Cortical-noradrenaline signaling in alcohol behavioral engagement

酒精行为参与中的皮质-去甲肾上腺素信号传导

• 批准号: 10808515
• 负责人: Phillip A Starski
• 金额: $ 14.45万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10808515
• 关键词: Address; Advisory Committees; Alcohol abuse; Alcohol consumption; Alcohols; Anatomy; Animals; Anterior; Attention; Attenuated; Award; Awareness; Behavior; Behavior assessment; Behavioral; Behavioral Paradigm; Brain; Chronic; Clinical; Collaborations; Communities; Consumption; Data Set; Dedications; Disease; Electrophysiology (science); Ensure; Environment; Faculty; Foundations; Future; Genetic; Genetic Predisposition to Disease; Goals; Habits; Impairment; Implant; Impulsivity; Indiana; Individual; Individual Differences; Institution; Insula of Reil; Intake; Interoception; Journals; Learning; Link; Measures; Mediating; Mentors; Methods; Milk; Modeling; Molds; Motivation; Mus; Neurons; Neurosciences; Norepinephrine; Oral; Pathologic; Pattern; Performance; Phase; Phenotype; Play; Populations at Risk; Positioning Attribute; Preparation; Principal Component Analysis; Publishing; Reaction Time; Research; Research Personnel; Resources; Rewards; Risk; Rodent; Role; Signal Transduction; Silicon; Supervision; System; Techniques; Testing; Therapeutic; Training; Universities; Water; Work; alcohol behavior; alcohol exposure; alcohol research; alcohol reward; alcohol risk; alcohol seeking behavior; alcohol use disorder; awake; career; career development; cingulate cortex; density; design; drinking; endophenotype; experimental study; genetic manipulation; in vivo; interest; locus ceruleus structure; male; neural; neural circuit; neuroadaptation; neuromechanism; noradrenergic; novel therapeutic intervention; posters; preference; premature; reinforcer; response; success; sugar; symposium; therapeutic target; trait impulsivity; vigilance

Project Summary The primary training objective of the K99 phase of this award application is to mold the candidate into an expert in assessing behavioral engagement for reward using advanced in vivo electrophysiology methods. He will learn required analytical techniques for comprehensively measuring aspects of behavioral engagement and correlated brain activity patterns. The overarching hypothesis of this proposal is that Locus Coeruleus-cortical circuits regulate engagement when responding for alcohol, which is increased by protracted alcohol drinking. To address this hypothesis, this award will use Cambridge NeuroTech high-density silicon probes to record neural activity within the anterior cingulate cortex (ACC) and anterior insula (aINS), and also will use chemogenetic manipulation of noradrenaline signaling, during the 5-choice serial reaction time task (5-CSRTT) in mice responding for alcohol. During the K99 phase, the candidate will be trained in the use of high-density probes to generate large neural recording data sets to discover the relationship of ACC and aINS activity to behavioral engagement for sugar within the 5-CSRTT (a robust and widely used model). To obtain this training, the candidate will work with leading researchers at Indiana University with expertise in neural recording implementation and analyses. During the R00 phase, the candidate will use his recently published paradigm of behavioral engagement for alcohol in 5-CSRTT combined with K99 training to further support his hypothesis. Critical goals of this award are publishing results in high-impact journals, oral and poster presentations at conferences and attending relevant seminars to further the candidate’s career development and exposure within neuroscience/alcohol research community. In this proposal, Drs. Frederic Hopf, Christopher Lapish, Catharine Winstanley, Brian Mathur, and Nicholas Grahame will form a dedicated mentoring team for the candidate. Combined, these individuals hold expertise in relevant rodent behavior, in vivo electrophysiology in awake animals, alcohol research, noradrenaline signaling, and relevant cortical regions investigated in this proposal. The Indiana Alcohol Research Center, a collaboration between Indiana University and Indiana University-Purdue University-Indianapolis, provides a nationally recognized research environment with the resources necessary to complete the Aims within this proposal, as well as an exceptional mentoring environment. At the end of the K99 phase, the candidate will be seeking a faculty position as an independent investigator at an institution well-suited to for his R00 phase. The experiments in these studies will provide valuable groundwork for future R01 applications that will incorporate methods for projection-specific circuit inhibition and explore potential therapeutic avenues to attenuate maladaptive alcohol-engagement behaviors for future clinical benefit. Together, this award will provide a strong foundation for the candidate to build a successful career as an independent researcher within the alcohol field and contribute to the forward progress needed for combating problem alcohol use.

项目摘要 本奖项申请K99阶段的主要培训目标是将候选人塑造成 使用先进的体内电生理学方法评估行为参与度以获得奖励的专家。他 将学习所需的分析技术，全面衡量行为参与的各个方面， 相关的大脑活动模式这个提议的首要假设是蓝斑皮质 当对酒精做出反应时，神经回路会调节参与度，而长期饮酒会增加参与度。 为了解决这一假设，该奖项将使用剑桥NeuroTech高密度硅探针来记录 前扣带皮层（ACC）和前扣带皮层（aINS）内的神经活动，也将使用 5-选择系列反应时间任务（5-CSRTT）中去甲肾上腺素信号传导的化学遗传学操作 对酒精有反应的老鼠。在K99阶段，候选人将接受高密度 探针产生大型神经记录数据集，以发现ACC和aINS活性与 在5-CSRTT（一个强大的和广泛使用的模型）内的糖行为参与。为了获得这种训练， 候选人将与印第安纳州大学在神经记录方面具有专长的主要研究人员合作 实施和分析。在R 00阶段，候选人将使用他最近发表的范例， 5-CSRTT中的酒精行为参与与K99训练相结合，以进一步支持他的假设。 该奖项的关键目标是在高影响力期刊上发表成果，在 会议和参加相关研讨会，以促进候选人的职业发展和接触 在神经科学/酒精研究界。在这份提案中，弗雷德里克·霍普夫博士，克里斯托弗·拉皮什博士， Catharine Winstanley、Brian Mathur和Nicholas Grahame将组成一个专门的指导团队， 候选人结合起来，这些人拥有相关啮齿动物行为，体内电生理学， 清醒的动物，酒精研究，去甲肾上腺素信号，以及在此研究中研究的相关皮层区域。 提议印第安纳州酒精研究中心是印第安纳州大学和印第安纳州之间的合作项目 普渡大学印第安纳波利斯分校提供了一个国家认可的研究环境， 完成本提案中的目标所需的资源，以及特殊的指导 环境在K99阶段结束时，候选人将寻求独立的教师职位 一个适合他R 00阶段的机构的调查员。这些研究中的实验将提供 为将来的R 01应用提供了有价值的基础，这些应用将结合特定于投影的电路的方法 抑制和探索潜在的治疗途径，以减轻适应不良的酒精参与行为 未来的临床效益。总之，这个奖项将为候选人建立一个强大的基础， 作为酒精领域的独立研究人员，我的职业生涯取得了成功，并为向前发展做出了贡献。 这是解决酗酒问题所必需的。