青少期早期社会应激对抑郁样行为和前额叶GABA能系统的影响及其关系研究

Adolescent social stress is an important risk factor for the development and onset of major depression during adulthood. However, the underlying neural and molecular mechanisms remain to be illustrated. Using a social defeat stress model, we found in the previous study that early adolescence (EA, PND28-37) was a critical time window during which social stress induced long-term changes in depressive behaviors characterized by the reduced social interaction and impaired cortically-mediated cognitive function, as well as in GABAergic activities of prefrontal cortex (PFC). Based on these findings, we will combine with brain region specific pharmacological, electrophysiological, molecular biological techniques such as western blotting, PCR, immunohistochemistry, behavioral and other methods to investigate the roles of PFC GABAergic system in the depressive behavior caused by EA social stress. This project aimed to determine whether developmental dysfunction of PFC GABAergic system induced by EA social stress is involved in the onset and development of depressive behavior. Moreover, the role of PFC GABAergic target molecules in mediating the negative effects of EA social stress will be further determined by using transgenic mice. We also determined the effects of direct PFC GABAergic pharmaceutical manipulation on depressive behavior induced by EA social stress. The proposed project will help to reveal the neurobiological mechanisms of EA social stress-induced social behavior, emotional and cognitive impairment, and a better understanding of GABAergic actions and their alteration by early stress will lead to improved antidepressant treatment strategies.

青少期社会应激是导致成年抑郁症发生发展的重要风险因素，但上述过程涉及的神经和分子机理目前并不清楚。采用一种拟人类社会挫败应激模型，前期研究发现青少期早期是社会应激导致以社交行为减少和前额叶执行功能障碍为特征的抑郁样行为持久改变的关键阶段，同时伴随前额叶GABA能活动改变。 在此基础上，本项目将深入研究抑郁样行为发生发展和抗抑郁治疗过程中前额叶GABA能作用机制。 采用转基因小鼠，综合运用药物学，行为学，分子生物学，神经化学和电生理等方法，研究青少期早期社会应激对行为及前额叶GABA能神经元形态和功能发育的影响及其相互关系，抗抑郁药物是否通过调节前额叶GABA能系统改善应激诱导的抑郁样行为，进一步直接通过前额叶GABA能药物拮抗应激诱导的抑郁样行为，从而为确立抑郁症高风险人群早期识别的行为和生物学指标，建立以GABA能调控为基础的新型抗抑郁分子靶标提供实验依据

青少期负性社会经历与成年期增加的抑郁症患病风险、难治率与高复发率密切相关，导致上述问题的心理神经基础认识尚不充分。采用一种拟人类病因学社会挫败应激模型，本项目深入研究了青少期社会应激诱发的抑郁样行为发生与治疗中的前额叶皮质GABA能作用机制。.首先，基于抑郁症症状维度诊断标准，系统评估了青少期社会应激诱发的成年抑郁症不同症状表型与前额叶皮质GABA能系统改变间的关系。青少期应激导致GABA能系统的输出能力持续降低，主要表现在GABA能神经元合成酶GAD65的转录和蛋白水平降低；椎体神经元接收到的GABA能神经元的sIPSC累计频率和振幅显著降低。.在此基础上，进一步调查了参与GABA能系统损害的潜在分子和通路机制。我们发现，GABA能突触传递抑制受脑源性神经营养因子（BDNF）-TrkB受体通路调节， Bdnf IV剪切体特异性调节GABA能突触传递介导了青少期应激诱导的抑郁样行为发生，且Bdnf IV启动子区组蛋白抑制性表观修饰改变参与该过程。另外，该部位主要免疫活性细胞小胶质细胞及其释放的免疫因子TNFα活动不足介导了青少期社会应激诱发的抑郁症认知功能障碍和GABA能突触传递损害，TNFα受体2，而非受体1表达降低参与这一过程。这些提示前额叶皮质GABA能系统作为神经可塑性-免疫交互作用的共同下游通路，可能是青少期社会应激诱导抑郁样行为的重要病理生理改变。.上述分子和通路调节的GABA能系统在抗抑郁治疗中的作用系列研究显示：慢性抗抑郁药物治疗能够改善或恢复青少期应激诱导的上述抑郁样行为和生理改变。进一步，急性给与TrkB受体激动剂激活BDNF信号转导，或者急性免疫激活剂增强中枢小胶质细胞及其相关细胞因子活动都可以快速（24小时内）改善青少期社会应激诱导的某些抑郁样行为改变和GABA能损害。.这些发现鉴别了一系列抑郁症高风险人群识别的行为学和生物学指标，并为建立以GABA能调控为基础的新型抗抑郁靶标提供了科学依据。. .