产后抑郁症中脑5-羟色胺能神经环路变化的分子机制研究

Postpartum depression (PPD) is a major public health problem for which epidemiological data has documented a high prevalence. In affected individuals, it has significant psychological and/or physical effects for both mother and child. Correlations between adolesent behavioral and cognitive disorders and exposure to PPD have been reported. However, the etiology of PPD remains elusive. Accumulated evidence suggests that the midbrain serotonin (5-HT) system is implicated in pathology, but the relevant mechanisms underlying neuronal plasticity of serotonergic neural pathways in the midbrain are still far from being understood.Our previous data demonstrated a correlation between 5-HT1A receptor deficiency and PPD, by showing an activation of the serotonergic pathway in a PPD rat model after colorectal balloon distention. Furthermore, exogenous progesterone could upregulate the expression level of 5-HT2A receptors. In order to evaluate the alteration of midbrain serotonergic neural circuits and amygdaloid projections, ascertain whether an activation of mTOR pathway is implicated in PPD, and elucidate the molecular mechanism underlying the modulation actions of progesterone in serotonergic neuronal circuits, the primary focus of this proposal is to investigate the alteration of midbrain serotonergic neural circuits in a rat PPD model by using an integrated multidisciplinary approach, including cellular, molecular, gene silencing, tract tracing, optogenetic, anterograde and retrograde tract tracing, as well as, diffusion tensor imaging methods. Our findings will provide novel theoretical bases which could provide poteintial therapeutic targets for the treatment of PPD.

产后抑郁症（PPD）是危害公共健康的重大难题，发病率高，严重危害产妇的身心健康，并影响婴幼儿智力和行为发育。迄今PPD确切病因尚不明了，脑内5羟色胺（5-HT）能系统参与PPD的发病和进展，但相关的中脑5-HT能神经通路内神经元活性和突触可塑性变化及机制仍不清楚。前期研究显示：5HT 1A受体缺乏与抑郁样行为有关；PPD大鼠直肠扩张刺激后出现5-HT神经通路激活；外源性孕酮可上调大鼠海马5-HT 2A受体水平。本项目在前期研究基础上，利用PPD大鼠模型，结合体光遗传学、基因沉默、神经束路示踪、DTI成像、行为学测试和分子生物学检测等方法，标记并实时调控5-HT能神经元活性，明确5-HT能神经通路内mTOR信号转导通路激活、神经元突触重塑和纤维束投射等变化，揭示孕酮影响中脑5-HT能神经通路参与PPD发病和进展的分子机制，为寻找治疗PPD的新药靶点提供参考。

产后抑郁症(PPD)发病率高，严重危害产妇的身心健康，影响婴幼儿智力和行为发育，但PPD确切病因不明，为目前神经科学研究的热点和难题。前期研究显示：脑内5-HT能神经参与PPD的发病和进程；神经元微管骨架是树突棘形成和维持的基础，而树突棘形态变化与许多精神疾病密切关联；自噬参与抑郁症的病理过程。本项目首先建立PPD大鼠模型，妊娠晚期给予孕酮或产后给予氟西汀药物干预，开展行为学评估并动态检测海马神经元突触重塑，探究5-HT能神经环路内自噬相关信号通路、突触重塑变化。研究发现孕酮和氟西汀可通过上调MAP-2和synaptophysin，保护微管骨架，提高PPD大鼠海马CA3区神经元树突棘密度，改善大鼠产前慢性应激引起产后抑郁样行为。其次利用5-HT能神经元携带红色荧光的ePET-Ai9转基因小鼠构建PPD模型，观察行为学变化，分析5-HTAR和自噬的表达变化，发现转基因PPD小鼠5-HT2AR和自噬相关蛋白ATG5、LC3表达上调，细胞自噬激活且有时间效应、5-HT2AR参与其中。再次基于cre-loxp技术构建Cx3CR1-ATG5转基因小鼠PPD模型，分析小胶质细胞和自噬在PPD中对5-HT2AR的调控作用，我们发现敲除ATG5蛋白，阻断自噬的发生可减轻Cx3CR1-ATG5转基因PPD小鼠的焦虑抑郁行为。最后运用生物信息学方法筛选出与抑郁症发生相关的部分miRNA，预测分析了miRNA参与PPD进程和疗效的机制。本项目通过利用多种转基因技术成功构建PPD模型，并给予孕酮或氟西汀干预，同时开展生物信息学分析，从多途径、多方式及多角度分析了PPD中脑5-HT能神经环路变化、自噬相关信号通路激活及神经元突触重塑等变化，明确药物影响PPD发病和进展的分子机制，为揭示PPD发病机制和寻找新的药物治疗靶点提供参考。