Determining optimal parameters for dynamic cholinergic modulation of associative learning

项目总结/摘要 乙酰胆碱是脑功能和认知的重要调节剂，胆碱能缺乏与此有关 包括谵妄在内的几种神经精神疾病胆碱能刺激似乎是一种 有前途的认知疗法，然而，胆碱酯酶抑制剂，广泛增强的作用， 乙酰胆碱具有有限的临床成功和显著的副作用。因此，迫切需要 更好地理解胆碱能回路，以开发能够精确地最大化其功能的疗法。到 为了满足这一需求，我们必须解决关于胆碱能功能是否会随着 受试者学习线索、反应和应答者之间的关联。结合了最先进的 电路解剖工具，我们现在可以选择性地将一个denatrium胆碱能投射靶向一个认知神经元。 回路：从基底前脑到基底外侧杏仁核的胆碱能投射。从事这项研究 一项提案将确定当受试者 不确定之间的联系线索和干扰，是假设的基础上的初步数据。 该项目旨在确定基底前脑胆碱能神经元的功能如何随着 联想学习，使用对胆碱能阻滞敏感的连续执行任务的框架 类似于谵妄评估中使用的那些。这一建议的一个成功结果将是 确定空间和时间靶向刺激如何显著有益于认知控制， 联想学习 该指导临床科学家研究职业发展奖（K 08）的其他目标是 申请人为1。发展回路解剖技术的专业知识，以研究特定回路的功能 改变行为需求; 2.发展靶向神经调节方面的专业知识， 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，成功地获得资金，包括独立赠款和指导 和领导能力来运行一个跨学科的研究计划。这一职业发展奖将延长 申请人之前接受过行为电生理学和临床重点关于谵妄和 心理状态，以便将生理和行为发现连接到特定的回路和网络中， 可能是潜在的治疗靶点该奖项将是实现以下总体目标的关键垫脚石： 发展成为一名独立的临床科学家，从床边到长凳研究急性 认知障碍是常见的，但在临床实践中知之甚少，特别是谵妄。

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.