AKT/mTOR/BDNF Pathway Mediates the Antidepressant-like Effects of NAc-DBS in a Mouse Model of Depression

Ranran Li^1*Xuhui Huang¹Siwen Lv¹Yongtao Liu¹Ruijiao Li²Qianqian Li³Junyao Zhu²Wenjie Ren⁴Lujing Geng¹Shuangping Ma⁵Yi Yu²Lei Wang¹Wei Wang⁶

• ¹School of Life Sciences and Technology, North Henan Medical University, Xinxiang, China
• ²Engineering Technology Research Center of Neurosense and Control of Henan Province, North Henan Medical University, Xinxiang, China
• ³Genetics and Prenatal Diagnosis Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
• ⁴Henan Collaborative Innovation Center of Prevention and treatment of mental disorder, North Henan Medical University, Xinxiang, China
• ⁵Henan Institutes of Health Central Plains, North Henan Medical University, Xinxiang, China
• ⁶Department of Physiology, School of Basic Medicine, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China

Deep brain stimulation of the nucleus accumbens (NAc-DBS) has been shown to ameliorate 6 depressive-like behaviors. However, the underlying mechanisms of action remain elusive. We 7 aimed to investigate the impact of NAc-DBS on synaptic spine alterations in hippocampus in a 8 depression mice model and unveil the possible signal pathway mediating such effects. The 9 experimental protocol involved exposing adult mice to chronic unpredictable mild stress (CUMS) 10 with or without NAc-DBS. Behavioral assessments were performed to evaluate the impact of 11 NAc-DBS on emotional alterations. Local field potential (LFP) recordings were employed to 12 examine the hippocampal neuronal activity in awake mice. Golgi-Cox staining was applied to 13 quantify modifications in dendritic spine density. Additionally, hippocampal protein expression of 14 postsynaptic density protein-95 (PSD-95), brain-derived neurotrophic factor (BDNF), and the 15 protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway were 16 analyzed. Results indicate that CUMS mice exhibited apparent depressive-like behaviors, 17 concomitant with reduced hippocampal high gamma oscillation power and synaptic spine density. 18 In addition, CUMS reduced the expression level of PSD-95 and BDNF in mice hippocampus, as 19 well as phosphorylated AKT and mTOR protein. The study revealed that NAc-DBS could 20 attenuate depression-like behaviors, restore high gamma oscillation power and enhance synaptic 21 spine density, potentially by increasing BDNF protein expression level and activating AKT/mTOR 22 signaling pathway. Furthermore, Rapamycin, a potent and specific mTOR inhibitor, was found to 23 moderate the effects of NAc-DBS. These findings suggest that NAc-DBS could enhance synaptic 24 spine density via AKT/mTOR/BDNF signal pathway, which may partially underline its potential 25 antidepressant effects in CUMS induced depressive models.