基于VTA-NAc多巴胺通路介导的伏隔核突触重塑探究生命早期应激诱发青春期抑郁损伤的机制及四逆散干预作用

神经元亚群及神经环路重塑是抑郁症研究的热点。伏隔核（NAc）突触重塑在生命早期应激（ELS）后青春期抑郁损伤中起重要作用。新近研究表明，NAc不同神经元亚群D1-MSNs和D2-MSNs突触可塑性呈现出差异性，对抑郁样行为发挥不同作用。腹侧被盖区（VTA）投射至NAc的多巴胺通路可调控NAc突触重塑，且VTA-NAc多巴胺通路异常与抑郁样行为相关，但ELS下VTA-NAc多巴胺通路的作用以及调控D1/D2-MSNs突触重塑的机制尚不明确。基于肝调畅情志理论，以调肝解郁组方的四逆散可改善抑郁症状并调节中枢多巴胺含量。课题组近期发现，四逆散抗青春期抑郁作用与NAc突触重塑密切相关。因此，本研究拟利用特异性D1/D2R启动子病毒、光遗传学等手段，靶向VTA-NAc多巴胺通路，探讨生命早期应激下NAc不同神经元亚群突触重塑的机制及四逆散干预效应，为中医药防治青春期抑郁提供理论及实验依据。

Subtype-specific neuronal remodeling and circuits remodeling are the central focus of depression research. The synaptic remodeling in the nucleus accumbens (NAc) plays an important role in adolescent depression induced by early life stress (ELS).Recent studies have confirmed that D1-MSNs and D2-MSNs within the NAc display different adaptations in synaptic plasticity and contribute differentially to depression-like behavior. It has been shown that the ventral tegmental area (VTA) to NAc dopamine pathway could directly regulate synaptic remodeling in the NAc and the pathological adaptations in the VTA-NAc pathway contributed to depression-like behaviors. However, the role of VTA-NAc dopamine pathway in adolescent depression induced by early life stress and its potential mechanism of regulating D1/D2-MSNs synaptic remodeling are still unclear. SiNiSan, a classic prescription derived from the theory that it can regulate liver and smooth emotions, could improve depression symptoms and regulate dopamine concentration in the central system. Our latest researches have elucidated that the protective effect of SiNiSan on adolescent depression induced by ELS is closely related to the synaptic remodeling of NAc. Therefore, we intend to explore the role of SiNiSan in adolescent depression and its potential mechanism underlying synaptic remodeling on distinct neuronal subpopulations of NAc through the VTA-NAc dopamine pathway by using specific D1/D2R promoter viruses、photogenetic technology and other methods. The research may provide theoretical and experimental basis for the prevention and treatment of adolescent depression with traditional Chinese medicine.