Attentional processes, such as stimulus selection and stimulus processing, represent critical stages of information processing. Attentional dysfunctions have been considered major components, and even causes, of the cognitive impairments of senile dementia and schizophrenia. Furthermore, normal aging is associated with impairments in attentional abilities. The goal of the proposed research is to determine the role of cortical cholinergic afferents (which originate in the basal forebrain) in sustained and divided attention. The proposed experiments will utilize novel, validated behavioral paradigms for the test of attentional abilities in rats. Results from our previous experiments have suggested that the GABAergic innervation of basal forebrain neurons represents a major anatomical substrate mediating the bidirectional effects of benzodiazepine receptor (BZR) agonists and inverse agonists, respectively, on behavioral measures of learning and memory, and on cortical acetylcholine (ACh) release (measured by in vivo microdialysis). The proposed experiments will test the hypothesis that the basal forebrain GABA-cholinergic link mediates the attentional effects of BZR ligands. Furthermore, it will be determined whether cortical cholinergic deafferentation (achieved by infusions of the immunotoxin 192 IgG-saponin into cortical areas) result in impairments in attentional abilities. A third series of experiments will test the hypotheses that age-related impairments in attentional abilities are due to functional impairments in cortical cholinergic afferents and, thus, can be attenuated by infusions of BZR inverse agonists into the basal forebrain. Taken together, these experiments will determine the role of basal forebrain GABA-cholinergic interactions in general, and of cortical cholinergic projections originating from this area in particular, in attentional abilities. Furthermore, this research will examine the hypothesis that the effects of BZR ligands on vigilance and brain information processing capacity are mediated via cortical cholinergic afferent projections. Finally, hypotheses about a major neuronal substrate of the age-related impairments in attentional abilities will be tested, and a pharmacological approach for the treatment of these impairments will be evaluated. Generally, the findings from these experiments will advance our understanding about the neurobiological mechanisms underlying attentional functions.
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