Regulation of cortical ACh and Cognition

描述(申请人提供)：这是一份K02奖项的竞争性续签申请。在之前的获奖期间，候选人的研究重点是皮质胆碱能输入的调节和功能。结果证实了皮层胆碱能传入对注意功能的调节、基底前脑传入对注意功能的调节的假说，包括伏隔核和前额叶皮质的投射。此外，关于调节异常的皮质胆碱能输入对主要神经精神障碍的认知症状的贡献的假说被开发和测试。这项研究使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可操作性程序，以及测量任务执行动物的乙酰胆碱(ACh)外排和神经元活动。除了在这些领域的持续研究外，还提出了三个新的研究途径，以便在下一个获奖期内进一步发展。这些活动将集中在(1)验证生物传感器方法作为高时间分辨率的ACh释放的快速测量方法，并将该方法整合到我们的主要研究计划中，(2)调查早期营养因子中断对皮质胆碱能输入的支持、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的影响之间的交互作用，以及(3)在神经心理学和精神药理学研究计划中使用的任务的开发，该研究计划旨在测试有关胆碱能系统在调节人类相互竞争的认知需求之间的注意力分配能力方面的损害的假设。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的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.