Dissecting the role of ventral pallidal projections to nucleus accumbens in reward processing

剖析腹侧苍白球投射到伏隔核在奖励处理中的作用

• 批准号: 10343827
• 负责人: Meaghan C Creed
• 金额: $ 37.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10343827
• 关键词: Affective Symptoms; Anatomy; Anhedonia; Basal Ganglia; Behavior; Behavior monitoring; Chronic; Consumption; Deep Brain Stimulation; Detection; Dialysis procedure; Disease; Dopamine D1 Receptor; Dopamine D2 Receptor; Electrophysiology (science); Etiology; Fishes; Fluorescent in Situ Hybridization; Functional disorder; Globus Pallidus; Goals; Health; Impairment; Infusion procedures; Interneurons; Measures; Mediating; Modeling; Mood Disorders; Motivation; Neural Pathways; Neurons; Nucleus Accumbens; Opioid agonist; Output; Pathway interactions; Peptides; Play; Population; Public Health; Reaction; Relapse; Rewards; Role; Source; Structure; Substance Use Disorder; Symptoms; Synapses; System; Testing; Transgenic Mice; Viral; addiction; base; cholinergic; chronic pain; chronic painful condition; endogenous opioids; gamma-Aminobutyric Acid; hedonic; in vivo; insight; interest; kappa opioid receptors; molecular imaging; neurochemistry; neuropsychiatric disorder; novel; optogenetics; patch clamp; pleasure; relating to nervous system; response; reward processing; symptom treatment; tool; translational approach; transmission process

PROJECT SUMMARY Impairments in reward processing and related behavior is a core symptom of addiction, chronic pain, and mood disorders. Dysfunction of the ventral basal ganglia, which is comprised of the ventral pallidum (VP) and nucleus accumbens shell (NAcSh) has been implicated in the etiology of affective symptoms in each of these disorders. Canonical basal ganglia models posit that the VP is exclusively an output of the NAc. However, a subpopulation of VP neurons project to the NAcSh, and reward-related neural activity in the VP precedes reward-related activity in the NAcSh. It is completely unknown whether VP terminals in the NAcSh form functional synapses, or whether this pathway modulates reward-related neural activity in the NAcSh or reward behavior. Moreover, infusion of GABA or endogenous opioid (EOs) receptor agonists in the NAcSh potently increases hedonic reactions to and consumption of reward. While VP neurons synthesize GABA and EOs, it is not known whether the VP is a source of these compounds in the NAcSh. To mechanistically understand how the basal ganglia coordinates reward behavior in health and disease, it is crucial to elucidate the functional role of the VP-NAcSh pathway. The objective of this proposal is to determine whether NAcSh projecting-VP neurons release GABA and EOs to inhibit NAcSh neurons, which increases hedonic responses to rewards. To dissect the contribution of the VP-NAcSh pathway on reward-related behavior, we will first establish the post-synaptic targets and neurochemical identity of VP-NAcSh pathway using viral tracing and optogenetic-assisted circuit mapping (aim 1). We will next use in vivo electrophysiology and optogenetic manipulations to determine the effect of VP-NAcSh pathway activation on reward-related behavior and reward-related NAcSh activity in vivo (aim 2). We will determine whether the VP-NAcSh pathway releases EOs in the NAcSh using a novel opto-dialysis approach to detect evoked peptide release in vivo. Finally, we will elucidate whether EOs modulate function of the VP-NAcSh pathway using fISH and patch clamp electrophysiology (aim 3). This proposal will re-examine the classical model of the basal ganglia, which posits that the VP is exclusively an output structure of the NAc, and will determine the role of this pathway on NAcSh activity reward-related behavior. Our long-term goal is to elucidate the circuit basis of impaired reward processing in disease states, and to leverage this understanding to develop circuit-based therapies (such as deep brain stimulation) to treat deficits in reward processing and related behavior in addiction, chronic pain and substance use disorders.

项目摘要 奖励处理和相关行为的障碍是成瘾，慢性疼痛和 情绪障碍。腹侧神经节的功能障碍，该神经节由腹侧颗粒（VP）和 伏隔核壳（NACSH）已与每种情感症状的病因有关 疾病。规范基底神经节模型认为，VP仅是NAC的输出。但是， 副总裁神经元向NACSH进行了群体，并在VP之前与奖励相关的神经活动 NACSH中与奖励相关的活动。完全未知的副总裁终端是NACSH形式 功能突触，或该途径是否调节NACSH中与奖励相关的神经活动或奖励 行为。此外，在Nacsh中注入GABA或内源性阿片类药物（EOS）受体激动剂有效 增加享乐对奖励的反应和消费。而VP神经元合成GABA和EOS，它是 尚不清楚VP是否是NACSH中这些化合物的来源。机械理解 基底神经节如何协调健康和疾病的奖励行为，这对于阐明该行为至关重要 VP-NACSH途径的功能作用。该提议的目的是确定NACSH是否是否 投射-VP神经元释放GABA和EOS抑制NACSH神经元，这增加了享乐反应 奖励。为了剖析VP-NACSH途径对奖励相关行为的贡献，我们将首先 使用病毒跟踪和 光遗传辅助电路映射（AIM 1）。我们接下来将在体内电生理学和光遗传学中使用 操纵以确定VP-NACSH途径激活对奖励相关行为的影响和 体内与奖励相关的NACSH活动（AIM 2）。我们将确定是否释放VP-NACSH途径 NACSH中的EOS使用一种新型的光透析方法在体内检测诱发的肽释放。最后，我们 将阐明使用鱼和斑块夹是否调制VP-NACSH途径的功能 电生理学（AIM 3）。该建议将重新检查基底神经节的经典模型，该模型假设 VP仅是NAC的输出结构，并将确定该途径在NACSH上的作用 活动奖励相关的行为。我们的长期目标是阐明奖励受损的电路基础 疾病状态的处理，并利用这种理解来开发基于电路的疗法（例如 深脑刺激）治疗奖励处理和相关行为的缺陷，慢性疼痛 和药物使用障碍。