VTA microcircuit dynamics during chronic stress

摘要 在本研究中，我们将探讨腹侧被盖区（VTA）的抑制动力学 在慢性压力下。GABA能神经元占腹侧被盖区神经元的35%，但相对较少。 知道他们。这些细胞是邻近多巴胺能神经元的关键调节器， 被急性应激强烈激活因此，腹侧被盖区GABA神经元有望成为一个重要的介导者， 压力对VTA的影响然而，这些神经元如何对慢性炎症反应仍然是未知的。 应力在这项提案中，我们将采取多学科的方法，利用电生理学， 光遗传学、行为学和纤维光度学来解决慢性压力导致 VTA GABA神经元的持续过度活跃，这是适应不良出现的基础。 行为反应在第一个目标中，我们将研究VTA多巴胺抑制的动力学 VTA GABA神经元在应激过程中。在第二部分中，我们将研究 在应激过程中，VTA GABA神经元的突触输入强度发生变化。第三个目标，我们将 检查VTA GABA神经元的体内活性是否有助于个体差异， 应激后社交快感缺失的出现。这些研究有可能为 我们对奖励系统如何被压力改变的理解，并可能导致新的途径 用于开发抑郁症和其他压力相关疾病的治疗方法。

ABSTRACT In this project, we will investigate the dynamics of inhibition in the ventral tegmental area (VTA) during chronic stress. GABAergic neurons make up 35% of neurons in the VTA, but relatively little is known about them. These cells are critical regulators of neighboring dopaminergic neurons, and are robustly activated by acute stress. VTA GABA neurons are thus poised to be a significant mediator of stress’s effects on the VTA. It remains unknown, however, how these neurons respond to chronic stress. In this proposal, we will take a multidisciplinary approach, utilizing electrophysiology, optogenetics, behavior, and fiber photometry to address the hypothesis that chronic stress leads to persistent hyperactivity of VTA GABA neurons and that this underlies the emergence of maladaptive behavioral responses. In the first aim, we will examine the dynamics of inhibition of VTA dopamine neurons by VTA GABA neurons during stress. In the second, we will investigate how activity of and strength of synaptic inputs onto VTA GABA neurons changes during stress. In the third aim, we will examine whether in vivo activity of VTA GABA neurons contributes to individual differences in the emergence of social anhedonia post-stress. These studies hold the potential to contribute significantly to our understanding of how the reward system is altered by stress and may lead to novel avenues for the development of therapeutic treatments for depression and other stress-linked disorders.