P11调控NAc-mPFC/VTA投射通路参与抑郁症快感缺失的机制研究

Anhedonia is one of the core symptoms in depression which plays an critical role in occurrence, development and prognosis of the disorder, but the mechanism of anhedonia in depression is still poorly understood. According to our previous study and latest reports, the P11 expression in accumbens nucleus (NAc), medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) correlats closely with the depression happening and antidepressant effect. However, the regions listed above are also deeply involved in anhedonia. This stduy will focus on our previous findings on P11 and base on the neural circuit abnoraml hypothesis in depression. Marking anhedonia as the start point, observing excitatory and inhibitory synaptic structrue, digging into the relationship between synapse-associated protein and P11 expression will shed light on the research path. The optogenetics will be used to detect cholinergic and GABA neuron projecting and its association with anhedonia at the same point. Furthermore, genetic engineering will be deployed to explore the P11 gene silencing/over expression and the potential correlation with NAc-mPFC/VTA neuron projecting in the background of anhedonia. Stepwise into the role of P11 mediating NAc-mPFC/VTA projection pathways and more into depreesion will enrich the unstanding of anhedonia and help to improve the early diagnosis along with treatment outcome.

快感缺失是抑郁症的核心症状并显著影响疾病的发生、发展和转归，但其发生机制不详。我们的前期研究结果和最新文献报道均发现伏隔核（NAc）、内侧前额叶（mPFC）和腹侧被盖区（VTA）的P11表达与抑郁症发生和抗抑郁剂疗效关系密切，而上述脑区恰好是快感缺失发生的关键脑区。本研究将基于P11参与抑郁症的前期研究积累，以抑郁症快感缺失为切入点，紧扣抑郁症“神经环路异常”假说，结合突触显微结构观察方法探索以上脑区兴奋性和抑制性突触结构和突触相关蛋白与P11表达的关系；利用光遗传技术手段分析NAc-mPFC/VTA的胆碱能和γ-氨基丁酸能神经元投射及对快感缺失的作用；进一步探讨NAc脑区P11基因沉默/过表达对NAc-mPFC/VTA神经元投射和快感缺失的影响，逐层深入研究P11通过调控NAc-mPFC/VTA投射通路参与抑郁症快感缺失的机制，为抑郁症快感缺失的早期识别和有效治疗提供科学依据。

快感缺失是抑郁症（MDD）的核心症状并显著影响疾病的发生、发展和转归，但其发生机制不详。我们的前期研究结果和最新文献报道均发现伏隔核（NAc）、内侧前额叶（mPFC）和腹侧被盖区（VTA）的P11表达与MDD发生和抗抑郁剂疗效关系密切，而上述脑区恰好是快感缺失发生的关键脑区。本研究基于P11参与抑郁症的前期研究积累，以抑郁症快感缺失为切入点，观察慢性不可预见性温和应激（CUMS）抑郁模型及艾司西酞普兰抗抑郁治疗后快感缺失核心脑区P11-tPA-BDNF蛋白及mRNA表达水平改变。并对基础研究进行临床转化，对MDD及其他精神障碍患者外周血清中P11-tPA-BDNF通路蛋白及相关影响因子（VGF和BICC1）进行检测，发现其可作为外周血生物标记物，为抑郁症与其他精神障碍鉴别诊断提供生物学依据，也为抑郁症快感缺失的早期识别和有效治疗提供理论依据。