Midbrain neural circuit mechanisms underlying addiction

成瘾背后的中脑神经回路机制

基本信息

批准号：
10471102
负责人：
Thomas Hnasko
金额：
--
依托单位：
VA SAN DIEGO HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10471102
关键词：
Abstinence Affect Analgesics Anatomy Attention Aversive Stimulus Behavior Behavior Control Behavioral Brain Cell physiology Cells Communities Complex Dopamine Dopamine D2 Receptor Electrophysiology (science)Family Fiber Foundations Future Globus Pallidus Glutamates Health Individual Knowledge Literature Longevity Maps Measures Mediating Midbrain structure Motivation Mus Neurons Nucleus Accumbens Opiate Addiction Opioid Opioid replacement therapy Output Personal Satisfaction Persons Pharmaceutical Preparations Pharmacology Photometry Physiological Population Heterogeneity Process Psychological reinforcement Public Health Punishment Receptor Activation Rewards Role Signal Transduction Slice Synapses Synaptic Transmission Testing Ventral Tegmental Area Veterans Viral Vector Weaning Withdrawal Withdrawal Symptom Work addiction approach avoidance behavior approach behavior avoidance behavior behavior change behavioral response cell type dopaminergic neuron experimental study gamma-Aminobutyric Acid in vivo mouse genetics mu opioid receptors neural circuit neuroregulation opioid abuse opioid epidemic opioid use opioid use disorder opioid withdrawal optogenetics relapse risk response targeted treatment therapeutic development tool

项目摘要

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.

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后果。阿片类药物成瘾是由阿片类药物诱导的脑电路变化推动有益和厌恶刺激以及反向阿片类药物引起的变化的神经调节疗法迫切需要电路。从腹侧对段区域（VTA）到的中唇多巴胺（DA）投射到伏隔核（NAC）通常被描述为大脑的奖励电路，实际上有很多证据表明该预测在行为强化的基础过程中的核心作用。但是是什么控制活动 vta da神经元？ NAC在哪里发送已发布的DA调制的信号？答案这两个问题都是：腹侧粒子（VP）。然而，关于VP知之甚少。例如，它具有直到最近，VP包含兴奋性和抑制性的异质种群投射神经元在相反的方向上调节方法和回避行为。此外，MU-阿片类药物受体（MOR）介导滥用阿片类药物的镇痛和成瘾作用，VP是MOR 热点和VP中的MOR激活可以深刻地改变行为。因此，我们知道副总裁可以有效调节方法和回避行为，阿片类药物可以有效调节VP。但是我们知道关于VP单元类型如何连接到NAC和VTA单元类型，VP细胞类型和如何连接的VP细胞类型以及如何连接突触是由MORS调制的，或在VP单元格中的阿片类药物诱导的可塑性如何修改阿片类药物依赖性和退出中受到干扰的方法和回避行为。该提议将使用小鼠遗传学以及离体和体内解剖学，系统地攻击此知识差距生理和行为方法的方法：i）表征表达VP中的细胞类型和突触 MOR，ii）定义VP细胞类型如何连接到传入的NAC和Furdent VTA细胞类型，iii）确定如何 MOR激活调节这些细胞类型和突触的功能，iv）描述其功能是如何的在阿片类药物依赖和戒断中受到干扰。