Midbrain neural circuit mechanisms underlying addiction

项目摘要 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。 阿片类药物成瘾是由阿片类药物诱导的脑回路变化推动的，脑回路控制着对阿片类药物的行为反应。 奖励和厌恶刺激，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。中脑边缘核多巴胺（DA）从腹侧被盖区（VTA）向中脑腹侧被盖区（VTA）的投射 脑桥核（NAc）通常被描述为大脑的奖励回路，事实上，许多证据表明， 这种投射在行为强化过程中的核心作用。但是是什么控制着 腹侧被盖区DA神经元？NAc将被释放的DA调制的信号发送到哪里？一个答案 这两个问题的答案是腹侧苍白球（VP）。然而，对VP的了解却少得多。例如， 直到最近才意识到VP含有兴奋性和抑制性的异质群体， 投射神经元，在相反的方向上调节接近和回避行为。此外，μ-阿片类药物 阿片受体（莫尔）介导阿片类药物的镇痛和成瘾作用，VP是一种莫尔 VP中的热点和莫尔激活可以深刻地改变行为。因此，我们知道VP可以有效地 调节接近和回避行为，阿片类药物可以有效地调节VP。然而我们知道 关于VP细胞类型如何连接到NAc和VTA细胞类型，VP细胞类型和 突触是由MORs调节的，或者阿片样物质诱导的VP细胞类型和突触可塑性如何改变 在阿片类药物依赖和戒断中受到干扰的接近和回避行为。这项建议会 系统地利用小鼠遗传学和离体和体内解剖学， 生理和行为方法：i）表征VP中表达的细胞类型和突触 莫尔，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 莫尔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被激活的。 对阿片类药物依赖和戒断感到不安。

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.