The Impact of Stress-induced KCC2 Downregulation on Mesolimbic Dopamine Signaling and Reward Processing

环境压力是神经精神障碍的主要风险因素，但最根本的 该漏洞背后的机制尚不清楚。越来越多的证据表明，与压力有关 精神病理学的产生部分源于大脑中脑边缘奖赏回路的失调，这主要是 由腹侧被盖区(VTA)和伏隔核(NAC)组成。我们在啮齿动物身上的数据表明 应激通过位于VTA的负离子转运体KCC2功能降低来调节奖赏过程 GABA神经元。这种形式的应激诱导的GABA能信号的神经适应尚未完全完成 我们计划研究它对大鼠多巴胺信号和奖赏处理的影响。vt.给出 VTA GABA神经元为中脑边缘多巴胺神经元提供了主要的抑制输入，我们将测量 这些神经元和应激诱导的KCC2下调对多巴胺信号的影响。这些研究 将解释功能上不同的多巴胺神经元活动的强直和时相模式，这可以是 受VTA-GABA神经元的差异调节。不同种类的多巴胺神经元参与了 在解剖学上，调节奖赏处理的不同方面的回路是分开的。测试压力是否会导致 KCC2功能低下以电路特有的方式调节多巴胺信号，我们将测量GABA能 传递到特定的多巴胺投射到NAC的核心、内侧和外侧壳。最终，我们 将研究应激诱导的KCC2下调和VTA GABA神经元在不同方面的作用 奖励处理。大鼠将暴露在急性压力下，我们将测量奖励学习和激励 在VTA GABA神经元中操纵KCC2的动机。行为任务将伴随着多个单元 电生理学和光遗传学进一步探讨不同VTA神经元类型对区分的贡献 奖励流程。综上所述，这些研究将全面考察压力对奖励的影响 处理并保持提高我们对复杂多巴胺GABA能调节的理解的潜力 发信号。

Environmental stress is a major risk factor for neuropsychiatric disorders, but the fundamental mechanisms underlying this vulnerability remains unknown. A growing evidence indicates that stress-related psychopathology arises in part from the dysregulation of brain mesolimbic reward circuitry, which is primarily comprised of the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Our data in rodents indicate that stress dysregulates reward processing via decreased function of anion transporter KCC2 located in VTA GABA neurons. This form of stress-induced neuroadaptation in GABAergic signaling has not been fully characterized, and we plan to investigate its impact on dopamine signaling and reward processing in rats. Given that VTA GABA neurons provide a major inhibitory input to the mesolimbic dopamine neurons, we will measure the impact of these neurons and stress-induced KCC2 downregulation on dopamine signaling. These studies will account for functionally distinct tonic and phasic modes of dopamine neuron activity, which can be differentially regulated by VTA GABA neurons. Heterogeneous populations of dopamine neurons participate in anatomically separate circuits that mediate different aspects of reward processing. To test if stress-induced KCC2 hypofunction dysregulates dopamine signaling in a circuit-specific manner, we will measure GABAergic transmission onto specific dopamine projections to the core, medial, and lateral shell of the NAc. Ultimately, we will examine the role of stress-induced KCC2 downregulation and VTA GABA neurons in different aspects of reward processing. Rats will be exposed to acute stress and we will measure reward learning and incentive motivation while manipulating KCC2 in VTA GABA neurons. Behavioral tasks will be accompanied by multi-unit electrophysiology and optogenetics to further explore the contribution of different VTA neuron types to distinct reward processes. Taken together, these studies will comprehensively examine the impact of stress on reward processing and hold the potential to improve our understanding of GABAergic regulation of complex dopamine signaling.