VTA microcircuit dynamics during chronic stress

摘要 在这个项目中，我们将调查在腹侧被盖区（VTA）的抑制动力学过程中， 慢性压力GABA能神经元占腹侧被盖区神经元的35%，但相对而言知之甚少 关于他们这些细胞是邻近多巴胺能神经元的关键调节器，并且是鲁棒的。 由急性应激激活。因此，腹侧被盖区GABA神经元有望成为应激反应的重要介质。 对VTA的影响然而，这些神经元如何对慢性压力做出反应仍然是未知的。在 这个建议，我们将采取多学科的方法，利用电生理学，光遗传学， 行为，和纤维光度法来解决慢性压力导致持续性 VTA GABA神经元的过度活跃，这是适应不良行为出现的基础。 应答在第一个目标中，我们将研究VTA多巴胺神经元抑制的动力学， 压力下的VTA GABA神经元。在第二部分中，我们将研究 在应激过程中，VTA GABA神经元的突触输入发生变化。在第三个目标中，我们将研究 VTA GABA神经元的体内活性是否有助于出现个体差异 社交快感缺失症的症状这些研究有可能为我们的研究做出重大贡献。 了解奖励系统是如何被压力改变的，并可能导致新的途径， 开发抑郁症和其他与压力有关的疾病的治疗方法。

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.