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

基本信息

批准号：
10875076
负责人：
Jasper Heinsbroek
金额：
$ 36.15万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-26 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10875076
关键词：
Acceleration 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 Technology Thalamic structure Therapeutic Intervention Training United States Ventral Tegmental Area Viral addiction animal colony 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

项目摘要

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普遍存在的健康问题。我们仍然缺乏特定的治疗干预措施打破复发的复发模式，以寻求该疾病的特征；贫穷的结果了解负责复发的神经回路和细胞适应。非法药物的使用是在联合州稳步上升，死亡人数与药物过量有关在过去的5年中。复发和渴望在互连的神经元活动中驱动腹侧神经节的核，在动机行为和奖励学习中具有很好描述的作用。在该网络中，腹侧颗粒（VP）是对所有已知滥用药物复发的关键调节剂。到日期，许多成瘾研究集中在伏隔核上，这是VP的主要输入结构，但副总裁本身在很大程度上被视为与成瘾相关信息的抑制下游继电器。但是，副总裁神经元比上游核更快地对奖励情绪刺激的反应更快琼脂神经元。此外，虽然副总裁神经元通常被认为是GABA能，但副总裁也包含谷氨酸能神经元的亚群（约30％），将其投射到与抑制性GABA能VP神经元。这些发现挑战了公认的副总裁是抑制性继电器结构并提出独立于核的VP中情绪信息的高级处理伏隔族的投入，其含义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用于药物复发的小鼠模型，我确定了谷氨酸能VP神经元的抑制作用在复发期间，证明这些神经元与GABA能VP神经元相反。基于这些观察结果我预测，滥用药物会降低谷氨酸能VP神经元抑制药物寻求药物的能力，在GABA能VP神经元中的活动中，寻求药物期间的行为参与。这提案在神经回路功能的细胞类型特异性解剖中采用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监测钙活性的特异性监测自由行为的小鼠，并从遗传标记的谷氨酸能和 GABA能VP神经元研究细胞类型和途径特异性VP电路适应后的药物自我适应给药和复发。这些研究将把副总裁作为基底神经节电路的中心组成部分控制成瘾，并揭示VP谷氨酸能和GABA能神经元的不同功能调节寻求药物，这可以为新颖的副总裁针对成瘾的策略奠定基础。