Investigation of a novel ventral pallidum population expressing corticotropin-releasing factor receptor 1

表达促肾上腺皮质激素释放因子受体 1 的新型腹侧苍白球群体的研究

• 批准号: 10677069
• 负责人: Elizabeth Anne Eckenwiler
• 金额: $ 3.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-13 至 2025-03-12
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677069
• 关键词: Acute; Address; Amygdaloid structure; Anhedonia; Animals; Basal Ganglia; Bathing; Behavior; Behavioral; Brain; Brain region; CRF receptor type 1; Cells; Chemosensitization; Chronic; Chronic stress; Consumption; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Coupled; Data; Dependence; Detection; Development; Disease; Electrophysiology (science); Fellowship; Frequencies; Gases; Globus Pallidus; Glutamates; Goals; Immunohistochemistry; In Situ Hybridization; Individual; Intake; Investigation; Knowledge; Link; Measures; Mediating; Mental Depression; Motivation; Mus; Neurobiology; Neurons; Neuropeptides; Neurotransmitters; Nucleus Accumbens; Output; Pharmaceutical Preparations; Population; Property; Protocols documentation; Receptor Cell; Receptor Signaling; Research; Research Personnel; Rewards; Role; Signal Transduction; Slice; Stimulus; Stress; Structure; Substance Use Disorder; Swimming; Synapses; Synaptic Transmission; Testing; Time; Training; Viral; acute stress; antagonist; approach behavior; avoidance behavior; behavior prediction; behavioral outcome; cholinergic neuron; desensitization; detector; functional adaptation; intraperitoneal; motivated behavior; neurobiological mechanism; neurochemistry; novel; pharmacologic; postsynaptic; receptor; receptor expression; recruit; response; reward processing; stressor

PROJECT SUMMARY Stress is known to dysregulate a range of behaviors, impacting normal responses to environmental stimuli, and producing long-lasting internal state changes. Corticotropin-releasing factor (CRF) is a stress-associated neuropeptide and CRF signaling underlies many stress-induced neurobiological changes. Studies have focused on CRF signaling in the PVN and amygdala. However, within the basal ganglia circuitry, the ventral pallidum (VP) contains high expression of CRF receptors (CRF1). Yet, CRF-CRF1 signaling within VP remains unstudied. Stress-induced changes to reward-consumption have been described, but the neurobiological mechanism(s) underlying these alterations are not fully understood. Activity of a GABAergic VP population projecting to the nucleus accumbens (ventral arkypallidal) has been shown to potentiate reward consumption. Our preliminary data suggests that VP CRF1+ cells are part of this ventral arkypallidal population; thus, VP CRF-CRF1 signaling represents one potential mechanism by which stress potentiates reward consumption behaviors. This proposal investigates the neurochemical, connectivity, and functional properties of VP CRF1+ neurons. The central hypothesis of this proposal is that CRF1+ VP neurons are a GABAergic arkypallidal population, and that CRF1 signaling in these cells increases their overall activity following acute CRF application or stress exposure. I will determine the abundance, distribution, neurochemical composition, and connectivity of the VP CRF1 population (Aim1). This foundational investigation is important as the identity and connectivity of VP populations have been shown to impact behavioral output. To probe the electrophysiological properties of this novel population, I will measure intrinsic excitability and excitatory and inhibitory synaptic transmission in VP CRF1+ and CRF1- cells, both basally and following acute application of CRF (Aim2). This will provide the first evidence that VP CRF1+ cells are functionally distinct from CRF1- cells and that VP neurons are directly sensitive to CRF. The mechanism underlying stress-mediated adaptations of VP circuitry is important, as these changes may have negative consequences for individuals. I will investigate the impact of stress on intrinsic excitability and synaptic strength of VP CRF1+ and CRF1- populations, and the dependence of these alterations on CRF1 signaling (Aim3). This will provide evidence that VP is sensitive to stress and undergoes CRF1-mediated functional adaptations following stress exposure. With the guidance of my sponsor, Dr. Julia C Lemos, and co-sponsor, Dr. Kevin Wickman, completion of the proposed study will not only address a crucial scientific question but provide me with extensive technical, conceptual, and professional training. This research will contribute to the long-term goal of elucidating the mechanism underlying motivational deficits following stress and my development as an independent researcher.

项目摘要 已知压力会导致一系列行为失调，会影响对环境刺激的正常反应，并且 产生持久的内部状态变化。皮质激素释放因子（CRF）是应力相关的 神经肽和CRF信号传导是许多压力引起的神经生物学变化的基础。研究重点是 在PVN和杏仁核中的CRF信号传导上。但是，在基底神经节电路中，腹侧粒子 （VP）包含CRF受体的高表达（CRF1）。然而，VP内的CRF-CRF1信号传导仍未被研究。 已经描述了压力引起的奖励消耗的变化，但神经生物学机制 这些改变的基础尚未完全理解。 GABA能量副总量投射到 伏隔核（腹arkypallidal）已显示可增强奖励消耗。我们的初步 数据表明，VP CRF1+细胞是该腹侧arkypallidal种群的一部分。因此，VP CRF-CRF1信号传导 代表一种潜在的机制，通过这种机制，压力增强了奖励消费行为。 该建议研究VP CRF1+神经元的神经化学，连通性和功能特性。这 该提议的中心假设是CRF1+ VP神经元是GABA能的Arkypallidal人群，并且 这些细胞中的CRF1信号传导增加了急性CRF施加或应力暴露后的整体活性。 我将确定VP CRF1的丰度，分布，神经化学组成和连通性 人口（AIM1）。这项基本调查很重要，因为VP人群的身份和连通性 已证明会影响行为输出。探测这部小说的电生理特性 人口，我将测量VP CRF1+中的内在兴奋性以及兴奋性和抑制性突触传播 和CRF1-细胞，基本和急性应用CRF之后（AIM2）。这将提供第一个证据 VP CRF1+细胞在功能上与CRF1细胞不同，并且VP神经元对CRF直接敏感。 VP电路的应力介导的适应的基础机制很重要，因为这些变化可能具有 对个人的负面后果。我将研究压力对内在兴奋性和突触的影响 VP CRF1+和CRF1种群的强度，以及这些改变对CRF1信号传导的依赖性（AIM3）。 这将提供证据表明VP对压力敏感并经历CRF1介导的功能适应 在压力暴露之后。 在我的赞助商Julia C Lemos博士的指导下，共同提案者Kevin Wickman博士完成了 拟议的研究不仅将解决一个关键的科学问题，而且还为我提供广泛的技术， 概念和专业培训。这项研究将有助于阐明的长期目标 压力和我作为独立研究人员的发展后的动机赤字的机制。