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.
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