A circuit from dorsal hippocampal CA3 to parvafox nucleus mediates social novelty preference deficits induced by chronic social defeat stress / 中国药理学与毒理学杂志

OBJECTIVE The preference for social novelty is crucial to the social life of humans and rodents.However,the neural mechanisms underlying social novelty preference are poorly understood.Dorsal hippocampal CA3(dCA3)is an important brain area that responds to social defeat stress,and the neural circuitry of dCA3→lat-eral septum(LS)participates in the context-associated memory.Meanwhile,the parvafox nucleus(PFN)Foxb1+ neurons regulate the defensive reaction to life-threaten-ing situations.Therefore,we investigate a cell-specific cir-cuit of dCA3CaMKⅡα+→dorsal LSGABA+→PFNFoxb1+ in social novelty preference.METHODS Chronic social defeat stress(CSDS)and three-chamber social interaction test were performed in adult male C57BL/6J mice to detect social behaviors.Optogenetic and chemical-genetic experiments were conducted to regulate the circuit.RESULTS CSDS reduced the preference for social nov-elty in mice and the response of dCA3CaMKⅡα+ neurons dur-ing approach to an unfamiliar mouse was impaired by CSDS.Optogenetic inhibition of dCA3CaMKⅡα+→dLS pro-jection reduced the preference for the unfamiliar mouse versus a familiar mouse.Meanwhile,optogenetic activa-tion of dCA3CaMKⅡα+→dLS projection rescued the prefer-ence for social novelty of CSDS-treated mice.Manipula-tions dLSGABA+→PFN projection activation regulated the preference for social novelty in mice.Optogenetic activa-tion of PFNFoxb1+→lPAG projection reduced the prefer-ence for a familiar C57BL/6J mouse versus a novel object in control mice.CSDS decreased the excitability of dCA3CaMKⅡα+ neurons by up-regulation of Kir2.4(Kcnj14)expression.CONCLUSION Our present study suggest-ed that activation of a cell-specific circuit of dCA3CaMKⅡα+→dLSGABA+→PFNFoxb1+→lPAG reverses the deficits of social novelty preference in defeated mice,and inhibition of this circuit reduces the preference for social novelty.The cir-cuit that regulates the preference for social novelty deficits may provide a new information for the potential therapeu-tic targets for neuropsychiatric diseases.

Xiaoyao San, a Chinese herbal formula, ameliorates depression-like behavior in mice through the AdipoR1/AMPK/ACC pathway in hypothalamus / 中西医结合学报

OBJECTIVE@#Depression and metabolic disorders have overlapping psychosocial and pathophysiological causes. Current research is focused on the possible role of adiponectin in regulating common biological mechanisms. Xiaoyao San (XYS), a classic Chinese medicine compound, has been widely used in the treatment of depression and can alleviate metabolic disorders such as lipid or glucose metabolism disorders. However, the ability of XYS to ameliorate depression-like behavior as well as metabolic dysfunction in mice and the underlying mechanisms are unclear.@*METHODS@#An in vivo animal model of depression was established by chronic social defeat stress (CSDS). XYS and fluoxetine were administered by gavage to the drug intervention group. Depression-like behaviors were analyzed by the social interaction test, open field test, forced swim test, and elevated plus maze test. Glucose levels were measured using the oral glucose tolerance test. The involvement of certain molecules was validated by immunofluorescence, histopathology, and Western blotting. In vitro, hypothalamic primary neurons were exposed to high glucose to induce neuronal damage, and the neuroprotective effect of XYS was evaluated by cell counting kit-8 assay. Immunofluorescence and Western blotting were used to evaluate the influences of XYS on adiponectin receptor 1 (AdipoR1), adenosine 5'-monophosphate-activated protein kinase (AMPK), acetyl-coenzyme A carboxylase (ACC) and other related proteins.@*RESULTS@#XYS ameliorated CSDS-induced depression-like behaviors and glucose tolerance impairment in mice and increased the level of serum adiponectin. XYS also restored Nissl bodies in hypothalamic neurons in mice that exhibited depression-like behaviors and decreased the degree of neuronal morphological damage. In vivo and in vitro studies indicated that XYS increased the expression of AdipoR1 in hypothalamic neurons.@*CONCLUSION@#Adiponectin may be a key regulator linking depression and metabolic disorders; regulation of the hypothalamic AdipoR1/AMPK/ACC pathway plays an important role in treatment of depression by XYS.

Pathogenesis of chronic social defeat stress model induced depressive-like mouse model according to LC-MS/MS-based metabolomics / 中国药理学与毒理学杂志

OBJECTIVE To explore the pathogenesis of depression according to the LC-MS/MS-based metabolo?mics in the mouse model which exhibits social avoidance state induced by the chronic social defeat stress model (CSDS). METHODS Twenty male C57BL/6N mice were randomly divided into control group and model group suffering CSDS, and the ICR retired breeder mice were used to attack the model group for 14 d of chronic social defeated stress. The open field test and source preference test were both used to observe depression-like behavior. Besides, the social inter?action test is used to observe the social interaction state, especially. After the stress, the serum samples of mice were collected, and the changes of endogenous metabolites were analyzed by LC-MS metabolomics technology, and the pathway analysis of the differential metabolites was performed to explore the pathogenesis of the CSDS induced depres?sive-like mouse model. RESULTS After the stress of CSDS was completed, the mice in the model group showed a significant slowdown in body weight growth, a reduction in the source preference rate, and a significant reduction in the total distance and the number of rearing in the open field test. Distinctively, the social interaction rate is remarkably decreasing. There are 24 differential metabolites found in the serum of CSDS model mice. CONCLUSION The mouse who suffered CSDS stress would show depressive-like behavior. Based on the LC-MS/MS metabolomics, 24 differential metabolites were found in the serum of CSDS model mice. The amino acid metabolism might be significant to the patho?genesis of the CSDS induced depressive-like mouse model.