The Neural Basis of Social Stress-induced Depression

 描述(由申请人提供)：尽管严重抑郁障碍(MDD)的流行率增加，并继续投资于寻找有效的治疗方法，但大多数治疗方法只是缓解症状，而不是解决病因。这种疾病通常需要长期治疗，而且往往会有许多副作用。抑郁的发生通常是由压力和/或厌恶的刺激引起的。动物也容易受到压力的影响。例如，在啮齿动物身上反复的社会失败压力会导致普遍而持久的行为变化，类似于MDD患者的症状，包括社交障碍、缺乏动力、无助和快感缺失。虽然与抑郁相关的行为变化已经得到了很好的研究，但对伴随而来的神经回路变化的了解相对较少。因此，我们将从解剖学和功能上剖析不同的神经回路，这些神经回路调节各种应激诱导行为。 小鼠更好地了解伴随着人类MDD患者大脑的机械性变化，这将有助于设计革命性的电路特定和阶段特定的诊断和 治疗。为了实现这一点，我们将结合多种技术来研究奖赏回路的主要组成部分之一腹侧苍白球(VP)的神经回路机制，包括光遗传学、病毒介导的示踪、电生理学和实时体内纤维光度法，以解决由重复的社会失败应激引发的潜在抑郁行为。我们的初步发现表明，不同类型的神经元投射到不同的靶结构，这可能涉及抑郁行为的不同方面。首先，我们将利用光遗传学和病毒示踪的方法，确定VP环路在反复社会失败应激诱导的抑郁行为中的投影特定作用。其次，使用体内纤维光度法和新开发的病毒工具，我们将以细胞类型和投射特异性的方式直接监测VP回路的神经活动动态 在活体内实时观察社会交往过程中反复的社会失败应激前后，以及他们对抗抑郁治疗的反应。第三，使用体外电生理学分析，我们将检测应激诱导的电路特异性电生理和突触变化。这些工作的完成将极大地有利于MDD的研究和治疗，也将为以特定电路方式研究精神障碍提供一个基本的框架。

 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.