Midbrain neural circuit mechanisms underlying addiction

项目总结 阿片类药物危机对退伍军人及其社区的健康和福祉产生了巨大影响。 阿片成瘾是由阿片类药物引起的控制行为反应的大脑回路的变化推动的 奖赏和厌恶刺激，以及逆转阿片类药物诱导的这些变化的神经调节疗法 电路是非常需要的。腹侧被盖区(VTA)至中脑边缘多巴胺(DA)的投射 伏隔核(NAC)通常被描述为大脑的奖赏回路，事实上，许多证据表明 这种投射在行为强化的过程中起着核心作用。但是，是什么控制着 VTA DA神经元？而NAC将被释放的DA调制的信号发送到哪里？一个答案 这两个问题都是：腹侧苍白球(VP)。然而，人们对副总统的了解要少得多。例如，它有 直到最近人们才意识到VP包含兴奋和抑制的不同种群 向相反方向调节接近和回避行为的投射神经元。此外，Mu-阿片类药物 受体(MOR)介导阿片类药物滥用的镇痛和成瘾作用，VP是一种MOR HotSpot和MoR在VP中的激活可以深刻地改变行为。因此，我们知道VP可以有力地 调节接近和回避行为，阿片类药物可以有效地调节VP。但我们知道 关于VP细胞类型是如何与NAC和VTA细胞类型连接的，VP细胞类型和VTA细胞类型是如何连接的，这方面的研究非常少 突触受MORS调节，或阿片类药物诱导的VP细胞类型和突触的可塑性如何改变 在阿片类药物依赖和戒断中受到干扰的接近和回避行为。这项提议将 利用小鼠遗传学和体外和体内解剖学系统地解决这一知识鸿沟， 生理和行为学方法：i)表征VP中表达的细胞类型和突触 MOR，ii)定义VP细胞类型如何连接到传入NAC和传出VTA细胞类型，iii)确定如何 MOR的激活调节这些细胞类型和突触的功能，以及iv)描述它们的功能是如何 对阿片类药物依赖和戒断心烦意乱。

PROJECT SUMMARY The opioid crisis has enormous consequences on the health and well-being of Veterans and their communities. Opioid addiction is propelled by opioid-induced changes in brain circuits that control behavioral responses to rewarding and aversive stimuli, and neuromodulatory therapies that reverse opioid-induced changes in these circuits are sorely needed. The mesolimbic dopamine (DA) projection from ventral tegmental area (VTA) to nucleus accumbens (NAc) is often described as the brain's reward circuit, and indeed much evidence points to a central role for this projection in processes underlying behavioral reinforcement. But what controls activity of VTA DA neurons? And where does NAc send signals that have been modulated by released DA? An answer to both those questions is: the ventral pallidum (VP). Yet much less is known about VP. For example, it has only recently become appreciated that VP contains heterogeneous populations of excitatory and inhibitory projection neurons that regulate approach and avoidance behaviors in opposite directions. Further, Mu-opioid receptors (MOR) mediate both the analgesic and addictive effects of abused opioid drugs, the VP is a MOR hotspot, and MOR activation in VP can profoundly change behavior. Thus, we know that VP can potently modulate approach and avoidance behaviors and that opioids can potently modulate VP. Yet we know remarkably little about how VP cell types are connected to NAc and VTA cell types, how VP cell types and synapses are modulated by MORs, or how opioid-induced plasticity in VP cell types and synapses modify approach and avoidance behaviors that are perturbed in opioid dependence and withdrawal. This proposal will systematically attack this knowledge gap using mouse genetics and both ex vivo and in vivo anatomical, physiological and behavioral approaches to: i) characterize the cell types and synapses in VP that express MOR, ii) define how VP cell types are connected to afferent NAc and efferent VTA cell types, iii) identify how MOR activation modulates the function of these cell types and synapses, and iv) describe how their function is perturbed in opioid dependence and withdrawal.