Chronic ethanol effects on cholinergic interneurons of the striatum

慢性乙醇对纹状体胆碱能中间神经元的影响

• 批准号: 10187131
• 负责人: Armando Salinas
• 金额: $ 6.77万
• 依托单位: GEORGE MASON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187131
• 关键词: Ablation; Acute; Address; Advisory Committees; Affect; Agreement; Alcohol consumption; Alcoholism; Alcohols; Anatomy; Attention; Basal Ganglia; Behavior; Behavioral; Biochemical; Biological Assay; Brain; Brain region; Cell Count; Cellular Morphology; Cholinergic Agonists; Chronic; Cognitive; Cognitive deficits; Corpus striatum structure; Data; Desire for food; Disease; Dopamine; Electrophysiology (science); Ensure; Ethanol; Extramural Activities; Faculty; Functional disorder; Glutamates; Grant; Impaired cognition; Impairment; Impulsive Behavior; Interneuron function; Interneurons; Learning; Light; Literature; Macaca mulatta; Manuscripts; Mentors; Mentorship; Monkeys; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Neurons; Performance; Phase; Positioning Attribute; Process; Property; Psychological reinforcement; Regulation; Relapse; Research; Research Personnel; Reversal Learning; Rewards; Role; Running; Scientist; Self Administration; Source; Specific qualifier value; Synaptic plasticity; System; Techniques; Testing; Training; Transgenic Mice; Universities; Work; addiction; alcohol craving; alcohol effect; alcohol exposure; alcohol relapse; alcohol seeking behavior; alcohol sensitivity; base; behavioral phenotyping; career; chemical property; cholinergic; cholinergic neuron; design; designer receptors exclusively activated by designer drugs; experimental study; improved; in vivo; interest; preference; problem drinker; skills; vapor; varenicline

Chronic ethanol effects on cholinergic interneurons of the striatum Project Summary: The striatum is implicated in learning, reward and addiction, including alcoholism. Within the striatum, ablation of cholinergic interneurons (CINs) results in behavioral and cognitive deficits similar to those observed in alcoholics. Interestingly, there is evidence indicating a decrease in CINs following chronic ethanol exposure. In agreement, I have found that striatal cholinergic function is impaired in monkeys following long-term ethanol consumption. Therefore, the overarching hypothesis of this proposal is that chronic ethanol exposure decreases striatal CIN numbers or function and that these ethanol-induced cholinergic impairments underlie the behavioral and cognitive deficits associated with alcoholism. To test this hypothesis, I propose three specific aims: Specific Aim 1 – I will determine the effect of acute ethanol on striatal CIN subtypes using transgenic mice, immunohistochemical, RNAscope, and electrophysiological techniques. The characterization of CIN subtype sensitivity to ethanol will be of broad interest to alcohol and basal ganglia researchers alike. Specific Aim 2 – I will determine if chronic ethanol-induced deficits in striatal CINs are due to a loss of CINs, an impairment of CIN function, or both. There is agreement in the literature that the striatal cholinergic circuit is hypo-functional following chronic ethanol exposure but the source of this dysfunction is not clear. Therefore, I will determine if CINs are lost and/or if CIN function is compromised (with electrophysiology) following chronic ethanol exposure. These results will be the first to examine the effects of chronic ethanol on striatal CIN function. Specific Aim 3 – I will then determine if in vivo chemogenetic manipulation of CIN activity after chronic ethanol are sufficient to ameliorate the behavioral and cognitive deficits that accompany chronic ethanol exposure including ethanol consumption and performance on an operant reversal learning task. Throughout my career, I have been interested in the mechanisms underlying normal and aberrant behaviors. I have been fortunate to have mentors that taught me the skills required to engage in meaningful research. At every stage of my career, I have advanced in my technical ability and scientific sophistication and as I continue to train, my mentors, Kim Blackwell and David Lovinger, will challenge me to constantly improve as a scientist and to ask impactful questions, to design compelling experiments to address those questions, and to present my findings clearly and effectively in manuscripts and presentations. Furthermore, we have a plan to ensure that I receive training to conduct exciting experiments, run a successful lab, and mentor trainees. In addition, Drs. Adron Harris and Marisa Roberto, two successful researchers, have agreed to serve on my advisory committee to ensure that I am successful in my transition to an independent investigator. Thus, I am confident that with the mentorship of my mentors, my extramural advisory committee, my technical consultants, and the institutional support of NIAAA and George Mason University, I will be able to execute the proposed experiments, attain a faculty position, and thrive as a successful independent neuroscientist. In the extension period of this grant, I will continue to work on the established specific aims and I will be able to conduct more work on some of the aims that were initially intended to done in the R00 phase. In particular, I will be able to conduct the preliminary chemogenetic experiments specified in aim 3. I will also continue to search for an independent faculty position.

