Dissecting ventral pallidal plasticity in punishment-resistant opioid self-administration

项目摘要 阿片类药物使用障碍（OUD）是一个日益严重的公共卫生问题，已导致超过550，000例过量用药 1999年至2020年期间死亡。具体而言，初次接触处方阿片类药物，如羟考酮 (OXY)自2018年以来，每年平均造成13，850人死亡（疾病控制中心）。 虽然许多人能够按照规定使用阿片类药物，但一部分人会过渡到强迫性 药物使用，其定义为尽管有负面后果但仍持续摄入药物，是一个标志性特征 的OUD。同样，大多数啮齿类动物会很容易地自我管理阿片类药物，但会抑制他们的药物消费 当药物摄入与惩罚配对时，如足部电击（惩罚敏感）;而约20-25%的人会 尽管有这种惩罚，但仍坚持吸毒（抗拒惩罚）。阐明神经机制 潜在的个体差异在惩罚抵抗药物寻求将是至关重要的， 了解对强迫性药物使用的敏感性和治疗策略。腹侧苍白球 (VP)已经成为编码奖励的相对价值和动机的关键大脑区域， 将这种动机转化为奖励追求。VP是一个异质核，具有不同的种群 在食欲行为中扮演着相反的角色。具体来说，我们和其他人已经确定， VP神经元（VPGlu）对于在面对令人厌恶的后果时限制奖励寻求至关重要， 调节参与惩罚学习的下游大脑区域的活动，包括外侧缰 (LHb)和头内侧被盖核（RMTg）。本提案的目的是确定OXY- SA降低了VPGlu神经元的兴奋性、体内活性和突触输出，并确定这些是否 适应与抗惩罚氧合酶的摄入有因果关系。采用互补办法， 电生理学，钙检测与纤维光度法和化学遗传操作，我们将建立 OXY自身给药是否降低VPGlu神经元的兴奋性，以及这种活性降低是否 必要的和足够的出现惩罚抵抗氧摄入量（目标1）。我们下次将使用 电生理学和双向光遗传学操作，以确定是否减少突触输出 从VPGlu神经元到LHb或RMTg的变化与惩罚抵抗性OXY摄入有因果关系（目的2）。 最后，我们将对来自VPGlu神经元的主动翻译mRNA进行测序，以确定赋予 风险和保护免受惩罚抵抗氧摄入（目标3）。这也将使我们能够识别和 验证可在体内调节VPGlu神经元活性的潜在药理学靶点作为治疗剂 战略我们的长期目标是阐明抗惩罚阿片类药物摄入的神经回路基础， 为了利用这种理解来开发神经调节疗法（例如， 靶向药理学），以治疗持续药物摄入，尽管有负面后果的患者OUD。

PROJECT SUMMARY Opioid use disorder (OUD) is an escalating public health concern, and has resulted in over 550,000 overdose deaths between 1999 and 2020. Specifically, initial exposure to prescription opioids, such as oxycodone (OXY), has contributed to an average of 13,850 deaths annually since 2018 (Centers for Disease Control). While many individuals are able to use opioids as prescribed, a subset of individuals transition to compulsive drug use, which is defined as continued drug intake despite negative consequences, and is a hallmark feature of OUD. Similarly, most rodents will readily self-administer opioids, but will suppress their drug consumption when drug intake is paired with punishment such as foot shock (punishment-sensitive); while ~20-25% will persist in drug intake despite this punishment (punishment-resistant). Elucidating the neural mechanisms underlying individual differences in punishment-resistant drug seeking will be critical for understanding susceptibility to and treatment strategies for compulsive drug use. The ventral pallidum (VP) has emerged as a critical brain area for encoding the relative value and motivation for rewards and translating this motivation into reward seeking. The VP is a heterogeneous nucleus, with different populations playing opposing roles in appetitive behavior. Specifically, we and others have established that glutamatergic VP neurons (VPGlu) are crucial for constraining reward seeking in the face of aversive consequences, by modulating activity of downstream brain areas involved in punishment learning, including the lateral habenula (LHb) and rostromedial tegmental nucleus (RMTg). The objective of this proposal is to establish whether OXY- SA decreases the excitability, in vivo activity and synaptic output of VPGlu neurons, and determine if these adaptations are causally related to punishment-resistant OXY intake. Using complementary approaches of electrophysiology, calcium detection with fiber photometry and chemogenetic manipulations, we will establish whether OXY self-administration decreases excitability of VPGlu neurons, and whether this reduced activity is necessary and sufficient for the emergence of punishment-resistant OXY intake (Aim 1). We will next use electrophysiology and bidirectional optogenetic manipulations to determine whether reduced synaptic output from VPGlu neurons to the LHb or RMTg is causally related to punishment-resistant OXY intake (Aim 2). Finally, we will sequence actively translated mRNA from VPGlu neurons to determine gene networks that confer risk and protection against punishment-resistant OXY intake (Aim 3). This will also allow us to identify and validate potential pharmacological targets that could modulate VPGlu neuron activity in vivo as a therapeutic strategy. Our long-term goal is to elucidate the neural circuit basis of punishment-resistant opioid intake, and to leverage this understanding to develop neuromodulation therapies (such as deep brain stimulation with targeted pharmacology) to treat persistent drug intake despite negative consequences in patients with OUD.