Characterizing the Activity Dynamics and Function of Thalamostriatal Circuits During Opioid Seeking

项目总结 阿片使用障碍(OUD)是美国国内的一种主要流行病，这一问题因 阿片类药物的高度成瘾性。当出现与药物相关的环境线索时，患者会遭受 从OUD更有可能复发到强制寻求和服用阿片类药物，即使有显著的风险 负面后果。尽管知道这一点，但阿片类药物相关线索是如何参与大脑奖励回路的 对阿片类药物寻找行为的控制尚不清楚。更好地理解线索如何影响大脑奖励 刺激药物寻找的回路可以为治疗OUD的新疗法提供更好的洞察力。 已知的与奖赏相关线索有关的一个特定大脑区域是脑室旁 丘脑核(PVT)。PVT在架构上组织在与以下各项关联的区域之间 有条件的寻求奖励行为，并已被证明在食欲动机中发挥作用， 摄食、记忆和自然奖赏或寻求毒品的行为。除了这些输入之外，PVT本身还具有 致密的阿片受体(OR)表达，已知可以调节PVT的活性。此外，我的数据显示 阿片受体在投射到伏核的PVT神经元上特异表达 (pvtánac)，这条路径为寻求奖励提供了一个关键的“刹车”。尽管知道了这一点，但这种影响 阿片类药物的使用情况以及与阿片类药物相关的提示对PVTàNAC活动的影响尚不清楚。此外， 这条通路在寻找阿片类药物方面的作用尚不清楚。在这里，我提出了一个中心假设 PPVTàNAC神经元在阿片类药物使用和阿片类药物相关线索的呈现过程中受到抑制，并且 这种抑制是寻找阿片类药物所必需的。这些数据得到了我广泛的初步数据集的支持， 其中，我显示在海洛因预测线索的呈现过程中，PVTàNAC神经元受到抑制，而 在灭绝条件下，光遗传模仿这种抑制会直接和贪婪地驱动目标导向型 吸食海洛因。使用我们实验室开发的创新技术，我将用两个 实验。在目标1中，我将使用一种新的头部约束海洛因自我给药方案，该方案允许 同步体内双光子钙显像法测定pPVTàNaC的精确活性动力学 神经元在自我管理的获得、消亡和恢复阶段。在《目标2》中，我将使用 行为光遗传学确定pPVTàNAC神经元在线索诱导的恢复中的功能 吸食海洛因。 总之，这些实验将确定精确定义的PVT的活动动力学和功能 输出寻找海洛因的神经元。这些信息将使我们从整体上更好地了解 开发新的治疗方法。

PROJECT SUMMARY Opioid use disorder (OUD) is a major epidemic within the United States, and this issue is exacerbated by the highly addictive nature of opioids. When presented with drug-associated environmental cues, patients suffering from OUD are more likely relapse to compulsive opioid seeking and taking, even with the risk of significant negative consequences. Despite knowing this, how opioid-associated cues engage brain reward circuits for the control of opioid-seeking behaviors is unclear. Having a better understanding of how cues affect brain reward circuits to provoke drug seeking could provide better insight into novel therapeutics for the treatment of OUD. One particular brain region known to be engaged by reward-associated cues is the paraventricular nucleus of the thalamus (PVT). The PVT is architecturally organized between areas that are associated with conditioned reward-seeking behaviors, and has been demonstrated to play roles in appetitive motivation, feeding, memory, and natural reward or drug-seeking behaviors. In addition to these inputs, the PVT itself has dense opioid receptor (OR) expression, which is known to modulate PVT activity. Furthermore, my data reveals that opioid receptors are specifically expressed on PVT neurons that project to the nucleus accumbens (PVTàNAc), a pathway that provides a critical “brake” for reward seeking. Despite this knowledge, the influence of opioid use and the presentation of opioid-associated cues on PVTàNAc activity is unknown. Furthermore, the function of this pathway for opioid seeking is unknown. Here I propose the central hypothesis that pPVTàNAc neurons are inhibited during opioid use and by the presentation of opioid-associated cues, and that this inhibition is required for opioid seeking. These data are supported by my extensive preliminary datasets, wherein I show that PVTàNAc neurons are inhibited during the presentation of heroin predictive cues, whereas optogenetically mimicking this inhibition in extinction conditions drives immediate and voracious goal-directed heroin seeking. Using innovative techniques developed in our laboratory, I will test my hypothesis with two experiments. In Aim 1, I will use a novel head-restrained heroin self-administration protocol that allows simultaneous in vivo two-photon calcium imaging to determine the precise activity dynamics of pPVTàNAc neurons during acquisition, extinction, and reinstatement phases of self-administration. In Aim 2, I will use behavioral optogenetics to determine the function of pPVTàNAc neurons for cue-induced reinstatement of heroin seeking. Together, these experiments will identify the activity dynamics and function of precisely-defined PVT output neurons for heroin seeking. This information will provide an overall better understanding of OUD for the development of novel therapeutics.