Neurophysiological Mechanisms of Variable Alcohol Drinking Behaviors

可变饮酒行为的神经生理学机制

基本信息

批准号：
8696163
负责人：
Ming-Hu Han
金额：
$ 33.8万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-10 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8696163
关键词：
Alcohol consumption Alcohol dependence Amygdaloid structure Animal Model Behavioral Brain Chronic stress Cocaine Complex Consumption Data Dependence Dissection Drug Targeting Environment Ethanol Event Exhibits Experimental Models Genes Healthcare Human In Vitro Inbred Mouse Inbred Strains Mice Inbreeding Individual Ion Channel Knowledge Link Medial Mediating Modeling Molecular Mus Neurologic Neurons Nucleus Accumbens Pattern Phenotype Physiological Population Prefrontal Cortex Preparation Property Psyche structure Regulation Rewards Rodent Role Signal Transduction Slice Substance Use Disorder System Testing Therapeutic Variant Ventral Tegmental Area Virus Work addiction alcohol research alcohol use disorder base care burden cell type clinically relevant dopamine system dopaminergic neuron drinking drinking behavior drug of abuse drug reinforcement effective therapy experience global health improved in vivo mouse model neural circuit neuromechanism neurophysiology novel optogenetics preference public health relevance receptor relating to nervous system response therapeutic target translational study

项目摘要

DESCRIPTION (provided by applicant): Alcohol-use disorders create a huge global health care burden, which ranks number two in the mental, neurological and substance-use disorders, indicating an urgent need for more effective treatments. It is well known that alcohol-use is very different from other drugs of abuse such as cocaine in multiple aspects: whereas some individuals drink alcohol for decades in a controlled manner and without developing dependence, others have an uncontrollable desire to drink and develop severe alcohol addiction. To understand the neurophysiological mechanisms that underlie the evidently different drinking behaviors, we hypothesize that there is alcohol drinking variability even in genetically identical inbred mice. This hypothesis is important because previous efforts to understand the drinking variations in animal models have encountered huge challenges, which is in part induced by the variable gene backgrounds and the unknown complex interactions between genes and the environment. In our preliminary studies toward testing this hypothesis, we observed that in C57BL/6J mice, an inbred strain typically used in alcohol research because of its high ad libitum consumption of alcohol, roughly 10% had lower alcohol drinking behaviors (preference and consumption). This provides us with an exceptional experimental model to explore the individual variations in alcohol drinking behaviors. To investigate the neurophysiological basis underlying variable alcohol drinking behaviors, we focus on the brain's reward circuit, a well-known neural system that is critically involved in mediating natural reward and drug reinforcement. We propose to: (1) characterize the differences in the firing activity of ventral tegmental area (VTA) dopamine neurons in low and high alcohol drinking mice, and, more specifically, of the subpopulations of VTA neurons projecting to the nucleus accumbens (NAc), medial prefrontal cortex (mPFC) and amygdala (BLA); (2) optogenetically dissect the functional roles of VTA dopamine neurons and their specific projections to NAc, mPFC and BLA in mediating the variable alcohol drinking behaviors; (3) intensively explore the ion channel and receptor mechanisms underlying the differences in the firing properties of VTA dopamine neurons and projection-specific neurons in the VTA to identify possible novel drug targets. In this project, we will provide the direct causal links between alcohol drinking behaviors and the specific roles of firing patterns, cell types and neural circuits via the combined use of state-of-the-art electrophysiological and sophisticated optogenetic approaches in freely behaving mice. These proposed molecular, cellular and neural circuit studies will provide very useful and highly novel information, both for improving our knowledge of variable alcohol drinking behaviors and for identifying new drug targets to develop more effective, individualized treatments for alcohol-use disorders.

描述（由申请人提供）：酒精使用障碍造成了巨大的全球医疗保健负担，在心理，神经和物质使用疾病中排名第二，表明迫切需要更有效的治疗。众所周知，酒精使用与其他滥用药物（例如可卡因）在多个方面有很大不同：虽然有些人以受控的方式喝酒数十年，而没有发展依赖，但其他人则渴望喝酒和发展严重的酒精成瘾。为了理解显然不同的饮酒行为的神经生理机制，我们假设即使在遗传上相同的杂交小鼠中也存在饮酒变异性。这一假设很重要，因为以前的努力了解动物模型的饮酒变化遇到了巨大的挑战，这部分是由可变基因背景和基因与环境之间未知的复杂相互作用引起的。在我们针对检验这一假设的初步研究中，我们观察到，在C57BL/6J小鼠中，由于酒精的多余性消费量高，通常用于酒精研究中的近交菌株，大约10％的酒精饮酒行为（偏好和消费）较低。这为我们提供了一个非凡的实验模型，以探索饮酒行为的个体变化。为了研究神经生理基础可变的饮酒行为，我们专注于大脑的奖励电路，大脑奖励电路是一种众所周知的神经系统，与介导自然奖励和药物增强的重要性有关。我们提出：（1）表征低饮水小鼠和高饮酒小鼠中腹侧偏段面积（VTA）多巴胺神经元的发射活性的差异，更具体地说，是指向核核（NAC），内侧前纹状体Cortex（MPFC）和Am aMygdal的VTA神经元的亚群（NAC）（NAC）（NAC）（NAC）（bla）（Bla）（Bla）（Bla）（2）在光遗传学上剖析VTA多巴胺神经元的功能作用及其对NAC，MPFC和BLA的特定预测在介导可变的酒精饮酒行为中；（3）强烈探索VTA多巴胺神经元和VTA中投影特异性神经元的差异差异的离子通道和受体机制，以识别可能的新药物靶标。在这个项目中，我们将通过在自由表现的小鼠中的最先进的电生理学和精致的光遗传学方法共同使用饮酒行为与发射模式，细胞类型和神经回路的特定作用之间的直接因果关系。这些提出的分子，细胞和神经回路研究将提供非常有用且高度新颖的信息，既可以提高我们对可变饮酒行为的了解，又可以识别新药物靶标，以开发针对酒精使用疾病的更有效，个性化的治疗方法。