Circuit-based study of sex differences in stress-induced dopamine down regulation

项目总结 女性被诊断为抑郁症的可能性是男性的两倍，而且抑郁症更严重， 与女性更严重的功能障碍有关。然而，这其中的神经生物学基础 女性对抑郁症的易感性增加是未知的。传统上，多巴胺(DA)系统是 与快感缺乏有关，即无法从通常有益的刺激中获得快感，并且一直 最近与抑郁症的病理生理学有关。重要的是，快感缺乏症是 抑郁症和其他涉及DA系统失调的精神疾病，其特征是 其患病率和性质存在性别差异，如精神分裂症和吸毒成瘾。事实上，最近 有证据表明，DA系统功能低下(即DA神经元减少)之间存在因果联系 与抑郁相关的行为(如快感缺乏、绝望)。令人惊讶的是，人们对DA知之甚少 女性体内的系统功能。因此，表征基线DA系统功能，以及应激诱导 在这个系统内的改变，是理解性二型在病因中的重要一步。 抑郁症和其他精神疾病。此外，鉴于发展议程系统与 抑郁症，针对DA系统功能障碍的新干预措施有显著的潜在好处 抑郁症。总之，这项提议的目的有三个：1)定义基线行为和DA系统 雄性和雌性大鼠的功能2)比较应激诱导的行为和VTA DA神经元的适应 雄性和雌性大鼠，以及3)识别调节对应激源(即急性， 慢性)，对女性有不同的影响。我们的主要假设是，女性更容易患上 应激对行为和VTA活动的有害影响，这些影响是通过 VSub-NAC途径的代偿(即活性)减少。为了测试这一点，我们将使用集成的 系统导向的方法侧重于体内的行为分析、电生理学、化学遗传学。在这 我们希望为男性和女性的DA系统的调节提供一个独特的视角 DA系统在应激诱导的抑郁样症状(如快感缺失、绝望)中的作用 在基线条件下，在急性发作后，两性DA系统的潜在调节机制 应激(即FST后)和UCMS后。最终，这些发现可能会揭示女性人数增加的原因 易患抑郁症，并导致抑郁症和其他疾病的新治疗策略的发展 与DA系统功能异常和快感缺乏有关的精神障碍。

PROJECT SUMMARY Women are twice more likely than men to be diagnosed with depression, and depression is more severe and associated with greater functional impairment in women. However, the neurobiological underpinnings of this increased female susceptibility to depression are unknown. The dopamine (DA) system has traditionally been associated with anhedonia, the inability to derive pleasure from normally rewarding stimuli, and has been recently implicated in the pathophysiology in depression. Importantly, anhedonia is a core symptom of depression and other psychiatric diseases involving DA system dysregulation and characterized by substantial sex differences in their prevalence and nature, such as schizophrenia and drug addiction. Indeed, recent evidence has demonstrated a causal link between a hypofunctioning DA system (i.e. decreased DA neuron activity) and depression-related behaviors (i.e. anhedonia, despair). Surprisingly, little is known about DA system function in females. Thus, characterizing baseline DA system function, as well as stress-induced alterations within this system, is an essential step in understanding sexual dimorphism in the etiology of depression and other psychiatric disorders. Moreover, given the strong link between the DA system and depression, there is a significant potential benefit from novel interventions targeting DA system dysfunction in depression. In sum, the purpose of this proposal is threefold: 1) to define baseline behavioral and DA system function in male and female rats 2) to compare stress-induced behavioral and VTA DA neuron adaptations in male and female rats and 3) to identify potential pathways mediating susceptibility to stressors (i.e. acute, chronic) that differentially impact females. Our overarching hypothesis is that females are more susceptible to the deleterious effects of stress on behavior and VTA activity, and that these effects are mediated by decreased compensation (i.e. activity) in the vSub-NAc pathway. To test this, we will use an integrated systems-oriented approach focused on behavioral assays in vivo electrophysiology, chemogenetics. In this way, we hope to provide a unique perspective on the regulation of the DA system in males and females, the role of the DA system in stress-induced depressive-like symptomatology (i.e. anhedonia, despair), and the mechanisms underlying modulation of the DA system in both sexes under baseline conditions, following acute stress (i.e. post-FST) and after UCMS. Ultimately, these findings could shed light on the increased female vulnerability to depression and lead to the development of novel treatment strategies for depression and other psychiatric disorders implicating aberrant DA system function and anhedonia.