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: 10548885
• 负责人: Armando Salinas
• 金额: $ 24.9万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-10 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548885
• 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; Educational process of instructing; Electrophysiology (science); Ethanol; Exposure to; Extramural Activities; Faculty; Functional disorder; Glutamates; Impaired cognition; Impairment; Impulsive Behavior; Institution; Interneuron function; Interneurons; Learning; Light; Literature; Macaca mulatta; Manuscripts; Mentors; Mentorship; Monkeys; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Neurons; Performance; Positioning Attribute; Process; Property; Psychological reinforcement; Regulation; Relapse; Research; Research Personnel; Reversal Learning; Rewards; Role; Running; Scientist; Self Administration; Source; Synaptic plasticity; System; Techniques; Testing; Training; Transgenic Mice; Universities; addiction; alcohol craving; alcohol effect; alcohol exposure; alcohol seeking behavior; alcohol sensitivity; behavioral phenotyping; career; chemical property; cholinergic; cholinergic neuron; design; designer receptors exclusively activated by designer drugs; experimental study; genetic manipulation; improved; in vivo; interest; preference; problem drinker; skills; vapor; varenicline

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.

项目摘要：纹状体与学习、奖励和成瘾有关，包括酗酒。 在纹状体中，胆碱能中间神经元（CIN）的消融会导致行为和认知缺陷，类似于 那些在酗酒者中观察到的象征性的结果，有证据表明慢性酒精中毒后 CIN 会减少。 与此一致的是，我发现猴子的纹状体胆碱能功能受到损害。 因此，该提案的总体假设是长期的乙醇消耗。 乙醇暴露会降低纹状体 CIN 数量或功能，并且这些乙醇诱导的胆碱能 与酗酒相关的行为和认知缺陷是由损伤造成的。 假设，我提出三个具体目标： 具体目标 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 和电生理学技术确定 CIN 亚型。 CIN 亚型对乙醇敏感性的表征将引起酒精和基底神经节的广泛兴趣 具体目标 2 – 我将确定慢性乙醇引起的纹状体 CIN 缺陷是否是由于 文献中一致认为，纹状体会导致 CI​​N 丧失、CIN 功能受损。 长期接触乙醇后，胆碱能回路功能低下，但这种功能障碍的根源并不是 因此，我将确定 CIN 是否丢失和/或 CIN 功能是否受到损害（通过电生理学） 这些结果将首次检验长期乙醇对人体的影响。 具体目标 3 – 然后我将确定是否对 CIN 活性进行体内化学遗传学操作。 长期饮酒后足以改善伴随慢性饮酒的行为和认知缺陷 乙醇暴露，包括乙醇消耗和操作性逆向学习任务的表现。 在我的整个职业生涯中，我一直对正常和异常行为背后的机制感兴趣。 我很幸运有导师教会我从事有意义的研究所需的技能。 在我职业生涯的每个阶段，我的技术能力和科学水平都得到了提高，并且随着我的继续 为了训练，我的导师 Kim Blackwell 和 David Lovinger 将挑战我作为一名科学家不断进步 并提出有影响力的问题，设计引人注目的实验来解决这些问题，并展示我的 此外，我们有一个计划来确保我在手稿和演示文稿中清楚有效地发现结果。 接受培训以进行令人兴奋的实验、成功运营实验室并指导学员。 阿德伦·哈里斯 (Adron Harris) 和玛丽莎·罗伯托 (Marisa Roberto) 这两位成功的研究人员已同意加入我的顾问委员会 确保我成功过渡为独立调查员 因此，我有信心 我的导师、校外咨询委员会、技术顾问和机构的指导 在 NIAAA 和乔治梅森大学的支持下，我将能够执行拟议的实验，获得 教职，并成为一名成功的独立神经科学家。