Thalamostriatal Circuitry in Opioid Seeking

总结/摘要 当行为不恰当时，与奖励相关的线索不太可能激发奖励寻求， 在阿片类药物使用障碍（OUD）患者中引发阿片类药物寻求， 适应不良人们对大脑系统如何正常抑制非生产性奖励的理解很少 阿片类药物的使用改变了寻求，并导致阿片类药物寻求。这部分是由于技术原因。 可行性，作为测量在发病，维持和复发阶段的单个神经元的适应性， 阿片类药物的使用具有挑战性。在这里，我使用我的实验室开发的一种新的测定方法克服了这个问题， 纵向跟踪活动，在精确定义的神经元在整个海洛因自我管理，灭绝， 在头部受限的小鼠中使用双光子钙成像进行恢复。我们检验了一个重要的假设 丘脑纹状体子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， 寻求行为。为了支持这一假设，我的初步数据表明， 投射到丘脑背侧核的丘脑神经元（pPVT NAc）变得活动减退和低兴奋 由于重复使用海洛因，并显示在线索和药物诱导的活动迅速减少， 恢复海洛因寻求。此外，我表明，光遗传学模拟这种抑制， 灭绝引发了对海洛因的追求。为了验证我的具体假设，在目标1中，我将纵向跟踪活动 在海洛因自我给药过程中单个pPVT NAc神经元和神经元集合的动力学， 灭绝和恢复。在目标2中，我将评估长期持久的内在和突触适应， 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神经元活性在消退过程中抑制海洛因寻求的功能和表达 在复职期间寻求海洛因总的来说，这个项目将确定大脑回路如何抑制奖励 在不适当的条件下寻求被阿片类药物的使用所改变，并因果地影响阿片类药物寻求行为。

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.