Ventral Pallidum Circuits Underlying Preclinical Models of Opioid Addiction

项目摘要 成瘾，尤其是阿片类药物使用障碍(OUD)，是美国人生活中的一大祸害。尽管我们知道的很多 从阿片类药物如何作用于大脑的动物模型来看，我们还没有开发出新的OUD治疗方法 基于这方面的知识。这是为什么？我们的实验室，就像近年来的其他实验室一样，辩称部分原因是缺乏 与翻译相关的啮齿动物模型，捕捉成瘾的关键行为特征，例如 不适应的、强迫的和反复使用的，在一部分人身上发展起来的。 在人类中，OUD的特点是尽管有负面后果，但仍继续使用阿片类药物， 使用这些药物，以及戒烟后再次吸毒，以及海洛因等长期阿片类药物，也 使用、容忍和退出的升级。这些与翻译相关的行为现象中的每一个都可以 现在是以啮齿动物为模型，但每种动物背后的神经网络仍然知之甚少。 腹侧苍白球(VP)，特别是其向腹侧被盖区(VTA)的密集投射， 因为它们在激励和上瘾方面的强大作用而引起了越来越多的关注。我们最近展示了VP神经元 是翻译相关的可卡因复吸样行为所必需的，而GABA能VP神经元(VPGABA) 他们对VTA的投射具体负责一系列强烈的动机行为-推测 通过与更广泛的动机神经网络相互作用。我们希望通过了解这些神经是如何 网络在捕捉OUD的关键方面的行为中发挥作用，我们可以利用这些信息来开发 以神经科学为基础的新治疗策略。 在这里，我们系统地剖析了VPGABA神经元的参与，以及更广泛的奖赏和厌恶 它们在与OUD相关的行为中调节网络。在经过良好验证的GAD1：Cre转基因大鼠中，我们使用Cre 以及依赖于FLP的化学发生操作，以展示VPGABA神经元如何调制更广泛的网络 潜在的阿片类药物复发，2)通过其功能分离的输出参与OUD的食欲方面， 3)这些通路是如何调节OUD的厌恶方面的。我们假设VPGABA神经元调制 更广泛的神经网络来产生OUD行为，抑制这一关键途径将减少强迫 寻找毒品。

Project Summary Addiction, and opioid use disorder (OUD) in particular, is a scourge on American life. Though we know much from animal models about how opioid drugs act on the brain, we have yet to develop new OUD treatments based on this knowledge. Why is this? Our lab, like others in recent years, have argued that in part it is due to a lack of translationally-relevant rodent models that capture the key behavioral features of addiction, such as the maladaptive, compulsive, and relapsing use that develops in a subset of individuals. In humans, OUD is characterized by continued use of opioids despite negative consequences, preoccupation with using these drugs, and relapse to drug use after quitting, and for long-lasting opioids like heroin, also escalation of use, tolerance, and withdrawal. Each of these translationally-relevant behavioral phenomena can now be modelled in rodents, but the neural networks underlying each of them are yet poorly understood. The ventral pallidum (VP), and especially its dense projections to the ventral tegmental area (VTA), have drawn increasing attention for their potent roles in motivation and addiction. We recently showed VP neurons are essential for translationally-relevant cocaine relapse-like behavior, and that GABAergic VP neurons (VPGABA) and their projections to VTA are specifically responsible for a range of strongly motivated behaviors—presumably via interactions with wider neural networks of motivation. We hope that by understanding how these neural networks function during behaviors that capture key aspects of OUD, we can leverage this information to develop new neuroscience-based treatment strategies. Here, we systematically dissect the involvement of VPGABA neurons, and the wider reward and aversion networks they modulate, in OUD-relevant behaviors. In well-validated GAD1:Cre transgenic rats, we use Cre and Flp-dependent chemogenetic manipulations to show how VPGABA neurons 1) modulate wider networks underlying opioid relapse, 2) participate via their functionally-segregated outputs in appetitive aspects of OUD, and 3) how these pathways mediate aversive aspects of OUD. We hypothesize that VPGABA neurons modulate wider neural networks to generate OUD behaviors, and that inhibiting this key pathway will reduce compulsive drug seeking.