Determining optimal parameters for dynamic cholinergic modulation of associative learning

确定联想学习动态胆碱能调节的最佳参数

• 批准号: 9505000
• 负责人: Eyal Yaacov Kimchi
• 金额: $ 19.71万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9505000
• 关键词: Accelerometer; Acetylcholine; Acute; Address; Adverse effects; Affect; Amygdaloid structure; Animals; Association Learning; Attention; Attention deficit hyperactivity disorder; Award; Behavior; Behavioral; Brain; Cholinesterase Inhibitors; Chronic; Clinical; Clinical Research; Cognition; Cognition Disorders; Cognitive; Cognitive Therapy; Cues; Data; Delirium; Discrimination; Disease; Dissection; Educational process of instructing; Electrophysiology (science); Evaluation; Functional disorder; Funding; Goals; Grant; Impairment; Interdisciplinary Study; K-Series Research Career Programs; Knowledge; Leadership; Learning; Memory; Mental disorders; Mentors; Monitor; Neurons; Noise; Outcome; Paper; Pattern; Pharmacology; Photometry; Physiological; Positioning Attribute; Psychological reinforcement; Research; Research Proposals; Reversal Learning; Running; Schizophrenia; Scientist; Signal Transduction; Stimulus; Task Performances; Techniques; Testing; Time; Training; Work; associated symptom; basal forebrain; basal forebrain cholinergic neurons; base; behavioral impairment; behavioral response; bench to bedside; calcium indicator; cholinergic; cholinergic neuron; classical conditioning; clinical practice; cognitive benefits; cognitive control; cognitive function; experience; fluorescence imaging; improved; in vivo; mental state; neuropsychiatric disorder; neuropsychiatric symptom; neuroregulation; novel therapeutics; optogenetics; programs; reinforcer; relating to nervous system; response; skills; success; targeted treatment; therapeutic target; therapy development; tool; two-photon

Project Summary / Abstract Acetylcholine is an important modulator of brain function and cognition, and cholinergic deficiency is implicated in several neuropsychiatric diseases, including delirium. Cholinergic stimulation would appear to be a promising cognitive therapy, however, cholinesterase inhibitors that broadly augment the action of acetylcholine have had limited clinical success and significant side effects. Therefore, there is a critical need to understand cholinergic circuits better to develop therapies that can precisely maximize their function. To address this need, we must address a knowledge gap regarding whether cholinergic function changes as subjects learn associations between cues, responses, and reinforcers. With a combination of cutting-edge circuit dissection tools, we can now selectively target one of the densest cholinergic projections to a cognitive circuit: the cholinergic projection from the basal forebrain to the basolateral amygdala. Work in this research proposal will identify if the activity and effects of this cholinergic projection are strongest when subjects are uncertain about the associations between cues and reinforcers, as is hypothesized based on preliminary data. The proposed project seeks to determine how the function of basal forebrain cholinergic neurons changes with associative learning, using the framework of a continuous performance task sensitive to cholinergic blockade and analogous to those used in delirium evaluations. A successful outcome of this proposal will be the determination of how spatially and temporally targeted stimulation can significantly benefit cognitive control and associative learning. The additional goals of this Mentored Clinical Scientist Research Career Development Award (K08) for the applicant are to 1. Develop expertise in circuit dissection techniques to investigate how specific circuit functions change with behavioral demands; 2. Develop expertise in targeted neuromodulation in order to maximize circuit function for cognitive benefit; 3. Develop professional skills, including sharing scientific knowledge through papers and presentations, successfully obtaining funding including independent grants, and mentoring and leadership skills to run an interdisciplinary research program. This career development award will extend the applicant's prior training in behavioral electrophysiology and clinical focus on delirium and alterations in mental status in order to connect physiologic and behavioral findings into specific circuits and networks that could be potential therapeutic targets. This award will be a crucial stepping-stone towards the overall goal of developing into an independent clinician-scientist, moving from bedside to bench to research the acute cognitive disorders that are common and yet poorly understood in clinical practice, in particular delirium.

项目摘要 /摘要 乙酰胆碱是脑功能和认知的重要调节剂，胆碱能缺乏症 在几种神经精神疾病中，包括ir妄。胆碱能刺激似乎是 然而，有希望的认知疗法是胆碱酯酶抑制剂，可以广泛地增强 乙酰胆碱的临床成功和显着副作用有限。因此，迫切需要 更好地理解胆碱能电路可以更好地开发可以精确最大化其功能的疗法。到 满足这一需求，我们必须解决有关胆碱能功能是否改变的知识差距 受试者学习提示，响应和增强剂之间的关联。与前沿的结合 电路解剖工具，我们现在可以选择性地将最密集的胆碱能预测靶向认知 电路：从基础前脑到基底外侧杏仁核的胆碱能投影。在这项研究中工作 提案将确定当受试者是该胆碱能投射的活动和影响是否最强 不确定提示与增强剂之间的关联，这是基于初步数据的假设。 拟议的项目旨在确定基础前脑胆碱能神经元的功能如何随着 相关学习，使用对胆碱能封锁敏感的连续性能任务的框架 并且类似于ir妄评估的那些。该提议的成功结果将是 确定如何在空间和时间靶向的刺激中显着受益于认知控制和 协会学习。 这个指导的临床科学家研究职业发展奖（K08）的其他目标 申请人为1。开发电路解剖技术方面的专业知识，以研究特定电路功能如何 随着行为需求的改变； 2。在靶向神经调节方面发展专业知识，以最大化 认知益处的电路功能； 3。发展专业技能，包括分享科学知识 通过论文和演讲，成功获得包括独立赠款在内的资金和指导 和领导技能，以运行跨学科研究计划。这个职业发展奖将延长 申请人先前在行为电生理学和临床上的培训对ir妄和改变的临床关注和改变 精神状态以将生理和行为发现连接到特定电路和网络 可能是潜在的治疗靶标。该奖项将是针对整体目标的至关重要的垫脚石 发展成独立的临床医生科学家，从床边到长凳，研究急性 在临床实践，尤其是del妄中，常见却又不了解的认知障碍。