Dissecting Ventral Pallidal Subcircuit Contributions to Drug Seeking in Addiction

摘要 吸毒成瘾是我们社会普遍存在的健康问题。我们仍然缺乏具体的治疗干预措施 打破以吸毒为特征的反复出现的模式；贫穷的结果 了解导致复发的神经回路和细胞适应。非法药物的使用是 美国的死亡人数稳步上升，与药物过量有关的死亡人数急剧增加 在过去的五年里。复发和药物渴求是由互联网络中的神经元活动关键驱动的 腹侧基底节的核，它们在动机行为和奖赏学习中的作用得到了很好的描述。 在这个网络中，腹侧苍白球(VP)是所有已知的滥用药物复发的关键调节器。至 迄今为止，许多成瘾研究都集中在伏隔核，这是VP的主要输入结构，但 VP本身在很大程度上被忽视了，认为它是成瘾相关信息的抑制下游传递。 然而，VP神经元对奖励情绪刺激的时间反应比上游核团更快 伏隔神经元。此外，虽然VP神经元通常被认为主要是GABA能的，但VP也 包含一个亚群(~30%)的谷氨酸能神经元，这些神经元投射到与 抑制性GABA能VP神经元。这些发现挑战了公认的VP是抑制性继电器的观点 独立于核团的VP中情绪信息的结构和建议的高级加工 伏隔传入，其含义改变了我们对基底节功能的理解。通过使用我的 最近建立了药物复发的小鼠模型，我发现了谷氨酸能VP神经元的抑制作用 在复发过程中，表明这些神经元与GABA能VP神经元的作用相反。基于这些 观察我预测，药物滥用会降低谷氨酸能VP神经元抑制药物寻找的能力， 在寻找药物的过程中，行为参与是由GABA能VP神经元的活动进行的。这 建议在神经回路功能的细胞类型特定解剖中采用尖端技术进步 和连接性，如光遗传学，化学遗传学，体内细胞类型特异性监测钙活动 自由行为的小鼠，和切片电生理记录从基因标记的谷氨酸和 GABA能VP神经元研究药物自身后细胞类型和通路特异性VP回路的适应 管理和故态复萌。这些研究将把VP定位为基底节环路的中心组成部分 控制成瘾，揭示VP谷氨酸能神经元与GABA能神经元在成瘾中的不同功能 规范药物寻找，这可能为治疗成瘾的新的VP靶向策略奠定基础。

ABSTRACT Drug addiction is a pervasive health problem in our society. We still lack specific therapeutic interventions to break the recurrent pattern of relapse to drug seeking that characterizes the disorder; a result of poor understanding of the neural circuits and cellular adaptations responsible for relapse. The use of illicit drugs is rising steadily in the Unites States, with the number of deaths related to drug overdose dramatically accelerating over the last 5 years. Relapse and drug craving are critically driven by neuronal activity in the interconnected nuclei of the ventral basal ganglia, which have a well described role in motivated behavior and reward learning. Within this network the ventral pallidum (VP) is a critical regulator of relapse to all known drugs of abuse. To date, much addiction research has focused on the nucleus accumbens, a primary input structure to the VP, but the VP itself has been largely disregarded as an inhibitory downstream relay of addiction-related information. However, VP neurons respond temporally quicker to rewarding emotional stimuli than upstream nucleus accumbens neurons. Furthermore, while VP neurons are generally thought to be largely GABAergic, the VP also contains a subpopulation (~30%) of glutamatergic neurons that project to the same downstream areas as inhibitory GABAergic VP neurons. These findings challenge the accepted idea that the VP is an inhibitory relay structure and suggest advanced processing of emotional information in the VP independent of nucleus accumbens inputs, with implications that transform our understanding of basal ganglia function. By using my recently developed mouse model for drug relapse, I identified an inhibitory role for glutamatergic VP neurons during relapse, demonstrating that these neurons act oppositely to GABAergic VP neurons. Based on these observations I predict that drug abuse reduces the capacity of glutamatergic VP neurons to inhibit drug seeking, and that behavioral engagement during drug seeking is carried by activity in GABAergic VP neurons. This proposal employs cutting edge technological advances in the cell type specific dissection of neural circuit function and connectivity such as optogenetics, chemogenetics, in vivo cell-type specific monitoring of calcium activity in freely behaving mice, and slice electrophysiology recordings from genetically labeled glutamatergic and GABAergic VP neurons to investigate cell type and pathway specific VP circuit adaptations following drug self administration and relapse. These studies will place the VP as a central component of basal ganglia circuits controlling addiction, and reveal the distinct functions of VP glutamatergic versus GABAergic neurons in regulating drug seeking, which could lay the groundwork for novel VP targeted strategies to treat addiction.