慢性乙醇对纹状体的胆碱能中间神经元的影响 项目摘要：纹状体在学习，奖励和成瘾（包括酒精中毒）中暗示。之内 纹状体，胆碱能中间神经元（CIN）的消融导致行为和认知缺陷类似 那些在酗酒者中观察到的。有趣的是，有证据表明慢性后CINS的减少 乙醇暴露。同意，我发现猴子的纹状体胆碱能功能受损 长期乙醇消耗。因此，该提议的总体假设是慢性 乙醇暴露会减少纹状体CIN数或功能，并且这些乙醇诱导的胆碱能 障碍是行为和认知与酒精中毒相关的基础。测试这个 假设，我提出了三个特定目的：特定目标1 - 我将确定急性乙醇对纹状体的影响 使用转基因小鼠，免疫组织化学，rNascope和电生理技术的CIN亚型。 CIN亚型对乙醇的敏感性的表征将引起酒精和基本神经节的广泛关注 研究人员。具体目标2 - 我将确定脊柱质CINS慢性乙醇引起的缺陷是否应到期 损失CIN，CIN功能的损害或两者兼而有之。文献中有同意的纹状体 慢性乙醇暴露后，胆碱能回路是功能低下的，但这种功能障碍的来源不是 清除。因此，我将确定CINS是否丢失和/或CIN功能是否受到损害（具有电生理学） 慢性乙醇暴露。这些结果将是第一个检查慢性乙醇对 纹状体CIN功能。特定目标3 - 然后我将确定CIN活性的体内化学发生操作是否 慢性乙醇足以改善行为和认知定义可容纳慢性的行为和认知 乙醇暴露在于操作逆转学习任务中的乙醇消耗和性能。 在我的职业生涯中，我一直对正常和异常行为的基本机制感兴趣。 很幸运能有导师教我从事有意义的研究所需的技能。 我职业生涯的每个阶段，我都在技术能力和科学社会化方面发展，随着我的继续 训练我的导师金·布莱克威尔（Kim Blackwell）和大卫·洛夫（David Lovinger）将挑战我不断发展作为科学家 并提出有影响力的问题，设计引人注目的实验以解决这些问题，并提出我的 在手稿和演示中清晰有效地发现。此外，我们还计划确保我 接受培训以进行令人兴奋的实验，开展成功的实验室和心理学生。另外，博士。 两位成功的研究人员Adron Harris和Marisa Roberto已同意在我的咨询委员会任职 为了确保我成功地过渡到独立调查员。那我有信心与 我的导师，我的校外咨询委员会，我的技术顾问和机构的遗产 NIAAA和George Mason University的支持，我将能够执行拟议的实验，达到 教师的职位，并作为成功的独立神经科学家壮成长。 在这笔赠款的延长期间，我将继续致力于既定的特定目标，我将能够 对最初打算在R00阶段进行的一些目标进行更多工作。特别是，我会 能够进行AIM 3中指定的初步化学发生实验。我还将继续搜索 对于独立的教师职位。