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

项目总结 奖赏处理和相关行为的障碍是成瘾、慢性疼痛和 情绪障碍。腹侧基底节功能障碍，包括腹侧苍白球(VP)和 伏隔核壳核(NAcSh)与这些患者情感性症状的病因有关。 精神错乱。经典的基底节模型假定VP完全是NAC的输出。然而，a VP神经元亚群投射到NAcSh，且VP内奖赏相关神经活动先于 NAcSh中与奖励相关的活动。Vp终端是否以NAcSh形式存在是完全未知的 功能性突触，或者这条通路是否调节NAcSh或Reward中与奖赏相关的神经活动 行为。此外，在NAcSh内注入GABA或内源性阿片(Eos)受体激动剂 增加对奖励的享乐反应和消耗。当VP神经元合成GABA和Eos时，它 目前尚不清楚VP是否是NAcSh中这些化合物的来源。机械地理解 基底节如何协调健康和疾病中的奖励行为，至关重要的是阐明 VP-NAcSh通路的功能作用。该提案的目标是确定NAcSh是否 投射-VP神经元释放GABA和Eos抑制NAcSh神经元，从而增加享乐反应 为奖励干杯。为了剖析VP-NAcSh通路对奖赏相关行为的贡献，我们首先 用病毒示踪法建立VP-NAcSh通路的突触后靶点和神经化学特征 光遗传辅助电路测绘(目标1)。接下来我们将使用体内电生理学和光遗传学 VP-NAcSh通路激活对奖赏相关行为和行为的影响 体内奖赏相关的NAcSh活性(目标2)。我们将确定VP-NAcSh通路是否释放 NAcSh中的Eos使用一种新的光透析方法来检测体内诱发的多肽释放。最后，我们 我将阐明Eos是否利用FISH和膜片钳来调节VP-NAcSh通路的功能 电生理学(目标3)。这一提议将重新审视基底节的经典模型，该模型假设 VP是NAC的唯一输出结构，并将决定这一通路在NAcSh中的作用 活动奖励相关行为。我们的长期目标是阐明奖赏受损的回路基础 在疾病状态下的处理，并利用这一理解来开发基于电路的疗法(例如 脑深部刺激)治疗成瘾、慢性疼痛的奖赏处理和相关行为缺陷 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.