Thalamostriatal Circuitry in Opioid Seeking

摘要/摘要 当行为不当时，与奖励相关的线索不太可能激起寻求奖励的行为，但线索 当阿片类药物使用障碍(OUD)患者的行为无效或 适应不良。对于正常情况下可以抑制非生产性奖励的大脑系统，人们几乎不了解 寻求被阿片类药物的使用所改变，并在因果上促成阿片类药物的寻求。这在一定程度上是由于技术上 可行性，因为测量单个神经元在发病、维持和复发阶段的适应性 阿片类药物的使用是具有挑战性的。在这里，我使用了我的实验室开发的一种新的分析方法来克服这个问题，其中我 在海洛因的自我给药、消退和治疗过程中，纵向追踪精确定义的神经元的活动 利用双光子钙成像技术恢复头枕束缚小鼠的功能。我们检验了最重要的假设 丘脑纹状体亚回路被阿片类药物的使用和启动阿片类药物的刺激所抑制- 寻找行为。为了支持这一假设，我的初步数据表明，后脑室旁 投射到伏核的丘脑神经元(PPVT NAC)变得低活动和低兴奋性 作为反复使用海洛因的结果，并在线索和药物诱导期间表现出活动迅速减少 恢复寻找海洛因。此外，我证明了在光遗传学上模仿这种抑制在 灭绝引发了海洛因的寻觅。为了测试我的具体假设，在目标1中，我将纵向跟踪活动 海洛因自我给药过程中单个pPVT NAC神经元和神经丛的动态变化， 灭绝和复活。在目标2中，我将评估长期持续的内在和突触适应 海洛因自我给药后多个时间点的pPVT NAC神经元。在目标3中，我将确定 PPVT NAC神经元活动在海洛因消退抑制中的作用及其表达 在复职期间寻找海洛因。总体而言，这个项目将确定大脑回路如何抑制奖赏 在不适当的条件下寻找会因阿片类药物的使用而改变，并对阿片类药物的寻找行为产生因果影响。

SUMMARY/ABSTRACT Reward-associated cues are unlikely to provoke reward seeking when that behavior is inappropriate, yet cues elicit opioid seeking in patients with opioid use disorder (OUD) when that behavior is unproductive or maladaptive. There is little understanding of how brain systems that can normally suppress unproductive reward seeking are modified by opioid use and causally contribute to opioid seeking. This is in part due to technical feasibility, as measuring adaptations in single neurons across the onset, maintenance, and relapse phases of opioid use is challenging. Here, I overcome this issue using a novel assay developed in my lab, wherein I longitudinally track activity in precisely defined neurons throughout heroin self-administration, extinction, and reinstatement using two-photon calcium imaging in head-restrained mice. We test the overarching hypothesis that a thalamostriatal subcircuit is inhibited by opioid use and by the presentation of stimuli that initiate opioid- seeking behaviors. In support of this hypothesis, my preliminary data suggest that posterior paraventricular thalamic neurons that project to the nucleus accumbens (pPVT NAc) become hypoactive and hypoexcitable as a result of repeated heroin use and display rapid reductions in activity during cue- and drug-induced reinstatement of heroin seeking. Furthermore, I show that optogenetically mimicking this inhibition during extinction initiates heroin seeking. To test my specific hypotheses, in Aim 1, I will longitudinally track the activity dynamics of single pPVT NAc neurons and neuronal ensembles throughout heroin self-administration, extinction, and reinstatement. In Aim 2, I will evaluate the long-lasting intrinsic and synaptic adaptations among pPVT NAc neurons at multiple timepoints following heroin self-administration. In Aim 3, I will determine the function of pPVT NAc neuronal activity for the suppression of heroin seeking during extinction, and expression of heroin seeking during reinstatement. Overall, this project will identify how a brain circuit that inhibits reward seeking in inappropriate conditions is modified by opioid use and causally influences opioid-seeking behavior.