Alcohol-induced neuroadapation of prefrontal cortical projections

酒精诱导的前额皮质投射的神经适应

• 批准号: 10399584
• 负责人: Florence Prabha Varodayan
• 金额: $ 24.9万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399584
• 关键词: Acetylcholine; Adrenergic Receptor; Affinity; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdaloid structure; Anxiety; Area; Automobile Driving; Behavior; Cells; Chronic; Clinical; Data; Dependence; Disease; Electrophysiology (science); Emotional; Ensure; Ethanol; Ethanol dependence; Exhibits; Exposure to; Extinction (Psychology); Future; Glutamates; Heavy Drinking; Human; Immunohistochemistry; Impairment; In Vitro; Individual; Intake; Interneurons; Label; Learning; Link; Marble; Measures; Medial; Mediating; Microdialysis; Modality; Molecular; Molecular Analysis; Molecular Biology; Motivation; Mus; Nature; Neurons; Neurotransmitters; Norepinephrine; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Prefrontal Cortex; Pyramidal Cells; Rattus; Regulation; Relapse; Risk-Taking; Rodent; Role; Signal Transduction; Slice; Stress; Synapses; System; Techniques; Testing; Thalamic structure; Tracer; Training; Water; Withdrawal; Work; addiction; alcohol exposure; antagonist; anxiety-like behavior; awake; behavior test; behavioral pharmacology; design; drinking; drinking behavior; emotion dysregulation; excessive anxiety; experimental study; field study; flexibility; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; in vivo; insight; mouse model; negative affect; negative emotional state; neuroadaptation; neurobiological mechanism; noradrenergic; postsynaptic; presynaptic; problem drinker; recruit; response; withdrawal-induced anxiety

Project Summary / Abstract Alcoholism is a chronic relapsing disorder characterized by alcohol preoccupation, loss of control over intake and a negative emotional state. Alcoholics have reduced prefrontal cortex volumes and significant deficits in ventromedial prefrontal cortex (vmPFC)-related tasks, such as dysfunctional emotional processing and loss of inhibitory control. The rodent medial prefrontal cortex (mPFC) is functionally analogous to the vmPFC as both regions direct the flexible regulation of behavior by regulating subcortical regions in a “top-down” manner. Within the mPFC, the prelimbic (PrL) and infralimbic (IfL) cortices have opposing addiction-related functions, with the PrL driving drug-seeking and the IfL involved with extinction. The IfL is implicated in anxiety-like and excessive drinking behaviors, suggesting that alcohol dependence-induced dysregulation of specific IfL- subcortical projections may contribute to the negative affective state that emerges during alcohol addiction. Thus, the challenge of current and future studies is to identify the neuroadaptations within specific IfL- subcortical circuits that drive different aspects of these alcohol dependence-induced behaviors. CeA recruitment is a hallmark of alcohol dependence and leads to the emotional dysregulation that governs withdrawal-induced anxiety and drinking. The IfL directly projects to the CeA, and we propose that neuroadaptation of this pathway may activate the CeA after chronic ethanol exposure. Clinically, the noradrenergic system has been implicated in the alcohol consumption of alcohol-dependent patients, and tightly regulates IfL function. Therefore, here we will examine how alcohol dependence induces noradrenergic neuroadaptation within the IfL to dysregulate its output to the CeA, and whether this system mediates alcohol withdrawal-induced drinking and anxiety-like behaviors. We have intentionally designed this project to maximize its interdisciplinary nature by ensuring that the information obtained via the different experimental modalities can be compared. We will employ retrograde tracers to label IfL-CeA projection neurons, allowing for the electrophysiological and immunohistochemical characterization of alcohol dependence-induced noradrenergic influence over this pathway after chronic ethanol exposure. To extend these cellular and molecular results to the network level, during my K99 phase I will train in in vivo microdialysis to measure changes in IfL norepinephrine in awake, behaving mice exposed to chronic ethanol. I will also train in behavioral pharmacology techniques to assess the voluntary drinking of ethanol-dependent mice prior to their anxiety-like behavioral testing. Collectively, this work will provide insight into the influence of noradrenergic signaling on the IfL-CeA pathway, and its neuroadaptation with alcohol dependence.

项目概要/摘要 酒精中毒是一种慢性复发性疾病，其特征是对酒精的过度关注、对摄入量失去控制 酗酒者的前额皮质体积减少，大脑功能显着缺陷。 腹内侧前额叶皮层 (vmPFC) 相关任务，例如情绪处理功能失调和丧失 啮齿类动物内侧前额叶皮层 (mPFC) 的功能与 vmPFC 相似，因为两者都具有抑制控制功能。 区域通过“自上而下”的方式调节皮层下区域来指导行为的灵活调节。 在 mPFC 内，前边缘 (PrL) 和下边缘 (IfL) 皮质具有相反的成瘾相关功能， PrL 驱动药物寻求，IfL 与灭绝有关。 过度饮酒行为，表明酒精依赖引起特定 IfL- 的失调 皮质下投射可能会导致酒精成瘾期间出现的负面情感状态。 因此，当前和未来研究的挑战是确定特定 IfL- 内的神经适应。 驱动这些酒精依赖引起的行为的不同方面的皮质下回路。 CeA 募集是酒精依赖的一个标志，会导致情绪失调 IfL 直接投射到 CeA，我们建议： 临床上，长期接触乙醇后，该通路的神经适应可能会激活 CeA。 去甲肾上腺素能系统与酒精依赖患者的饮酒有关，并且 因此，这里我们将研究酒精依赖如何诱导去甲肾上腺素能。 IfL 内的神经适应失调其向 CeA 的输出，以及该系统是否介导酒精 戒断引起的饮酒和类似焦虑的行为。 我们有意设计这个项目，通过确保 我们将采用逆行法来比较通过不同实验方式获得的信息。 示踪剂标记 IfL-CeA 投射神经元，允许进行电生理学和免疫组织化学分析 慢性酒精依赖诱导的去甲肾上腺素能对该途径的影响的特征 在我的 K99 第一阶段期间，将这些细胞和分子结果扩展到网络水平。 将进行体内微透析训练，以测量暴露于暴露于 我还将接受行为药理学技术的培训，以评估自愿饮酒的情况。 总的来说，这项工作将在进行类似焦虑的行为测试之前对乙醇依赖的小鼠提供见解。 去甲肾上腺素能信号对 IfL-CeA 通路的影响及其对酒精的神经适应 依赖性。