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

压力诱导的 KCC2 下调对中脑边缘多巴胺信号传导和奖励处理的影响

基本信息

批准号：
10366588
负责人：
Alexey Ostroumov
金额：
$ 38.69万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366588
关键词：
Affect Anatomy Animals Anions Attenuated Basic Science Behavior Behavioral Brain Brain region Chlorides Chronic stress Complex Data Decision Making Desire for food Development Dopamine Down-Regulation Electrophysiology (science)Exposure to Fire - disasters Hyperactivity Impairment Incentives Individual Label Lateral Learning Link Measures Medial Mediating Molecular Motivation Neurons Nucleus Accumbens Pathway interactions Pattern Pharmacology Phase Population Heterogeneity Process Psychological reinforcement Psychopathology Rattus Receptor Activation Regulation Rewards Risk Risk Factors Rodent Role Signal Transduction Specificity Speed Stimulus Stress Stress Tests Synaptic plasticity Transgenic Organisms Ventral Tegmental Area acute stress aversive conditioning base classical conditioning dopamine system dopaminergic neuron gamma-Aminobutyric Acid improved insight neuroadaptation neuropsychiatric disorder novel optogenetics response reward circuitry reward processing signal processing stress related disorder synaptic inhibition translational model transmission process

项目摘要

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.

环境压力是神经精神疾病的主要危险因素，但其根本原因是该漏洞背后的机制仍然未知。越来越多的证据表明，与压力有关精神病理学部分源于大脑中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。我们在啮齿动物中的数据表明压力通过位于 VTA 的阴离子转运蛋白 KCC2 的功能下降来调节奖励处理 GABA 神经元。这种 GABA 信号传导中应激诱导的神经适应形式尚未得到充分研究。特征，我们计划研究它对大鼠多巴胺信号传导和奖励处理的影响。给定 VTA GABA 神经元为中脑边缘多巴胺神经元提供主要的抑制输入，我们将测量这些神经元和应激诱导的 KCC2 下调对多巴胺信号传导的影响。这些研究将解释多巴胺神经元活动的功能上不同的强直和相位模式，这可以是受 VTA GABA 神经元的差异调节。多巴胺神经元的异质群体参与解剖学上独立的电路调节奖励处理的不同方面。测试是否是压力引起的 KCC2 功能低下以电路特异性方式调节多巴胺信号传导，我们将测量 GABAergic 传输到 NAc 的核心、内侧和外侧壳的特定多巴胺投射上。最终，我们将检查应激诱导的 KCC2 下调和 VTA GABA 神经元在不同方面的作用奖励处理。老鼠将面临严重的压力，我们将衡量奖励学习和激励操纵 VTA GABA 神经元中的 KCC2 时的动机。行为任务将伴随多单元电生理学和光遗传学进一步探讨不同 VTA 神经元类型对不同类型的贡献奖励流程。总而言之，这些研究将全面检验压力对奖励的影响处理并有可能提高我们对复杂多巴胺 GABA 能调节的理解发信号。