Alzheimer's disease represents the classic example of basal forebrain dysfunction. Patients with this disorder have impairments in learning, memory and attention. Recent work with animals has confirmed the importance of the basal forebrain, in particular the cholinergic basal forebrain neurons, in attention. Parkinson's disease results from the degeneration of dopaminergic neurons in the substantia nigra. Similar impairments in attentional processes are observed in patients with Parkinson's disease. Because dopaminergic neurons in the substantia nigra project to basal forebrain neurons, the attentional impairments in Parkinson's disease may be related to dysfunction of the basal forebrain. Thus, the basal forebrain may be the common substrate for the attentional impairments in Alzheimer's and Parkinson's diseases. Dysfunction of basal forebrain function may result from degeneration of basal forebrain dopaminergic afferents in Parkinson's disease, whereas basal forebrain neurons themselves degenerate in Alzheimer's disease. The experiments in this proposal examine the mechanisms by which the dopaminergic system modulates basal forebrain function. The general hypothesis is that dopaminergic afferents from the substantia nigra excite cholinergic basal forebrain neurons. These cholinergic neurons project to the neocortex, and through its connections with cholinergic basal forebrain neurons, the substantia nigra can influence cortical activity and attention. The mechanisms by which dopaminergic nigral neurons influence the activity of cholinergic and noncholinergic basal forebrain neurons will be elucidated using in vivo intracellular and extracellular recordings. Neurophysiological experiments will also examine the importance of this dopaminergic nigral-basal forebrain pathway in regulating cortical activity. Finally, the behavioral relevance of dopaminergic projections to the basal forebrain will be investigated in a 2-choice reaction time task. Performance measures in this task, such as reaction time and discriminability, are sensitive to changes in attention. The combination of neurophysiological, neuroanatomical, behavioral and pharmacological approaches provides a powerful method to examine the dopaminergic modulation of basal forebrain function.
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