丘脑室旁核-伏隔核谷氨酸能神经环路介导社交挫败应激相关抑郁样行为的细胞与分子机制研究

Major depressive disorder, the second leading cause of disability worldwide, involves changes in neural circuit dynamics yet the mechanisms by which such changes occur remain largely unknown. The paraventricular thalamic nucleus (PVT), one of the putative stress sensors that are readily activated by both physical and mental stressors, sends heavy projections to the nucleus accumbens (NAc), a well-investigated brain region in the field of depression. This proposal is designed to dissect the paraventricular thalamic glutamatergic control of NAc for circuit-dynamics understanding of depression by using well-established sub-threshold and repeated social defeat stress (RSDS) paradigms in laboratory animals. Leveraging whole brain iDISCO+/ClearMapping, circuit-specific electrophysiology, optogenetics, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and retro-translating ribosome affinity purification combined with traditional pharmacological approaches, the project will focus on PVT-NAc neural circuit to 1) observe brain-wide, brain region- and projection-specific neuronal activity patterns following RSDS, 2) investigate potential causal links between brain region/circuit activity and depressive-like behaviors, 3) profile and validate potential circuit-specific molecules for treatment of depressive-like behaviors. Together, the approaches proposed here will integrate novel sophisticated technology to provide a novel thalamic circuit controlling social depressive-like behaviors as well as its pathway-specific molecular mechanisms. The findings of this project will not only contribute to our basic understanding of how a novel thalamic neural circuit controls social depressive-like behaviors, but will guide the development of new, potent, and specific therapies for depression.

重性抑郁障碍是全球第二大致残疾病，神经环路机制尚不清楚。丘脑室旁核是机体感受躯体和精神应激的前哨核团之一，有大量谷氨酸能纤维投射到伏隔核，后者在调控抑郁中发挥重要作用。本项目提出丘脑室旁核-伏隔核谷氨酸能投射可能是介导抑郁症的一个神经环路基础。基于该环路，本项目将采用小鼠社交挫败应激模型，运用全脑iDISCO+/ClearMap，环路特异性电生理学、光遗传学、DREADDs、逆向-翻译核糖体亲和纯化等技术结合药理学手段 1). 观察慢性社交挫败应激后全脑和脑区／投射特异性神经元活性改变，2). 研究脑区／投射特异性神经元活性与抑郁样行为之间的因果联系，3). 发现并验证社交挫败应激相关抑郁样行为的环路特异性分子机制。本项目的完成将揭示一个新的调控抑郁症的丘脑相关神经环路及其投射特异性分子机制，不但促进我们对丘脑相关神经环路调控抑郁行为的了解，还为开发新的、特异性治疗药物／策略提供了靶点。

重性抑郁障碍是全球第二大致残疾病，缺乏有效的治疗策略。探索重性抑郁障碍的脑机制有助于发现新的药物开发靶点或者物理干预靶向脑结构（比如深部脑刺激）。越来越多的证据提示，重性抑郁障碍是一个脑内神经环路相关的疾病，但其具体的神经环路与环路特异性的分子机制并不清楚。丘脑室旁核是机体感受躯体和精神应激的前哨核团之一，有大量纤维投射到伏隔核，后者在调控抑郁中发挥重要作用。在现有证据和申请人前期工作基础上，本项目提出丘脑室旁核-伏隔核投射可能是社交挫败应激相关抑郁样行为的一个神经环路基础。基于该环路，运用全脑iDISCO+/ClearMapping，环路特异性电生理学、光遗传学、DREADDs、逆向-翻译核糖体亲和纯化技术结合药理学手段，本项目1).观察了慢性社交挫败应激后全脑、脑区／投射特异性神经元活性改变，2).研究了脑区／投射特异性神经元活性与抑郁样行为之间的因果联系，3).发现了社交挫败应激相关抑郁样行为的环路特异性分子靶点。到目前为止，本项目取得了以下重要结果：1).利用iDISCO+/ClearMapping技术系统揭示了慢性社交挫败应激后全脑324个脑区的神经元活性变化，采用离体脑片电生理技术发现慢性社交挫败后易感动物丘脑室旁核及其伏隔核投射特异性神经元放电活动增加；2).发现丘脑室旁核-伏隔核谷氨酸能投射可以双向调控动物抑郁样行为；3).利用逆向-翻译核糖体亲和纯化技术初步揭示了调控丘脑室旁核-伏隔核投射特异性谷氨酸能神经元活动的分子基础，发现与整体丘脑室旁核神经元相比，投射特异性神经元高表达基因927个，低表达基因3078个，无差异表达基因51445个。本项目的结果初步证实丘脑室旁核-伏隔核谷氨能投射是一个新的调控社会型抑郁症的神经环路，并揭示了调控该环路活动的可能分子靶点，不但促进了我们对丘脑相关神经环路调控抑郁行为的了解，还为开发新的、特异性治疗药物／策略提供了靶点。另外，在原计划的基础上，本项目还初步构建了一个适用于雌性动物的社会型抑郁模型，为探索抑郁症性别差异性和性别特异性机制与治疗策略提供了模型工具。