Mechanisms of regulation of ethanol intake by lateral habenula

外侧缰核调节乙醇摄入的机制

• 批准号: 8459842
• 负责人: JIANG-HONG YE
• 金额: $ 38.76万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-20 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459842
• 关键词: AMPA Receptors; Abbreviations; Alcohol consumption; Alcohol dependence; Alcohols; Aminobutyric Acids; Animals; Anxiety; Area; Basal Ganglia; Behavior; Brain; Cell Nucleus; Cells; Chronic; Cocaine; Complex; Data; Dopamine; Dopaminergic Cell; Epithalamic structure; Ethanol; Ethanol dependence; Event; Frequencies; Fright; Glutamate Receptor; Glutamates; Goals; Habenula; Health; Heavy Drinking; Human; Laboratories; Lateral; Light; Literature; Measures; Mediating; Mental Depression; Microdialysis; Midbrain structure; Modeling; Molecular; Morphine; Negative Reinforcements; Neurons; Nicotine Dependence; Nicotine Withdrawal; Nucleus Accumbens; Output; Pharmaceutical Preparations; Physiologic pulse; Play; Process; Propionic Acids; Proteins; Rattus; Recording of previous events; Regulation; Rewards; Rodent; Role; Self Administration; Sensory; Signal Transduction; Slice; Source; Sprague-Dawley Rats; Stress; Synaptic Transmission; System; Techniques; Testing; Ventral Tegmental Area; Western Blotting; Withdrawal; Work; alcohol exposure; alcohol relapse; alcohol seeking behavior; alcohol use disorder; base; dopaminergic neuron; drinking; drinking behavior; expectation; extracellular; immunoreactivity; insight; interdisciplinary approach; interpeduncular nucleus; negative emotional state; neurobiological mechanism; optogenetics; postsynaptic; problem drinker; public health relevance; research study; transmission process

DESCRIPTION The goal of this application is to explore the role that neurons in the Lateral Habenula (LHb) play in regulating ethanol intake. Aversive, negative sensory input is processed by the habenular complex, an epithalamic structure involved in fear, anxiety, depression, stress and reward. The LHb receives inputs primarily from the basal ganglia and sends outputs mainly to dopaminergic (DA) and serotonergic neurons. The LHb provides an important source of negative reinforcing signals to midbrain DA cells. This profound and consistent inhibitory influence involves a disynaptic connection from glutamate neurons in the LHb to the GABA cells in the Rostromedial Mesopontine Tegmental Nucleus (RMTg) that, in turn, innervates DA neurons. Much work has shown that the habenula plays a key role in nicotine addiction and withdrawal and in the regulation of morphine self-administration, as well as cocaine seeking behavior. However, the role of LHb in ethanol addiction has not been well explored. It is well accepted that the DA system, including the ventral tegmental area (VTA), is involved in ethanol seeking and relapse. Although ethanol acutely activates mesolimbic DA transmission, withdrawal from chronic ethanol exposure leads to substantial decrements in VTA DA neuronal activities and extracellular levels of dopamine in the nucleus accumbens. It is believed that this dopamine hypofunction leads to a dysphoric state that drives drug seeking to restore dopamine to normal, drug-na¿ve levels. However, the mechanisms causing dopamine hypofunction are not well understood. Our proposed experiments will therefore specifically test the central hypothesis that over-activity of LHb neurons in alcohol dependent animals drives inhibitory RMTg neurons which reduce firing of VTA DA neurons. These inhibitory effects may underlie the dopamine hypofunction and aversive state that may substantially contribute to excessive drinking. We will test this hypothesis by the use of a rat model of chronic intermittent ethanol self-administration (CIESA) and a multidisciplinary approach, including state-of-the-art optogenetic techniques in the following two separate but integrated Specific Aims. Specific Aim 1 will test the hypothesis by assessing changes in voluntary ethanol drinking while the function of the LHb neurons is manipulated by electrical/light stimulation or pharmacologically. We will also measure changes caused by CIESA on the activity of neurons in the LHb and RMTg by means of Fos immunoreactivity, on protein levels of glutamate receptors using Western blotting, and extracellular levels of glutamate in the LHb and RMTg using microdialysis techniques. Specific Aim 2 will examine the cellular mechanisms underlying LHb regulation of ethanol drinking behaviors by electrophysiological recording in brain slices of alcohol dependent animals. We will characterize changes caused by CIESA in the activity of, and glutamatergic synaptic transmissions to, neurons in the LHb and RMTg. These studies will provide important new information that will significantly advance our understanding of the role of LHb and RMTg in alcohol use disorders. These studies could also provide insight into the cellular mechanisms governing negative reinforcement-associated drinking in human alcoholics.

描述 本应用的目的是探索外侧缰核 (LHb) 中的神经元在调节乙醇摄入中所起的作用。缰核复合体是一种涉及恐惧、焦虑、抑郁和压力的上丘脑结构。 LHb 主要接收来自基底神经节的输入，并将输出主要发送到多巴胺能 (DA) 和血清素能神经元。 LHb 提供了负性的重要来源。这种深刻而一致的抑制作用会影响 LHb 中的谷氨酸神经元与桥内侧中脑桥被盖核 (RMTg) 中的 GABA 细胞的非突触连接，进而神经支配 DA 神经元。缰核在尼古丁成瘾和戒断、吗啡自我给药以及可卡因寻求行为的调节中起着关键作用。 LHb 在乙醇成瘾中的作用尚未得到充分研究，但人们普遍认为，DA 系统（包括腹侧被盖区 (VTA)）参与乙醇寻找和复发，尽管乙醇会急剧激活中脑边缘 DA 传递，但从慢性乙醇中戒断。暴露导致伏隔核中 VTA DA 神经元活动和细胞外多巴胺水平显着降低。据信，这种多巴胺功能减退会导致烦躁不安。驱使药物寻求将多巴胺恢复到正常的状态，药物-na¿然而，导致多巴胺功能减退的机制尚不清楚，因此我们提出的实验将专门测试酒精依赖动物中 LHb 神经元的过度活动会驱动抑制性 RMTg 神经元，从而减少 VTA DA 神经元的放电效应。多巴胺功能减退和厌恶状态可能在很大程度上导致过度饮酒，我们将通过使用慢性间歇性自我给药大鼠模型（CIESA）和多学科来检验这一假设。方法，包括以下两个独立但综​​合的具体目标 1 中最先进的光遗传学技术，将通过评估自愿饮酒的变化来检验这一假设，同时通过电/光刺激操纵 LHb 神经元的功能。我们还将通过 Fos 免疫反应性测量 CIESA 对 LHb 和 RMTg 中神经元活性的变化，使用蛋白质印迹法测量谷氨酸受体的蛋白质水平以及细胞外水平。使用微透析技术检测 LHb 和 RMTg 中谷氨酸的含量。 具体目标 2 将通过酒精依赖动物脑切片的电生理记录来检查 LHb 调节乙醇饮酒行为的细胞机制。谷氨酸突触传递至 LHb 和 RMTg 中的神经元这些研究将提供重要的新信息，将显着增进我们对 LHb 和 RMTg 在酒精使用中的作用的理解。这些研究还可以深入了解控制人类酗酒者与负强化相关的饮酒的细胞机制。