Integrated 16S rDNA, metabolomics, and TNF-α/NF-κB signaling pathway analyses to explain the modulatory effect of Poria cocos aqueous extract on anxiety-like behavior. Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Poria cocos is an ancient medicine and modern functional food, which exerts excellent effects on anxiety, although its mechanism is unknown. PURPOSE:To explore the mechanisms of the aqueous extract of P. cocos (PCD) in ameliorating anxiety-like behavior caused by chronic sleep deprivation (CSD). METHODS:PCD chemical composition was analyzed by UPLC-QTOF-MS/MS. A CSD rat model was established over 21 days. We examined the effects and mechanisms after 10 days of CSD using open-field tests (OFTs), enzyme-linked immunosorbent assays, 16S rDNA, non-targeted metabolomics, and Western blot analyses. RESULTS:Sixty-two triterpenoids were identified in PCD. CSD-induced anxiety-like behavior was significantly attenuated by PCD treatment. PCD improved hypothalamic neurotransmitters, decreased proinflammatory cytokines, and depressed the proteins expression of tumor necrosis factor (TNF)-α/nuclear factor (NF)-κB signaling pathway. The full-length 16S rDNA sequence of bacterial cells was also sequenced by high-throughput analysis. CSD caused significant changes in the intestinal flora. PCD improved the species diversity and bacterial abundance in the intestines of rats with anxiety. Metabolomics analysis indicated that 12 PCD-related metabolites in serum and 32 PCD-related metabolites in feces were identified, respectively. Metabolite analysis in serum, PCD treatment affected taurine, hypotaurine, cysteine, methionine, glycine, serine, and threonine metabolism, among others. Metabolite analysis in feces showed significant effects of PCD treatment on the metabolism of vitamin B6, tyrosine, drugs, and glycerophospholipid. Additionally, the correlation analysis of heatmaps showed a tight relationship between inflammatory factors, metabolic parameters, and gut microbial phylotypes. CONCLUSIONS:PCD relieved anxiety by regulating intestinal flora, regulating metabolic disorders, and inhibiting inflammatory pathways in chronic sleep-deprived rats. 10.1016/j.phymed.2022.154300

Nicotine inhibits the VTA-to-amygdala dopamine pathway to promote anxiety. Nguyen Claire,Mondoloni Sarah,Le Borgne Tinaïg,Centeno Ines,Come Maxime,Jehl Joachim,Solié Clément,Reynolds Lauren M,Durand-de Cuttoli Romain,Tolu Stefania,Valverde Sébastien,Didienne Steve,Hannesse Bernadette,Fiancette Jean-François,Pons Stéphanie,Maskos Uwe,Deroche-Gamonet Véronique,Dalkara Deniz,Hardelin Jean-Pierre,Mourot Alexandre,Marti Fabio,Faure Philippe Neuron Nicotine stimulates dopamine (DA) neurons of the ventral tegmental area (VTA) to establish and maintain reinforcement. Nicotine also induces anxiety through an as yet unknown circuitry. We found that nicotine injection drives opposite functional responses of two distinct populations of VTA DA neurons with anatomically segregated projections: it activates neurons that project to the nucleus accumbens (NAc), whereas it inhibits neurons that project to the amygdala nuclei (Amg). We further show that nicotine mediates anxiety-like behavior by acting on β2-subunit-containing nicotinic acetylcholine receptors of the VTA. Finally, using optogenetics, we bidirectionally manipulate the VTA-NAc and VTA-Amg pathways to dissociate their contributions to anxiety-like behavior. We show that inhibition of VTA-Amg DA neurons mediates anxiety-like behavior, while their activation prevents the anxiogenic effects of nicotine. These distinct subpopulations of VTA DA neurons with opposite responses to nicotine may differentially drive the anxiogenic and the reinforcing effects of nicotine. 10.1016/j.neuron.2021.06.013

Midbrain projection to the basolateral amygdala encodes anxiety-like but not depression-like behaviors. Nature communications Anxiety disorders are complex diseases, and often co-occur with depression. It is as yet unclear if a common neural circuit controls anxiety-related behaviors in both anxiety-alone and comorbid conditions. Here, utilizing the chronic social defeat stress (CSDS) paradigm that induces singular or combined anxiety- and depressive-like phenotypes in mice, we show that a ventral tegmental area (VTA) dopamine circuit projecting to the basolateral amygdala (BLA) selectively controls anxiety- but not depression-like behaviors. Using circuit-dissecting ex vivo electrophysiology and in vivo fiber photometry approaches, we establish that expression of anxiety-like, but not depressive-like, phenotypes are negatively correlated with VTA → BLA dopamine neuron activity. Further, our optogenetic studies demonstrate a causal link between such neuronal activity and anxiety-like behaviors. Overall, these data establish a functional role for VTA → BLA dopamine neurons in bi-directionally controlling anxiety-related behaviors not only in anxiety-alone, but also in anxiety-depressive comorbid conditions in mice. 10.1038/s41467-022-29155-1

Reciprocal control of obesity and anxiety-depressive disorder via a GABA and serotonin neural circuit. Molecular psychiatry The high comorbidity between obesity and mental disorders, such as depression and anxiety, often exacerbates metabolic and neurological symptoms significantly. However, neural mechanisms that underlie reciprocal control of feeding and mental states are largely elusive. Here we report that melanocortin 4 receptor (MC4R) neurons located in the dorsal bed nucleus of the stria terminus (dBNST) engage in the regulation of mentally associated weight gain by receiving GABAergic projections from hypothalamic AgRP neurons onto α5-containing GABA receptors and serotonergic afferents onto 5-HT receptors. Chronic treatment with a high-fat diet (HFD) significantly blunts the hyperexcitability of AgRP neurons in response to not only hunger but also anxiety and depression-like stimuli. Such HFD-mediated desensitization reduces GABAergic outputs from AgRP neurons to downstream MC4R neurons, resulting in severe mental dysregulation. Genetic enhancement of the GABAR-α5 or suppression of the 5-HTR within the MC4R neurons not only abolishes HFD-induced anxiety and depression but also robustly reduces body weight by suppression of food intake. To gain further translational insights, we revealed that combined treatment of zonisamide (enhancing the GABAR-α5 signaling) and granisetron (a selective 5-HTR antagonist) alleviates mental dysfunction and yields a robust reversal of diet-induced obesity by reducing total calorie intake and altering food preference towards a healthy low-fat diet. Our results unveil a neural mechanism for reciprocal control of appetite and mental states, which culminates in a novel zonisamide-granisetron cocktail therapy for potential tackling the psychosis-obesity comorbidity. 10.1038/s41380-021-01053-w