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

项目摘要 女性被诊断为抑郁症的可能性是男性的两倍，抑郁症更严重， 与女性更大的功能障碍有关。然而，这一现象的神经生物学基础 女性对抑郁症的易感性增加是未知的。多巴胺（DA）系统传统上是 与快感缺乏有关，无法从正常的奖励刺激中获得快乐， 最近与抑郁症的病理生理学有关。重要的是，快感缺乏是一个核心症状， 抑郁症和涉及DA系统失调的其他精神疾病，其特征在于 在患病率和性质上存在性别差异，如精神分裂症和吸毒成瘾。事实上，最近 有证据表明，功能减退的DA系统（即DA神经元减少） 活动）和抑郁相关行为（即快感缺乏，绝望）。令人惊讶的是，人们对DA知之甚少 女性的系统功能。因此，表征基线DA系统功能，以及应激诱导的 在这个系统中的改变，是理解性二型性的病因学的重要一步。 抑郁症和其他精神疾病。此外，鉴于DA系统与 抑郁症，有一个显着的潜在好处，从新的干预措施，针对DA系统功能障碍， 萧条总之，本提案的目的有三：1）定义基线行为和DA系统 2）比较应激诱导的行为和腹侧被盖区DA神经元适应， 雄性和雌性大鼠和3）鉴定介导对应激源（即急性， 慢性），对女性的影响不同。我们的总体假设是，女性更容易受到 压力对行为和VTA活性的有害影响，这些影响是由 vSub-NAc通路中的补偿（即活性）降低。为了测试这一点，我们将使用一个集成的 系统导向的方法集中在体内电生理学，化学遗传学的行为测定。在这 通过这种方式，我们希望为男性和女性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抑郁症（即快感缺乏、绝望）中的作用，以及 在基线条件下，急性给药后， 应激（即FST后）和UCMS后。最终，这些发现可能会揭示增加的女性 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。 涉及异常DA系统功能和快感缺乏的精神障碍。

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.