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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：
10014520
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
项目类别：
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/10014520
关键词：
Amygdaloid structure Anatomy Area Automobile Driving Award Basal Ganglia Behavior Behavioral Brain Breeding Calcium Cell Nucleus Cessation of life Chronic Cocaine 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 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.

摘要