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The role of SIRT1 in the basolateral amygdala in depression-like behaviors in mice
Authors:Hao Guo  Cuola Deji  Han Peng  Jinyu Zhang  Yuanyuan Chen  Yulei Zhang  Yunpeng Wang
Affiliation:1. College of Forensic Science, Xi'an Jiaotong University, Shaanxi, China;2. School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing, China
Abstract:Previous investigations have implicated the basolateral amygdala (BLA) epigenetic mechanisms in the pathophysiology of depression. SIRT1 is a NAD+-dependent class III histone deacetylase, widely expresses in BLA. However, epigenetic mechanisms in the BLA under the regulation of SIRT1 in the depression are largely uncharacterized. Under the chronic unpredictable chronic mild stress (CUMS) mouse model, we used adeno-associated viral vectors (AAV) that encoded SIRT1-shRNA or SIRT1 to specifically knockdown or overexpress SIRT1 in BLA neurons, respectively. CUMS procedure induced significant depression symptoms including the decreased sucrose preference, the less bodyweight gained, the decreased immobile latency and the increased immobile time both in forced swim test (FST) and tail suspension test (TST). Knockdown of SIRT1 in BLA glutamatergic neurons reversed these depression-like behaviors and restored the synaptic abnormalities. Overexpression of SIRT1 in BLA glutamatergic neurons induced depression-like behaviors in non-stressed control mice. The result of protein expressions and ultrastructural changes were consistent with the behavioral results. Our study suggested that downregulation of SIRT1 in BLA has certain beneficial effect on CUMS-induced depression-like behaviors such as anorexia, anhedonia, hopelessness and despair. In addition, the increased expression of SIRT1 may be the immediate cause of depressive-like symptoms. The abnormal expression of SIRT1 may affect the transcriptional regulation mechanism and signaling protein acetylation, affecting neuroplasticity and ultimately contribute to MDD. In the stress-susceptible mice, these two mechanisms may co-exist, but the specific mechanism needs further research.
Keywords:AAV-SIRT1  AAV-SIRT1-shRNA  BDNF  BLA  CUMS  NR1  SIRT1  TrkB
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