Chronic stress causes dysregulations of mood and energy homeostasis, but the neurocircuitry underlying these alterations remain to be fully elucidated. Here we demonstrate that chronic restraint stress in mice results in hyperactivity of pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (POMC ARH neurons) associated with decreased neural activities of dopamine neurons in the ventral tegmental area (DA VTA neurons). We further revealed that POMC ARH neurons project to the VTA and provide an inhibitory tone to DA VTA neurons via both direct and indirect neurotransmissions. Finally, we show that photoinhibition of the POMC ARH →VTA circuit in mice increases body weight and food intake, and reduces depression-Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERα vlVMH) or glucose-excited neurons (GE-ERα vlVMH). Hypoglycemia activates GI-ERα vlVMH neurons via the anoctamin 4 channel, and inhibits GE-ERα vlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERα vlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERα vlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERα vlVMH to mpARH circuit and inhibition of ERα vlVMH to DRN circuit both increase blood glucose. Thus, our results indicate that ERα vlVMH neurons detect glucose fluctuations and prevent severe hypoglycemia in mice.
IMPORTANCEThe genetic basis of bipolar disorder (BD) in Han Chinese individuals is not fully understood.OBJECTIVE To explore the genetic basis of BD in the Han Chinese population. DESIGN, SETTING, AND PARTICIPANTSA genome-wide association study (GWAS), followed by independent replication, was conducted to identify BD risk loci in Han Chinese individuals. Individuals with BD were diagnosed based on DSM-IV criteria and had no history of schizophrenia, mental retardation, or substance dependence; individuals without any personal or family history of mental illnesses, including BD, were included as control participants. In total, discovery samples from 1822 patients and 4650 control participants passed quality control for the GWAS analysis. Replication analyses of samples from 958 patients and 2050 control participants were conducted. Summary statistics from the European Psychiatric Genomics Consortium 2 (PGC2) BD GWAS (20 352 cases and 31 358 controls) were used for the trans-ancestry genetic correlation analysis, polygenetic risk score analysis, and meta-analysis to compare BD genetic risk between Han Chinese and European individuals. The study was performed in February 2020.MAIN OUTCOMES AND MEASURES Single-nucleotide variations with P < 5.00 × 10 −8 were considered to show genome-wide significance of statistical association. RESULTS The HanChinese discovery GWAS sample included 1822 cases (mean [SD] age, 35.43 [14.12] years; 838 [46%] male) and 4650 controls (mean [SD] age, 27.48 [5.97] years; 2465 [53%] male), and the replication sample included 958 cases (mean [SD] age, 37.82 [15.54] years; 412 [43%] male) and 2050 controls (mean [SD] age, 27.50 [6.00] years; 1189[58%] male). A novel BD risk locus in Han Chinese individuals was found near the gene encoding transmembrane protein 108 (TMEM108, rs9863544; P = 2.49 × 10 −8 ; odds ratio [OR], 0.650; 95% CI, 0.559-0.756), which is required for dendritic spine development and glutamatergic transmission in the dentate gyrus. Trans-ancestry genetic correlation estimation (ρ ge = 0.652, SE = 0.106; P = 7.30 × 10 −10 ) and polygenetic risk score analyses (maximum liability-scaled Nagelkerke pseudo R 2 = 1.27%; P = 1.30 × 10 −19 ) showed evidence of shared BD genetic risk between Han Chinese and European populations, and meta-analysis identified 2 new GWAS risk loci near VRK2 (rs41335055; P = 4.98 × 10 −9 ; OR, 0.849; 95% CI, 0.804-0.897) and RHEBL1 (rs7969091; P = 3.12 × 10 −8 ; OR, 0.932; 95% CI, 0.909-0.956).CONCLUSIONS AND RELEVANCE This GWAS study identified several loci and genes involved in the heritable risk of BD, providing insights into its genetic architecture and biological basis.
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