The goal of this research is to determine the cognitive functions of cortical acetylcholine (ACh). Cortical ACh is hypothesized to mediate attentional processes, specifically sustained attention. The proposed experiments will assess the attentional functions of cortical ACh by measuring cortical ACh release and single unit activity in rats while they perform a task designed and validated for the measurement of sustained attention. Our preliminary experiments demonstrated that increased demands on sustained attention, caused by the presentation of distractors and indicated by specific impairments in performance, are associated with increases in ACh release in the medial prefrontal cortex. Additionally, attention-associated increases in neuronal activity were observed and blocked by the removal of cholinergic inputs to the recording area (produced by an infusion of the cholinotoxin 192 IgG-saporin into the recording field). The proposed research will determine the role of cortical ACh in sustained attention by : 1) developing a series of distractors which serve to systematically vary the demands on attention; 2) demonstrating that the attentional performance under taxing conditions depends critically on the integrity of the cortical cholinergic afferent system; 3) demonstrating that increased demands on attention are associated with increases in medial prefrontal ACh release and predictable shifts in single unit activity; 4) demonstrating that the attention-associated increases in neuronal activity are blocked by loss of cholinergic inputs to the recording area; and 5) demonstrating that infusions of a benzodiazepine receptor agonist and an inverse agonist block and augment, respectively, the attentional performance-associated increases in cortical ACh efflux and neuronal activity. Collectively, the presynaptic (i.e., ACh release) and postsynaptic (single unit activity) measures of attention-associated changes in cortical ACh will yield a specific hypothesis about the role of cortical ACh in attention. The determination of the specific cognitive functions of cortical ACh will lead to a better understanding of the disastrous cognitive consequences of deviations in the integrity of cortical cholinergic afferents.
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