杏仁核-海马CA1区-前额叶皮层环路异常在抑郁发生中的作用

Anhedonia is the core symptom of major depressive disorder, which affects up to 8-12% of the population word wild and will be the leading cause of global disability burden by 2020. Although great development has been achieved since the first introduction of pharmacological antidepressant medications in the 1950s, we know little about the mechanisms that are involved in the dysfunctions of neural circuits..Amygdala (AMG), medial prefrontal cortex (mPFC) and hippocampus are three candidate areas for impaired functions of major depressive disorder. A new wonderful research published on Neuron this year found that parvalbumin-positive (PV) neurons are bias in target selection by both the excitatory and inhibitory local connections in CA1 region, and PV neurons further segregated among deep CA1 pyramidal cells (PC), preferentially innervating the AMG-projecting PCs but receiving preferential excitation from mPFC projecting PCs, indicating that PV neurons play the important role in the heterogeneous PV-PC microcircuits. Now, we found that the number of PV neurons was increased in CA1 in multiple behavioral models of depression, suggesting that dysfunction of the AMG-CA1-mPFC circuit was developed in the pathophysiology of depression..In this project, using optical genetics, gene modulations, behavioral tests and pharmacological approaches, we try to understand the role of dysfunction of AMG- CA1-mPFC neural circuit in depression and we hope our study will give spark ideas for the development of novel strategies for fast antidepressant.

“不快乐（anhedonia）”是抑郁症的核心症状，也是最为常见的、与恐惧相关的负性情绪；目前不清楚其环路异常抑制。最新的研究发现CA1区PV神经元在杏仁核-CA1-前额叶皮层环路中发挥重要的调节作用；而我们的前期研究发现，在多种抑郁动物模型上，抑郁动物CA1区PV神经元数目增加，而抑郁非易感动物无异常；提示杏仁核-CA1区-前额叶皮层环路异常在抑郁发生中具有重要的作用。本项目拟采用免疫荧光标记、动物行为学、药理学、电生理记录以及光遗传学等技术方法，阐明杏仁核-CA1区-前额叶皮层环路异常在抑郁发生中的作用，为揭示抑郁发生机制、寻找快速抗抑郁新方法提供新思路。

抑郁症是最为常见的心境障碍；以其高发病率、高致残率以及严重自杀倾向，已成为一个公共健康问题。目前不清楚抑郁症的发病机制。阐明抑郁发生的异常神经环路机制是当前抑郁症研究的关键科学问题之一。本课题采用基因干预、病毒示踪等技术方法在多种抑郁动物模型上研究了抑郁发生的神经环路异常机制。我们发现社会失败模型和慢性温和应激抑郁模型上，腹侧海马CA1区PV神经元数目增多；选择性杀死腹侧海马CA1的PV神经元能够诱导动物出现类似于精神分裂的行为表型；提示海马CA1区PV神经元，特别是腹侧海马CA1区PV神经元参与了情感调控。采用c-fos示踪技术，我们发现CSDS 1天后，动物未出现抑郁表型，但传统认识上与抑郁发生相关的脑区被激活；CSDS 10天后，动物出现了抑郁表型，这些脑区的c-fos阳性细胞无改变，但体感神经环路相关脑区发生了显著变化；采用药理学、基因干预策略，我们发现不同方式抑制听皮层产生不同的行为表型：TTX抑制AU1引起抑郁样行为；但激活AU1的PV神经元，抑制AU1的椎体神经元活动则引起抗抑郁样行为；提示PV神经元介导的AU1神经环路异常可能参与抑郁发生。本项目的开展为揭示抑郁发生神经环路异常机制提供了新思路。本项目进行期间，目前已完成3篇论文，其中发表1篇，修回1篇，投稿1篇；获得广东省科技进步一等奖1项；申请国家发明专利2项，其中获得批准1项；获得科技部创新团队等后续项目资助350万元；1人入选国家万人计划，1人入选广东特支计划领军人才；培养高级实验师1人，博士后2人，博士研究生4人。