目击应激对抑郁行为的影响及其神经机制

It is well known that exposure to severe stress increases the risk of developing mood disorders, including depression. The psychological effects of direct exposure to physical stressors have been well documented. However, stress-induced emotional disorder can not only occur in persons who directly affected by stressors, but also in those persons who become indirectly affected by their close contact with individuals directly exposed to stress. Such indirect experience of stress, also named witnessing stress, can precipitate a more depression-like syndrome in other individuals. Witnessing stress involves the transfer and acquisition of negative affective and dysfunctional cognitive states due to prolonged and extended contact with others, such as family members, who have been directly exposed to stress. As such, witnessing stress experience refers to a spread of stress from the victim to those who have close contact with them. It is claimed that exposure to intense video presentations of stressful events can also lead to witnessing stress-related disorder. Although depression occurs through direct experience of stress, humans and other animals can be affected by the stress of other individuals. However, very little is known about the neuronal architecture and mechanisms underlying the depressive behavior induced by witnessing stress.The main reason is that animal models of such witnessing emotional stress are scarce. In the current study, we used a modified social defeat paradigm to investigate the depression-like behavioral abnormalities. Subsequently, the neuronal activity in mesolimbic dopamine pathway, composed of dopaminergic neurons in the midbrain ventral tegmental area (VTA) and their projections to the nucleus accumbens (NAc), will be monitored. Additionally, the behavioral phenotype will be observed by excitation or inhibition of VTA-NAc reward circuit neuronal activity to determine the regulatory role of different types of neurons on the depressive-like behavior. Since neuronal activity is one of the important factors in encoding and regulating reward function, as well as closely related to the behavioral performance, further investigation on neuronal firing pattern in specific brain regions will provide new targets for the treatment of depression. Since being affected by others' stress is a pervasive feature of many species, the elucidation of underlying neuronal mechanisms is critically important as they underlie witnessing stress between individuals who have close contact each other as they underdoing witnessing stress and allow adaptive behavior in uncertain social environments.

直接暴露于应激环境会增加抑郁症等精神疾病的患病风险。应激引起的情感障碍不仅发生于应激事件的亲身经历者，同时还发生于应激事件的目击者。这种对目击者的间接应激也称为"目击应激"，即应激事件的目击者会将应激亲身经历者的负面情感体验及异常的行为表现转移到自身，从而使应激的不良影响从亲历者扩大到目击者。然而，目前尚缺少有效的模拟目击应激导致抑郁行为的动物模型。本研究采用改进的小鼠社会心理应激模型，研究目击应激对抑郁行为的继发影响，并分析在这一过程中，不同亲密程度的个体是否对目击应激的反应性不同。同时，从抑郁症相关神经环路的角度，揭示目击应激引起抑郁行为的神经元编码规律以及突触结构和功能的变化特征。此外，通过光遗传技术调节神经元兴奋性，明确特定类型神经元在目击应激诱导抑郁行为中的作用。目击应激是存在于多物种的普遍现象，研究目击应激的神经机制能够促进个体积极应对应激事件，降低间接应激对情绪的负面影响。

应激是除了遗传因素之外导致抑郁症的非常重要的环境因素。值得注意的是，应激不仅发生于个体的直接经历，同时还发生于目睹其他个体经历应激事件。这种间接的应激被称为目击应激，已经有实验证实目击应激可以同直接应激一样诱导动物出现抑郁样行为。然而，个体之间不同的亲密关系对于目击应激的反应性是不同的。本项目通过模拟不同亲密关系的个体对目击应激的不同反应性，并对其进行评价，并阐明这一现象背后的神经调控机制。研究结果显示，在小鼠社会心理应激实验中，具有亲密关系的小鼠目睹同伴经历应激后，也表现出与直接经历应激的小鼠同样的抑郁样行为，并伴有应激激素血浆皮质酮的含量升高。在大鼠束缚应激实验中，目睹亲密同伴经历应激也会使自身表现出抑郁样和焦虑样行为，而目睹陌生同伴经历束缚应激则不会引起自身出现行为学的异常。分子生物学检测结果显示，目击应激显著降低亲密小鼠奖赏脑区伏隔核(NAc)的神经元活性， 多巴胺D2受体、突触后密度蛋白PSD95以及突触素(synapsin)的蛋白表达水平，表明伏隔核脑区的多巴胺受体及突触后的信号分子参与了亲密小鼠之间经历目击应激后产生的抑郁行为。抑制伏隔核脑区神经元活性既不影响亲密关系的建立，也不影响个体对目击应激的反应。抑制前额叶皮质脑区神经元活性不仅诱导亲密个体出现抑郁行为，同时导致陌生小鼠在经历目击应激后也出现抑郁样行为，表明破坏前额叶皮质脑区会增加个体对目击应激诱导抑郁行为的敏感性。 经脑立体定位手术在双侧前额叶皮层(mPFC)微量注射催产素，发现mPFC微注射催产素有助于亲密关系的建立，提高陌生小鼠的社交互动行为，并进一步增加陌生小鼠对目击应激的易感性。本课题的研究结果对于深入理解不同亲密关系的个体对目击应激的不同反应性，阐明导致亲密个体对于应激反应的阈值降低的原因，从而揭示这一现象背后的神经环路及神经元编码机制具有重要的科学意义，并将有助于阐明应激抵抗和应激易感的神经生物学机制，同时有助于最终发现更有效的抑郁症治疗手段。