Mechanisms of regulation of ethanol intake by lateral habenula

外侧缰核调节乙醇摄入的机制

基本信息

  • 批准号:
    8459842
  • 负责人:
  • 金额:
    $ 38.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
描述该应用的目的是探讨神经元在侧向Habenula(LHB)在调节乙醇摄入中发挥的作用。厌恶,负面的感觉输入是由恐惧,焦虑,抑郁,压力和奖励涉及的上皮结构来处理的。 LHB从基底神经节中接收初级输入,并将输出主要发送到多巴胺能(DA)和血清素能神经元。 LHB为中脑DA细胞提供了负强化信号的重要来源。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to骨中膜桥细胞中的GABA细胞的双突触连接,从而支配了DA神经元。许多工作表明,Habenula在尼古丁成瘾和戒断以及吗啡自我管理以及寻求可卡因寻求行为中起关键作用。但是,LHB在乙醇添加中的作用尚未得到很好的探索。众所周知的是,包括腹侧对接区域(VTA)在内的DA系统参与寻求乙醇和继电器。尽管乙醇急性激活中脑的DA传播,但从慢性乙醇暴露中退出会导致Acumbens的VTA DA神经元活性和多巴胺细胞外多巴胺的大幅降低。据信,这种多巴胺功能障碍会导致烦躁的状态,该状态驱动药物寻求将多巴胺恢复到正常的药物水平。然而,引起多巴胺功能障碍的机制尚不清楚。因此,我们提出的实验将专门检验中心假设,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,从而减少VTA DA神经元的发射。这些抑制作用可能是多巴胺功能障碍和厌恶状态的基础,可能会导致过度饮酒。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,包括在以下两个单独但集成的特定目标中,包括最先进的光遗传学技术。具体目标1将通过评估自愿乙醇饮用的变化来检验假设,而LHB神经元的功能是通过电气/光刺激或药物操纵的。我们还将通过FOS免疫反应性,使用蛋白质印迹的蛋白质水平对LHB和RMTG神经元的活性的变化进行测量,使用蛋白质印迹和使用微透析技术对LHB和RMTG中的谷氨酸谷物水平的蛋白质水平。具体目标2将检查通过依赖酒精依赖动物的大脑切片中的电生理记录,通过电生理记录来调节乙醇饮用行为的细胞机制。我们将表征由CIESA在LHB和RMTG中的神经元的活性和谷氨酸能突触传播中引起的变化。这些研究将提供重要的新信息,从而大大提高我们对LHB和RMTG在酒精使用障碍中的作用的理解。这些研究还可以洞悉有关人类酒精中毒中与负增强相关的饮酒的细胞机制。

项目成果

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JIANG-HONG YE其他文献

JIANG-HONG YE的其他文献

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{{ truncateString('JIANG-HONG YE', 18)}}的其他基金

Role of Rostromedial Tegmental Nucleus in alcohol addiction
鼻内侧被盖核在酒精成瘾中的作用
  • 批准号:
    9210577
  • 财政年份:
    2014
  • 资助金额:
    $ 38.76万
  • 项目类别:
Role of Rostromedial Tegmental Nucleus in alcohol addiction
鼻内侧被盖核在酒精成瘾中的作用
  • 批准号:
    8997041
  • 财政年份:
    2014
  • 资助金额:
    $ 38.76万
  • 项目类别:
Glycine regulates ethanol intake
甘氨酸调节乙醇摄入量
  • 批准号:
    7896171
  • 财政年份:
    2010
  • 资助金额:
    $ 38.76万
  • 项目类别:
Glycine regulates ethanol intake
甘氨酸调节乙醇摄入量
  • 批准号:
    8046489
  • 财政年份:
    2010
  • 资助金额:
    $ 38.76万
  • 项目类别:
Alcohol and mesolimbic glutamatergic transmissions
酒精和中脑边缘谷氨酸能传递
  • 批准号:
    8709792
  • 财政年份:
    2008
  • 资助金额:
    $ 38.76万
  • 项目类别:
Alcohol and mesolimbic glutamatergic transmissions
酒精和中脑边缘谷氨酸能传递
  • 批准号:
    7586252
  • 财政年份:
    2008
  • 资助金额:
    $ 38.76万
  • 项目类别:
Alcohol and mesolimbic glutamatergic transmissions
酒精和中脑边缘谷氨酸能传递
  • 批准号:
    8061678
  • 财政年份:
    2008
  • 资助金额:
    $ 38.76万
  • 项目类别:
Alcohol and mesolimbic glutamatergic transmissions
酒精和中脑边缘谷氨酸能传递
  • 批准号:
    7799680
  • 财政年份:
    2008
  • 资助金额:
    $ 38.76万
  • 项目类别:
Alcohol and mesolimbic glutamatergic transmissions
酒精和中脑边缘谷氨酸能传递
  • 批准号:
    7466768
  • 财政年份:
    2008
  • 资助金额:
    $ 38.76万
  • 项目类别:
Ethanol and mesolimbic GABAergic neurons
乙醇和中脑边缘 GABA 能神经元
  • 批准号:
    7146489
  • 财政年份:
    2006
  • 资助金额:
    $ 38.76万
  • 项目类别:

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