branching, and high bouton density), ensuring fast AP propagation and high-frequency repetitive firing.
doi:10.1038/nn.3678
PMCID: PMC4286295  PMID: 24657965
17.  Prefrontal atrophy, disrupted NREM slow waves, and impaired hippocampal-dependent memory in aging 
Nature neuroscience  2013;16(3):357-364.
Aging has independently been associated with regional brain atrophy, reduced non-rapid eye movement (NREM) slow-wave activity (SWA), and impaired long-term retention of episodic memories. However, that the interaction of these factors represents a neuropatholgical pathway associated with cognitive decline in later life remains unknown. Here, we show that age-related medial prefrontal cortex (mPFC) grey-matter atrophy is associated with reduced NREM SWA activity in older adults, the extent to which statistically mediates the impairment of overnight sleep-dependent memory retention. Moreover, this memory impairment was further associated with persistent hippocampal activation and reduced task-related hippocampal-prefrontal cortex connectivity, potentially representing impoverished hippocampal-neocortical memory transformation. Together, these data support a model in which age-related mPFC atrophy diminishes SWA, the functional consequence of which is impaired long-term memory. Such findings suggest that sleep disruption in the elderly, mediated by structural brain changes, represent a novel contributing factor to age-related cognitive decline in later life.
doi:10.1038/nn.3324
PMCID: PMC4286370  PMID: 23354332
18.  ALK5-dependent TGF-β signaling is a major determinant of late stage adult neurogenesis 
Nature neuroscience  2014;17(7):943-952.
The transforming growth factor-β (TGF-β) signaling pathway serves critical functions in central nervous system (CNS) development, but apart from its proposed neuroprotective actions, its physiological role in the adult brain is unclear. We observed a prominent activation of TGF-β signaling in the adult dentate gyrus and expression of downstream Smad proteins in this neurogenic zone. Consistent with a function of TGF-β signaling in adult neurogenesis, genetic deletion of the TGF-β receptor ALK5 reduced the number, migration, and dendritic arborization of newborn neurons. Conversely, constitutive activation of neuronal ALK5 in forebrain caused a striking increase in these aspects of neurogenesis and was associated with higher expression of c-fos in newborn neurons and with stronger memory function. Our findings describe a new and unexpected role for ALK5-dependent TGF-β signaling as a regulator of the late stages of adult hippocampal neurogenesis which may have implications for changes in neurogenesis during aging and disease.
doi:10.1038/nn.3732
PMCID: PMC4096284  PMID: 24859199
19.  Identification of distinct ChAT+ neurons and activity-dependent control of postnatal SVZ neurogenesis 
Nature neuroscience  2014;17(7):934-942.
Postnatal/adult SVZ neurogenesis is believed to be primarily controlled by neural stem cell (NSC)-intrinsic mechanisms, interacting with extracellular/niche-driven cues. Although behavioral paradigms and disease states have suggested possibilities for higher-level inputs, it is currently unknown if neural activity patterns from discrete circuits can directly regulate SVZ neurogenesis. We have identified a previously undescribed population of ChAT+ neurons residing within the rodent SVZ neurogenic niche. These neurons showed morphological and functional differences from neighboring striatal counterparts, and released acetylcholine locally in activity-dependent fashion. Optogenetic inhibition and stimulation of subependymal ChAT+ neurons in vivo showed that they are necessary and sufficient to control neurogenic proliferation. Furthermore, whole-cell recordings and biochemical experiments revealed direct SVZ NSC responses to local acetylcholine release, synergizing with FGF receptor activation to increase neuroblast production. These results uncovered an unknown gateway connecting SVZ neurogenesis to neuronal activity-dependent control, and possibilities for modulating neuroregenerative capacities in health and disease.
doi:10.1038/nn.3734
PMCID: PMC4122286  PMID: 24880216
20.  Lesions of prefrontal cortex reduce attentional modulation of neuronal responses and synchrony in V4 
Nature neuroscience  2014;17(7):1003-1011.
It is widely held that the frontal eye field (FEF) in prefrontal cortex (PFC) modulates processing in visual cortex with attention, although the evidence for a necessary role is equivocal. To help identify critical sources of attentional feedback to area V4, we surgically removed the entire lateral PFC, including the FEF, in one hemisphere and transected the corpus callosum and anterior commisure in two macaques. This deprived V4 of PFC input in one hemisphere while keeping the other hemisphere intact. In the absence of PFC, attentional effects on neuronal responses and synchrony in V4 were significantly reduced and the remaining effects of attention were delayed in time indicating a critical role of PFC. Conversely, distracters captured attention and influenced V4 responses. However, because the effects of attention in V4 were not eliminated by PFC lesions, other sources of top-down attentional control signals to visual cortex must exist outside of PFC.
doi:10.1038/nn.3742
PMCID: PMC4122755  PMID: 24929661
21.  Mechanical coupling maintains the fidelity of NMDA receptor-mediated currents 
Nature neuroscience  2014;17(7):914-922.
