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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，但基本的造成这种脆弱性的机制仍然不明。越来越多的证据表明，精神病理学部分源于大脑中边缘奖赏回路的失调，由腹侧被盖区（VTA）和延髓核（NAc）组成。我们在啮齿动物身上的数据表明应激通过降低腹侧被盖区阴离子转运体KCC2的功能，使奖赏加工功能失调 GABA神经元。GABA能信号传导中这种形式的应激诱导的神经适应尚未完全阐明。特征，我们计划研究其对大鼠多巴胺信号和奖励处理的影响。给定 VTA GABA神经元提供了一个主要的抑制输入到中脑边缘多巴胺神经元，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紧张性和阶段性模式， VTA GABA神经元的差异调节。多巴胺神经元的异质群体参与了解剖学上分离的回路，调解奖励处理的不同方面。为了测试压力引起的 KCC2功能减退以回路特异性方式失调多巴胺信号传导，我们将测量GABA能在NAc的核心、内侧和外侧壳的特定多巴胺投射上的传递。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于急性应激，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。行为任务将伴随多单元电生理学和光遗传学，以进一步探索不同VTA神经元类型对不同VTA神经元类型的贡献。奖励过程。综合起来，这些研究将全面考察压力对奖励的影响处理和保持潜力，以提高我们的理解GABA能调节复杂的多巴胺信号