The Neural Basis of Social Stress-induced Depression

 描述（由申请人提供）：尽管重性抑郁症（MDD）的患病率增加，并继续投资于确定有效的治疗方法，但大多数治疗方法只是缓解症状，而不是解决原因。这种疾病通常需要长期治疗，并且通常包括许多副作用。抑郁症的发作通常是由压力和/或厌恶刺激引起的。动物也容易受到压力的影响。例如，啮齿类动物中反复的社交失败压力诱导了广泛和持久的行为变化，类似于MDD患者中观察到的症状，包括社交互动受损、缺乏动力、无助和快感缺乏。虽然与抑郁症相关的行为变化已经得到了很好的研究，但对伴随的神经回路变化的了解相对较少。因此，我们将解剖和功能解剖不同的神经回路介导的各种压力诱导的行为， 小鼠，以更好地了解人类患者伴随MDD的大脑机制变化，这将有助于设计革命性的特定于电路和特定于阶段的诊断， 治疗。为了实现这一点，我们将研究腹侧苍白球（VP）的神经回路机制，奖励回路的主要组成部分之一，与各种技术相结合，以解决电路水平的机制，包括光遗传学，病毒介导的跟踪，电生理学，和真实的时间在体内纤维光度测定引起的反复社交失败压力的抑郁行为。我们的初步研究结果表明，VP中不同类型的神经元投射到不同的靶结构，这些结构可能涉及抑郁行为的不同方面。首先，我们将使用光遗传学和病毒追踪的方法来确定VP环路在重复社交失败压力诱导的抑郁行为中的投射特异性作用。第二，利用在体纤维光度学和新开发的病毒工具，我们将直接监测VP回路的神经活动的动力学，在细胞类型和投影特异性的方式 在体内真实的时间内社会交往前后反复的社会失败应激，及其对抗抑郁治疗的反应。第三，使用离体电生理学分析，我们将检查由应力引起的电路特异性电生理和突触变化。这些工作的完成将对MDD的研究和治疗有很大的帮助，也将为以特定回路方式研究精神障碍提供一个基本框架。

 DESCRIPTION (provided by applicant): Despite the increased prevalence of major depressive disorder (MDD) and the continued investment into identifying effective cures, most treatments merely alleviate symptoms rather than addressing causes. Long-term treatments are generally required for this disease and often include many side-effects. The onset of depression is often precipitated by stressful and/or aversive stimuli. Animals, too, are susceptible to the effects of stress. For example, repeated social defeat stress in rodents induces pervasive and long-lasting behavioral changes similar to the symptoms seen in patients with MDD including impaired social interaction, lack of motivation, helplessness and anhedonia. While the behavioral changes associated with depression have been well-studied, there is relatively little knowledge about the accompanying changes in the neural circuitry. Thus, we will anatomically and functionally dissect the distinct neural circuits mediating various stress-induced behaviors in mice to better understand the mechanistic changes in the brain accompanying MDD in human patients, which will help to devise revolutionary circuit-specific and stage-specific diagnosis and treatments. To accomplish this, we will examine the neural circuit mechanism of ventral pallidum (VP), one of the major components of reward circuitry, underlying depressive behaviors elicited by repeated social defeat stress in combination with a variety techniques to address circuit-level mechanisms, including optogenetics, viral mediated tracing, electrophysiology, and real time in vivo fiber photometry. Our preliminary findings showed that different types of neurons in VP project to different target structures which may be involved in different aspects of depressive behaviors. First, we will define the projection specific roles of VP circuity in depressive behaviors induced by repeated social defeat stress using optogenetics and viral tracing methods. Second, using in vivo fiber photometry and newly developed viral tools, we will directly monitor the dynamics of neural activity of VP circuitry in cell-type and projection specific manner in vivo in real time during social interaction before and after the repeated social defeat stress, and their response to anti-depressant treatment. Third, using ex vivo electrophysiology analysis we will examine the circuit-specific electrophysiological and synaptic changes induced by the stress. The accomplishment of the proposed works will be greatly beneficial to both the research and treatment of MDD, and will also provide a fundamental framework for studying mental disorders in circuit-specific manner.