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 众所周知，压力会使一系列行为失调，影响对环境刺激的正常反应， 产生持久的内部状态变化。促肾上腺皮质激素释放因子（CRF）是一种应激相关因子， 神经肽和CRF信号转导是许多应激诱导的神经生物学变化的基础。研究都集中 室旁核和杏仁核的CRF信号。然而，在基底神经节回路中，腹侧苍白球 (VP)含有高表达的CRF受体（CRF 1）。然而，VP内的CRF-CRF 1信号转导仍未研究。 压力引起的奖赏消费的变化已经被描述，但神经生物学机制（S） 这些变化的根本原因还没有被完全理解。γ-氨基丁酸能VP群体投射到 已显示腹侧Arkypallidal核增强奖赏消费。我们的初步 数据表明VP CRF 1+细胞是腹侧Arkypallidal群体的一部分;因此，VP CRF-CRF 1信号传导 代表了压力增强奖励消费行为的一种潜在机制。 该提案研究了VP CRF 1+神经元的神经化学，连接和功能特性。的 这一提议的中心假设是CRF 1 + VP神经元是GABA能的Arkypallidal群体， 这些细胞中的CRF 1信号在急性CRF应用或应激暴露后增加其整体活性。 我将确定VP CRF 1的丰度、分布、神经化学成分和连接性， 人口（目标1）。这一基础性研究是重要的，因为VP种群的身份和连通性 会影响行为输出探讨这种新的电生理特性 人群中，我将测量VP CRF 1+中的内在兴奋性以及兴奋性和抑制性突触传递 和CRF 1-细胞，在基础和急性应用CRF后（Aim 2）。这将提供第一个证据 VP CRF 1+细胞与CRF 1-细胞在功能上不同，VP神经元对CRF直接敏感。 压力介导的VP电路适应的机制很重要，因为这些变化可能 对个人的负面影响。我将研究压力对内在兴奋性和突触的影响。 VP CRF 1+和CRF 1-群体的强度，以及这些改变对CRF 1信号传导的依赖性（Aim 3）。 这将为VP对应激敏感并经历CRF 1介导的功能适应提供证据 在压力暴露之后。 在我的赞助人Julia C Lemos博士和共同赞助人Kevin Wickman博士的指导下， 拟议中的研究将不仅解决一个关键的科学问题， 概念和专业培训。这项研究将有助于阐明 压力后动机缺陷的潜在机制以及我作为独立研究者的发展。