Regulation of cortical ACh and Cognition

描述（由申请人提供）：这是一个K02奖的竞争性续期申请。 在前一个奖项期间，候选人的研究集中在皮层胆碱能输入的调节和功能。结果证实了假设的注意功能的皮质胆碱能输入的调解，该系统的调节基底前脑传入，包括起源于丘脑核和前额叶皮层的预测。此外，假说的贡献异常调节皮质胆碱能输入的主要神经精神疾病的认知症状的发展和测试。这项研究利用了广泛的行为神经科学方法，包括设计用于评估注意力不同方面的操作程序，以及测量任务执行动物的乙酰胆碱（ACh）流出和神经元活动。除了继续在这些领域的研究，三个新的研究途径提出了进一步发展，在下一个奖项期间。这些活动将集中在（1）验证生物传感器方法，用于快速测量胆碱浓度，作为高时间分辨率ACh释放的测量方法，并将此方法纳入我们的主要研究计划，（2）调查早期生活中皮质胆碱能输入营养因子支持中断，短暂性脑缺血发作，和老化对皮质胆碱能输入的调节和功能，以及（3）在一个神经心理学和精神药理学研究计划中使用的任务的发展，该研究计划旨在测试关于胆碱能系统在介导人类竞争性认知需求之间的注意力分配能力障碍中的作用的假设。KO2的更新将允许该候选人将至少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.