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.

本申请的目的是探索外侧缰（LHb）神经元在调节乙醇摄入中的作用。厌恶的、负面的感觉输入是由缰复合体处理的，缰复合体是一种涉及恐惧、焦虑、抑郁、压力和奖励的上丘脑结构。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（DA）能和多巴胺能神经元。LHb为中脑DA细胞提供了一个重要的负强化信号来源。这种深刻而一致的抑制作用涉及从LHb中的谷氨酸神经元到Rostromedial Mesopontine Tegmental Nucleus（RMTg）中的GABA细胞的双突触连接，RMTg反过来又支配DA神经元。许多研究表明，缰在尼古丁成瘾和戒断、吗啡自我给药的调节以及可卡因寻求行为中起着关键作用。然而，LHb在乙醇成瘾中的作用尚未得到很好的研究。包括腹侧被盖区（VTA）在内的DA系统参与酒精寻求和复吸，这是公认的。虽然乙醇急性激活mesolimbic DA传输，退出慢性乙醇暴露导致腹侧被盖区DA神经元活动和多巴胺的细胞外水平在延髓核的大幅下降。据信，这种多巴胺功能减退导致烦躁不安的状态，驱使药物寻求恢复多巴胺到正常的，药物幼稚的水平。然而，引起多巴胺功能减退的机制还不清楚。因此，我们提出的实验将具体测试中心假设，即酒精依赖动物中LHb神经元的过度活性驱动抑制性RMTg神经元，其减少腹侧被盖区DA神经元的放电。这些抑制作用可能是多巴胺功能减退和厌恶状态的基础，而这种状态可能实质上导致过量饮酒。我们将通过使用慢性间歇性乙醇自我给药（CIESA）的大鼠模型和多学科方法（包括以下两个独立但综合的特定目标中的最先进的光遗传学技术）来测试这一假设。具体目标1将通过评估自愿饮用乙醇的变化来测试假设，同时通过电/光刺激或刺激来操纵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中神经元的活性引起的变化，使用Western印迹法测量谷氨酸受体的蛋白水平，以及使用微透析技术测量LHb和RMTg中谷氨酸的细胞外水平。具体目标2将通过酒精依赖动物脑切片的电生理记录来研究LHb调节酒精饮用行为的细胞机制。我们将描述CIESA引起的LHb和RMTg神经元的活动和突触传递的变化。 这些研究将提供重要的新信息，将显着推进我们对LHb和RMTg在酒精使用障碍中的作用的理解。这些研究还可以提供对人类酗酒者负性饮酒相关的细胞机制的深入了解。