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：
10544517
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/10544517
关键词：
Acceleration Action Potentials Affect Anatomy Anesthesia procedures Animals Anions Association Learning Attenuated Basic Science Behavior Behavioral Brain Brain region Chlorides Chronic stress Complex Data Decision Making Desire for food Development Disinhibition 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 Phase Population Heterogeneity Process Psychological reinforcement Psychopathology Rat Transgene Rattus Receptor Activation Regulation Rewards Risk Risk Factors Rodent Role Signal Transduction Specificity Speed Stimulus Stress Stress Tests Synaptic plasticity Ventral Tegmental Area acute stress aversive conditioning dopamine system dopaminergic neuron gamma-Aminobutyric Acid improved insight neuroadaptation neuronal excitability neuropsychiatric disorder neurotransmission novel optogenetics pharmacologic 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，但基本这种脆弱性的机制仍然未知。越来越多的证据表明与压力有关心理病理学部分是由于大脑中唇奖励电路的失调而产生的，这主要是由腹侧对接区域（VTA）和伏隔核（NAC）组成。我们的啮齿动物数据表明这种压力通过位于VTA的阴离子转运蛋白KCC2的功能降低奖励处理失调 GABA神经元。这种压力诱导的GABA能信号中的神经适应形式尚未完全表征了，我们计划研究其对大鼠多巴胺信号传导和奖励处理的影响。给出 VTA GABA神经元为中唇多巴胺神经元提供了主要的抑制性输入，我们将测量这些神经元和应力诱导的KCC2下调对多巴胺信号传导的影响。这些研究将考虑多巴胺神经元活动的功能上不同的补品和阶段模式，这可以是由VTA GABA神经元差异调节。多巴胺神经元的异质种群参与解剖学上分开的电路，介导奖励处理的不同方面。测试压力诱导的 KCC2功能低调以特异性的方式导致多巴胺信号传导，我们将测量GABA能将特定的多巴胺投影传输到NAC的核心，内侧和外侧外壳上。最终，我们将检查压力诱导的KCC2下调和VTA GABA神经元在不同方面的作用奖励处理。老鼠将面临急性压力，我们将衡量奖励学习和激励在VTA GABA神经元中操纵KCC2的动机。行为任务将伴随多单元电生理学和光遗传学，以进一步探索不同的VTA神经元类型的贡献奖励过程。综上所述，这些研究将全面研究压力对奖励的影响处理并具有提高我们对复杂多巴胺的GABA能调节的理解的潜力信号。