The fidelity of NMDA receptors (NMDARs) to integrate pre- and post-synaptic activity requires a match between agonist binding and ion channel opening. To address how agonist binding is transduced into pore opening in NMDARs, we manipulated the coupling between the ligand binding domain (LBD) and the ion channel by inserting residues in a linker between them. We find that a single residue insertion dramatically attenuates the ability of NMDARs to convert a glutamate transient into a functional response. This is largely due to a decreased likelihood for the channel to open and remain open. Computational and thermodynamic analyses suggest that insertions prevent the agonist-bound LBD from effectively pulling on pore lining elements, thereby destabilizing pore opening. Further, this pulling energy is more prominent in the GluN2 subunit. We conclude that an efficient NMDAR-mediated synaptic response relies on a mechanical coupling between the LBD and the ion channel.
doi:10.1038/nn.3724
PMCID: PMC4072853  PMID: 24859202
Synaptic transmission; ion channels; ionotropic glutamate receptors; molecular dynamics simulations; homology modeling; kinetic modeling; domain coupling
22.  Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia 
Nature neuroscience  2014;17(7):911-913.
SUMMARY
Melanocortin 4 receptors (Mc4rs) are expressed by extra-hypothalamic neurons including cholinergic autonomic pre-ganglionic neurons. However, whether Mc4rs in these neurons are required to control energy and glucose homeostasis is unclear. Here we report that Mc4rs in sympathetic, but not parasympathetic, pre-ganglionic neurons are required to regulate energy expenditure and body weight including brown and white adipose tissue thermogenic responses to diet and cold exposure. In addition, deletion of Mc4rs in both sympathetic and parasympathetic cholinergic neurons impairs glucose homeostasis.
doi:10.1038/nn.3737
PMCID: PMC4090093  PMID: 24908101
23.  Behavioral and neurophysiological correlates of regret in rat decision-making on a neuroeconomic task 
Nature neuroscience  2014;17(7):995-1002.
Summary
Disappointment entails the recognition that one did not get the value one expected. In contrast, regret entails the recognition that an alternate (counterfactual) action would have produced a more valued outcome. Thus, the key to identifying regret is the representation of that counterfactual option in situations in which a mistake has been made. In humans, the orbitofrontal cortex is active during expressions of regret, and humans with damage to the orbitofrontal cortex do not express regret. In rats and non-human primates, both the orbitofrontal cortex and the ventral striatum have been implicated in decision-making, particularly in representations of expectations of reward. In order to examine representations of regretful situations, we recorded neural ensembles from orbitofrontal cortex and ventral striatum in rats encountering a spatial sequence of wait/skip choices for delayed delivery of different food flavors. We were able to measure preferences using an economic framework. Rats occasionally skipped low-cost choices and then encountered a high-cost choice. This sequence economically defines a potential regret-inducing instance. In these situations, rats looked backwards towards the lost option, the cells within the orbitofrontal cortex and ventral striatum represented that missed action, rats were more likely to wait for the long delay, and rats rushed through eating the food after that delay. That these situations drove rats to modify their behavior suggests that regret-like processes modify decision-making in non-human mammals.
doi:10.1038/nn.3740
PMCID: PMC4113023  PMID: 24908102
24.  A shrewd insight for vision 
Nature neuroscience  2004;7(8):796-797.
The circuitry responsible for generating orientation-specific responses in primary visual cortex remains controversial. A new study identifies an anatomical substrate for orientation selectivity and suggests the mechanism may be conserved across species.
doi:10.1038/nn0804-796
PMCID: PMC4277864  PMID: 15280890
25.  Resolving human object recognition in space and time 
Nature neuroscience  2014;17(3):455-462.
A comprehensive picture of object processing in the human brain requires combining both spatial and temporal information about brain activity. Here, we acquired human magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) responses to 92 object images. Multivariate pattern classification applied to MEG revealed the time course of object processing: whereas individual images were discriminated by visual representations early, ordinate and superordinate category levels emerged relatively later. Using representational similarity analysis, we combine human fMRI and MEG to show content-specific correspondence between early MEG responses and primary visual cortex (V1), and later MEG responses and inferior temporal (IT) cortex. We identified transient and persistent neural activities during object processing, with sources in V1 and IT., Finally, human MEG signals were correlated to single-unit responses in monkey IT. Together, our findings provide an integrated space- and time-resolved view of human object categorization during the first few hundred milliseconds of vision.
doi:10.1038/nn.3635
PMCID: PMC4261693  PMID: 24464044

Results 1-25 (1105)