The rockefeller university

Addictive diseases, including addiction to alcohol, pose massive public health costs. Addiction is a chronic relapsing disease caused by both the direct effects induced by drugs and persistent neuroadaptations at the molecular, cellular, and behavioral levels. These drug-type specific neuroadaptations are brought on largely by the reinforcing effects of drugs on the central nervous system and environmental stressors. Results from animal experiments have demonstrated important interactions between alcohol and stressresponsive systems. Addiction to specific drugs such as alcohol, psychostimulants, and opioids shares some common direct or downstream effects on the brain's stress-responsive systems, including arginine vasopressin and its V1b receptors, dynorphin and the kappa-opioid receptors, pro-opiomelanocortin/beta-endorphin and the mu-opioid receptors, and the endocannabinoids. Further study of these systems through laboratory-based and translational research could lead to the discovery of novel treatment targets and the early optimization of interventions (for example, combination) for the pharmacologic therapy of alcoholism.

Endocannabinoid signaling regulates feeding and metabolic processes and has been linked to obesity development. Several hormonal signals, such as glucocorticoids and ghrelin, regulate feeding and metabolism by engaging the endocannabinoid system. Similarly, studies have suggested that leptin interacts with the endocannabinoid system, yet the mechanism and functional relevance of this interaction remain elusive. Therefore, we explored the interaction between leptin and endocannabinoid signaling with a focus on fatty acid amide hydrolase (FAAH), the primary degradative enzyme for the endocannabinoid N-arachidonoylethanolamine (anandamide; AEA). Mice deficient in leptin exhibited elevated hypothalamic AEA levels and reductions in FAAH activity while leptin administration to WT mice reduced AEA content and increased FAAH activity. Following high fat diet exposure, mice developed resistance to the effects of leptin administration on hypothalamic AEA content and FAAH activity. At a functional level, pharmacological inhibition of FAAH was sufficient to prevent leptin-mediated effects on body weight and food intake. Using a novel knock-in mouse model recapitulating a common human polymorphism (FAAH C385A; rs324420), which reduces FAAH activity, we investigated whether human genetic variance in FAAH affects leptin sensitivity. While WT (CC) mice were sensitive to leptin-induced reductions in food intake and body weight gain, low-expressing FAAH (AA) mice were unresponsive. These data demonstrate that FAAH activity is required for leptin's hypophagic effects and, at a translational level, suggest that a genetic variant in the FAAH gene contributes to differences in leptin sensitivity in human populations.

All primates communicate. To dissect the neural circuits of social communication, we used fMRI to map non- human primate brain regions for social perception, second- person (interactive) social cognition, and orofacial movement generation. Face perception, second- person cognition, and face motor networks were largely non- overlapping and acted as distinct functional units rather than an integrated feedforward- processing pipeline. Whereas secondperson context selectively engaged a region of medial prefrontal cortex, production of orofacial movements recruited distributed subcortical and cortical areas in medial and lateral frontal and insular cortex. These areas exhibited some specialization, but not dissociation, of function along the mediolateral axis. Production of lipsmack movements recruited areas including putative homologs of Broca's area. These findings provide a new view of the neural architecture for social communication and suggest expressive orofacial movements generated by lateral premotor cortex as a putative evolutionary precursor to human speech.

Liver organogenesis requires complex cell-cell interactions between hepatic endoderm cells and adjacent cell niches. Endothelial cells are key players for endoderm hepatic fate decision. We previously demonstrated that the endothelial cell niche promotes hepatic specification of mouse embryonic stem cell(ESC)-derived endoderm through dual repression of Wnt and Notch pathways in endoderm cells. In the present study, we dissected further the mechanisms by which endothelial cells trigger endoderm hepatic specification. Using our previously established in vitro mouse ESC system mimicking the early hepatic specification process, endoderm cells were purified and co-cultured with endothelial cells to induce hepatic specification. The comparison of transcriptome profiles between hepatic endoderm cells isolated from co-cultures and endoderm cells cultured alone revealed that VEGF signaling instructs hepatic specification of endoderm cells through endothelial VEGFR2 activation. Additionally, epigenetic mark inhibition assays upon co-cultures uncovered that histone acetylation and DNA methylation promote hepatic specification while histone methylation inhibits it. This study provides an efficient 2D platform modelling the endothelial cell niche crosstalk with endoderm, and reveals mechanisms by which endothelial cells promote hepatic specification of mouse ESC-derived endoderm cells through endothelial VEGFR2 activation and endoderm epigenetic modifications.

