Dissecting Ventral Pallidal Subcircuit Contributions to Drug Seeking in Addiction

剖析腹侧苍白球亚电路对成瘾药物寻求的贡献

• 批准号: 10324576
• 负责人: Jasper Heinsbroek
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324576
• 关键词: Amygdaloid structure; Anatomy; Area; Automobile Driving; Award; Basal Ganglia; Behavior; Behavioral; Brain; Breeding; Calcium; Cell Nucleus; Cessation of life; Chronic; Data; Disease; Dissection; Doctor of Philosophy; Drug Addiction; Drug Controls; Drug abuse; Drug usage; Electrophysiology (science); Elements; Emotional; Environment; Equilibrium; Faculty; Genetic; Globus Pallidus; Glutamates; Green Card; HRK gene; Health; In Vitro; Influentials; Institution; Label; Learning; Maps; Measures; Medicine; Mentors; Microscopy; Monitor; Mus; Neurons; Neurosciences; Nucleus Accumbens; Overdose; Pathway interactions; Pattern; Pharmaceutical Preparations; Physiology; Population; Population Sizes; Positioning Attribute; Postdoctoral Fellow; Process; Rabies; Recurrence; Regulation; Relapse; Reporter; Research; Research Personnel; Resources; Rewards; Role; Self Administration; Series; Slice; Societies; Stimulus; Structure; Synapses; Thalamic structure; Therapeutic Intervention; Training; United States; Ventral Tegmental Area; Viral; addiction; animal colony; base; career; cell type; cocaine relapse; cocaine self-administration; college; drug craving; drug of abuse; drug relapse; emotional stimulus; experimental study; gamma-Aminobutyric Acid; global health; graduate student; illicit drug use; in vivo; interest; motivated behavior; mouse model; neural circuit; neuroadaptation; neuropsychiatric disorder; novel; operation; optogenetics; post-doctoral training; professor; programs; tool

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.

抽象的 吸毒成瘾是我们社会中普遍存在的健康问题。我们仍然缺乏具体的治疗干预措施 打破这种疾病特有的反复吸毒复发模式；贫穷的结果 了解导致复发的神经回路和细胞适应。使用非法药物是 在美国，与药物过量相关的死亡人数稳步上升，死亡人数急剧增加 过去5年。复发和药物渴望在很大程度上是由相互关联的神经元活动驱动的 腹侧基底神经节的核，在动机行为和奖励学习中具有明确的作用。 在这个网络中，腹侧苍白球（VP）是所有已知药物滥用复发的关键调节器。到 迄今为止，许多成瘾研究都集中在伏隔核上，伏隔核是 VP 的主要输入结构，但是 VP 本身在很大程度上被忽视为成瘾相关信息的抑制性下游中继。 然而，VP 神经元在时间上比上游核对奖励性情绪刺激的反应更快 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 包含谷氨酸能神经元亚群（~30%），它们投射到与 抑制性 GABA 能 VP 神经元。这些发现挑战了 VP 是抑制性继电器这一公认观点 结构并建议 VP 中独立于核的情感信息的高级处理 伏隔核的输入，其影响改变了我们对基底神经节功能的理解。通过使用我的 最近开发的药物复发小鼠模型，我发现了谷氨酸能 VP 神经元的抑制作用 在复发期间，证明这些神经元的作用与 GABA 能 VP 神经元相反。基于这些 观察结果 我预测药物滥用会降低谷氨酸能 VP 神经元抑制药物寻求的能力， 药物寻找过程中的行为参与是由 GABA 能 VP 神经元的活动来实现的。这 该提案采用了神经回路功能的细胞类型特异性解剖方面的尖端技术进步 和连通性，例如光遗传学、化学遗传学、体内细胞类型特异性钙活性监测 自由行为的小鼠，并从基因标记的谷氨酸能和 GABAergic VP 神经元研究药物自体后细胞类型和途径特异性 VP 电路适应 给药和复发。这些研究将 VP 作为基底神经节回路的核心组成部分 控制成瘾，并揭示 VP 谷氨酸能神经元与 GABA 能神经元的不同功能 规范药物寻求，这可能为治疗成瘾的新型 VP 靶向策略奠定基础。