Optogenetic dissection of neural circuits underlying alcohol drinking behaviors

饮酒行为背后的神经回路的光遗传学解剖

• 批准号: 8786227
• 负责人: Barbara Juarez
• 金额: $ 3.84万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8786227
• 关键词: Alcohol consumption; Alcohol dependence; Alcohols; Area; Consumption; Dependence; Dissection; Dopamine; Functional disorder; Genes; Goals; Health; Healthcare; Heterogeneity; Human; In Vitro; Inbred Mouse; Inbred Strains Mice; Inbreeding; Individual; Investigation; Laboratories; Link; Medial; Mediating; Mental Depression; Mental Health; Mission; Motivation; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurons; Nucleus Accumbens; Pharmaceutical Preparations; Phenotype; Population; Prefrontal Cortex; Prevention; Prevention strategy; Recruitment Activity; Rewards; Role; Signal Transduction; Site; Stimulus; System; Techniques; Therapeutic; United States National Institutes of Health; Variant; Ventral Tegmental Area; alcohol use disorder; base; dopaminergic neuron; drinking; drinking behavior; drug reward; global health; in vivo; innovation; insight; interest; mouse model; neural circuit; neuroadaptation; neurophysiology; new therapeutic target; novel; novel therapeutics; optogenetics; preference; relating to nervous system; research study

DESCRIPTION (provided by applicant): Alcohol-use disorders create a substantial global healthcare burden and it is imperative to identify novel therapeutic targets for their prevention and treatment. An interesting phenomenon with alcohol is the variability of consumption that occurs within individuals of the human population: some individuals drink alcohol in a controlled manner without developing dependence while others develop severe alcohol addiction. To understand this phenomenon of alcohol drinking variability, I propose to utilize a mouse model to investigate the neurophysiological basis of evidently distinct alcohol drinking behaviors. In C57BL/6J mice, an inbred mouse strain typically used to study high alcohol drinking behaviors, I have found a stable low alcohol drinking population. This mouse model provides me with a unique opportunity to investigate the neurophysiological mechanisms that underlie low and high alcohol drinking behaviors in a genetically identical mouse line without the challenge of variable gene background interactions. It is known that a hallmark of the progression of alcohol-use disorders is the dysfunction of dopamine (DA) neurons in the ventral tegmental area (VTA), an area critical to encoding the salience of drug stimuli. The VTA sends functionally diverse DA projections to two neural substrates highly involved in drug reward and motivation - the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC). In my preliminary studies, I demonstrate that the in vivo firing activity and burst activity of all VTA DA neurons are higher in low C57BL/6J alcohol drinkers compared to high alcohol drinking and EtOH naïve mice. Furthermore, optogenetically mimicking this observed increase of VTA DA activity in previously high drinking TH-Cre mice reduced alcohol drinking behaviors. Because of the increasing body of evidence suggesting functional diversity of VTA DA neurons based on their target neural projection site, I hypothesize, based on my preliminary findings, that individual drinking differences in genetically identical mice arise from projection-specific (NAc versus mPFC) neuronal alterations of VTA DA neurons during alcohol consumption. My project will use a systematic approach to investigate the neural circuit functional roles VTA DA neurons have in generating different alcohol-drinking behaviors in C57BL/6J mice. To characterize projection-specific neuronal alterations between low and high alcohol drinking mice, I will use retrograde fluorescent beads to differentiate VTA DA neurons during in vitro electrophysiological investigations (Aim 1). I will then use innovative, circuit-specific optogenetic techniques to mimi the identified neurophysiological alterations observed in VTA neurons in order to drive specific alcohol drinking behaviors (Aim 2). This project will identify the neuroadaptations of VTA DA neuron firing underlying individual alcohol drinking behaviors. Furthermore, this proposed state-of-the-art neural circuit dissection will provide novel insight to identify more effective therapeuic target sites 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卫生保健负担，必须确定新的治疗靶点来预防和治疗。关于酒精的一个有趣现象是，在人群中个体的消费变化：一些人以可控的方式饮酒，不会产生依赖，而另一些人则会产生严重的酒精成瘾。为了理解这种饮酒变异性现象，我建议利用小鼠模型来研究明显不同的饮酒行为的神经生理基础。在C57BL/6J小鼠（一种通常用于研究高酒精饮酒行为的近亲繁殖小鼠品系）中，我发现了一个稳定的低酒精饮酒群体。这个小鼠模型为我提供了一个独特的机会，可以在没有可变基因背景相互作用的挑战下，在基因相同的小鼠系中研究低酒精和高酒精饮酒行为背后的神经生理机制。众所周知，酒精使用障碍进展的一个标志是腹侧被盖区（VTA）多巴胺（DA）神经元的功能障碍，该区域对编码药物刺激的显著性至关重要。VTA向两个与药物奖励和动机高度相关的神经基质——伏隔核（NAc）和内侧前额叶皮层（mPFC）——发送功能多样的DA投射。在我的初步研究中，我证明了低C57BL/6J饮酒者的所有VTA DA神经元的体内放电活性和爆发活性高于高饮酒和EtOH naïve小鼠。此外，光遗传学模拟观察到，在先前高饮酒TH-Cre小鼠中，VTA DA活性的增加减少了饮酒行为。由于越来越多的证据表明VTA DA神经元的功能多样性基于它们的目标神经投射位点，我假设，基于我的初步发现，在基因相同的小鼠中，个体饮酒差异是由酒精消耗时VTA DA神经元的投射特异性（NAc与mPFC）神经元改变引起的。我的项目将采用系统的方法来研究VTA - DA神经元在C57BL/6J小鼠产生不同饮酒行为中的神经回路功能作用。为了表征低酒精和高酒精小鼠之间投射特异性神经元的改变，我将在体外电生理研究中使用逆行荧光珠来区分VTA DA神经元（目的1）。然后，我将使用创新的电路特异性光遗传学技术来模拟在VTA神经元中观察到的已确定的神经生理改变，以驱动特定的饮酒行为（目标2）。该项目将确定VTA - DA神经元的神经适应性，激发个体饮酒行为。此外，这项提出的最先进的神经回路解剖将为识别更有效的酒精使用障碍治疗靶点提供新的见解。