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

项目摘要 奖励处理和相关行为的障碍是成瘾、慢性疼痛和 情绪障碍腹侧基底神经节功能障碍，包括腹侧苍白球（VP）和 核壳（NAcSh）已被牵连在病因的情感症状，在每一个这些 紊乱典型的基底神经节模型表明VP完全是NAc的输出。但 VP神经元的亚群投射到NAcSh，VP中的奖励相关神经活动先于NAcSh 在NAcSh中的奖励相关活动。完全不知道NAcSh形式的VP末端是否 功能性突触，或者这条通路是否调节NAcSh或奖赏中与奖赏相关的神经活动。 行为此外，在NAcSh中注入GABA或内源性阿片样物质（EOs）受体激动剂， 增加了对奖励的享乐反应和消费。当VP神经元合成GABA和EO时， 不知道VP是否是NAcSh中这些化合物的来源。机械地理解 基底神经节如何协调健康和疾病中的奖励行为，这对于阐明 VP-NAcSh通路的功能作用。本提案的目的是确定NAcSh是否 投射VP神经元释放GABA和EOs来抑制NAcSh神经元，从而增加享乐反应 奖励。为了剖析VP-NAcSh通路对奖励相关行为的贡献，我们将首先 使用病毒追踪建立VP-NAcSh通路的突触后靶点和神经化学特性， 光遗传学辅助电路映射（aim 1）。我们接下来将使用体内电生理学和光遗传学 操作以确定VP-NAcSh通路激活对奖励相关行为的影响， 奖励相关的体内NAcSh活性（目的2）。我们将确定VP-NAcSh通路是否释放 使用新型光透析方法检测体内诱发肽释放的NAcSh中的EO。最后我们 将使用fISH和膜片钳阐明EO是否调节VP-NAcSh通路的功能 电生理学（目标3）。这项提议将重新审视基底神经节的经典模型， VP仅是NAc的输出结构，并将决定该途径对NAcSh的作用 与奖励相关的行为。我们的长期目标是阐明受损奖励的电路基础 处理疾病状态，并利用这种理解来开发基于电路的治疗方法（如 深部脑刺激）来治疗成瘾、慢性疼痛、 和物质使用障碍。

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.