Depressive disorders constitute a set of debilitating diseases with psychological, societal, economic and humanitarian consequences for millions of people worldwide. Scientists are beginning to understand the reciprocal communication between the brain and the rest of the body in the etiology of these diseases. In particular, scientists have noted a connection between depressive disorders, which are primarily seen as brain-based, and, insulin resistance (IR), a modifiable metabolic inflammatory state that is typically seen as peripheral. We highlight evidence showing how treating IR, with drugs or behavioral interventions, may ameliorate or possibly prevent, depressive disorders and their long-term consequences at various stages of the life course. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders. (C) 2017 Elsevier Ltd. All rights reserved.

A measurement of the electroweak (EW) production of two jets in association with a Z boson in proton-proton collisions at root s = 13 TeV is presented, based on data recorded in 2016 by the CMS experiment at the LHC corresponding to an integrated luminosity of 35.9 fb(-1). The measurement is performed in the lljj final state with l including electrons and muons, and the jets j corresponding to the quarks produced in the hard interaction. The measured cross section in a kinematic region defined by invariant masses m(ll) > 50 GeV, m(jj) > 120 GeV, and transverse momenta P-Tj > 25 GeV is sigma(EW) (lljj) = 534 +/- 20 (stat) fb (syst) fb, in agreement with leading-order standard model predictions. The final state is also used to perform a search for anomalous trilinear gauge couplings. No evidence is found and limits on anomalous trilinear gauge couplings associated with dimension-six operators are given in the framework of an effective field theory. The corresponding 95% confidence level intervals are -2.6 < cwww/Lambda(2) < 2.6 TeV-2 and -8.4 < cw/Lambda(2) < 10.1 TeV-2. The additional jet activity of events in a signal-enriched region is also studied, and the measurements are in agreement with predictions.

A search is presented for new high-mass resonances decaying into electron or muon pairs. The search uses proton-proton collision data at a centre-of-mass energy of 13TeV collected by the CMS experiment at the LHC in 2016, corresponding to an integrated luminosity of 36 fb(-1). Observations are in agreement with standard model expectations. Upper limits on the product of a new resonance production cross section and branching fraction to dileptons are calculated in a model-independent manner. This permits the interpretation of the limits in models predicting a narrow dielectron or dimuon resonance. A scan of different intrinsic width hypotheses is performed. Limits are set on the masses of various hypothetical particles. For the Z(SSM)' (Z(psi)') particle, which arises in the sequential standard model (superstring-inspired model), a lower mass limit of 4.50 (3.90) TeV is set at 95% confidence level. The lightest Kaluza-Klein graviton arising in the Randall-Sundrum model of extra dimensions, with coupling parameters k/(M) over bar (Pl) of 0.01, 0.05, and 0.10, is excluded at 95% con fi dence level below 2.10, 3.65, and 4.25TeV, respectively. In a simpli fi ed model of dark matter production via a vector or axial vector mediator, limits at 95% con fi dence level are obtained on the masses of the dark matter particle and its mediator.

Feeding is a complex motivated behavior controlled by a distributed neural network that processes sensory information to generate adaptive behavioral responses. Accordingly, studies using appetitive Pavlovian conditioning confirm that environmental cues that are associated with food availability can induce feeding even in satiated subjects. However, in mice, appetitive conditioning generally requires intensive training and thus can impede molecular studies that often require large numbers of animals. To address this, we developed and validated a simple and rapid context-induced feeding (Ctx-IF) task in which cues associated with food availability can later lead to increased food consumption in sated mice. We show that the associated increase in food consumption is driven by both positive and negative reinforcement and that spaced training is more effective than massed training. Ctx-IF can be completed in ~1 week and provides an opportunity to study the molecular mechanisms and circuitry underlying non-homeostatic eating. We have used this paradigm to map brain regions that are activated during Ctx-IF with cFos immunohistochemistry and found that the insular cortex, and other regions, are activated following exposure to cues denoting the availability of food. Finally, we show that inhibition of the insular cortex using GABA agonists impairs performance of the task. Our findings provide a novel assay in mice for defining the functional neuroanatomy of appetitive conditioning and identify specific brain regions that are activated during the development of learned behaviors that impact food consumption.

The lateral-line neuromast of the zebrafish displays a restricted, consistent pattern of innervation that facilitates the comparison of microcircuits across individuals, developmental stages, and genotypes. We used serial blockface scanning electron microscopy to determine from multiple specimens the neuromast connectome, a comprehensive set of connections between hair cells and afferent and efferent nerve fibers. This analysis delineated a complex but consistent wiring pattern with three striking characteristics: each nerve terminal is highly specific in receiving innervation from hair cells of a single directional sensitivity; the innervation is redundant; and the terminals manifest a hierarchy of dominance. Mutation of the canonical planar-cell-polarity gene vangl2, which decouples the asymmetric phenotypes of sibling hair-cell pairs, results in randomly positioned, randomly oriented sibling cells that nonetheless retain specific wiring. Because larvae that overexpress Notch exhibit uniformly oriented, uniformly innervating hair-cell siblings, wiring specificity is mediated by the Notch signaling pathway.