Regulation of cortical ACh and Cognition

描述（由申请人提供）：这是K02奖的竞争性更新申请。在之前的奖励期间，候选人的研究重点是皮质胆碱能输入的调节和功能。结果证实了关于皮层胆碱能输入介导注意功能的假设，以及基底前脑传入（包括源自伏隔核和前额皮质的投射）对该系统的调节。此外，关于异常调节的皮质胆碱能输入对主要神经精神疾病的认知症状的贡献的假设得到了发展和检验。本研究利用了广泛的行为神经科学方法，包括为评估注意力的不同方面而设计的操作程序，以及测量任务执行动物的乙酰胆碱（ACh）外排和神经元活动。除了继续在这些领域进行研究外，还提出了三个新的研究途径，以便在下一个奖励期间进一步发展。这些活动将集中在(1)验证一种生物传感器方法，用于快速测量胆碱浓度，以高时间分辨率测量乙酰胆碱释放，并将该方法整合到我们的主要研究项目中；(2)研究早期营养因子支持皮质胆碱能输入的中断、短暂性脑缺血发作和衰老对皮质胆碱能输入的调节和功能之间的相互作用。(3)开发一项用于神经心理学和精神药理学研究项目的任务，该项目旨在测试有关胆碱能系统在调节人类在竞争性认知需求之间分配注意力的能力障碍中的作用的假设。KO2的更新将允许这位候选人将至少75%的时间用于注意力功能神经生物学的多学科研究。

DESCRIPTION (provided by applicant): This is a competitive renewal application for a K02 award. During the prior award period, the candidate's research focused on the regulation and function of cortical cholinergic inputs. Results substantiated hypotheses about the mediation of attentional functions by cortical cholinergic inputs, the regulation of this system by basal forebrain afferents, including projections originating in the nucleus accumbens and prefrontal cortex. Furthermore, hypotheses about the contribution of abnormally regulated cortical cholinergic inputs to the cognitive symptoms of major neuropsychiatric disorders were developed and tested. This research utilized a broad range of behavioral neuroscience methods, including operant procedures designed for the assessment of different aspects of attention, and the measurement of acetylcholine (ACh) efflux and neuronal activity in task-performing animals. In addition to continuing research in these areas, three new research avenues are proposed for further development during the next award period. These activities will focus on (1) the validation of a biosensor method for the rapid measurement of choline concentrations as a measure of ACh release with high temporal resolution, and the integration of this method into our main research program, (2) the investigation of interactions between the effects of early-life disruption of trophic factor support of cortical cholinergic inputs, transient ischemic attacks, and aging on the regulation and function of cortical cholinergic inputs, and (3) on the development of a task to be used in a neuropsychological and psychopharmacological research program designed to test hypotheses about the role of the cholinergic system in mediating impairments in the ability to divide attention between competing cognitive demands in humans. The renewal of the KO2 would allow this candidate to devote at least 75% of his time for multidisciplinary research on the neurobiology of attentional functions.