The research proposed in this competitive renewal application would examine the role of the basal forebrain cortical cholinergic system in behavioral and cardiovascular features of fear and anxiety. The research is guided by two hypotheses: a) that rostral neurobehavioral mechanisms underlying fear and anxiety can modulate autonomic control, and b) that autonomically mediated visceral reactions can modulate the cortical processing of anxiety-related contexts via central ascending pathways. The latter includes the basal forebrain cortical cholinergic projection, which has been implicated in cardiovascular reactivity associated with fear and anxiety. The proposed work will further develop and test a neurobiological model of central systems underlying fear and anxiety. Specific emphasis is on the basal forebrain cholinergic system and its role in integrating behavioral and cardiovascular reactions. The work will identify relevant target sites of the basal forebrain cholinergic system in rats, by central infusions of a cholinergic-specific immunotoxin (192IgG-saporin), as well as cholinergic and adrenergic drugs and benzodiazepine receptor agonists, antagonists, and inverse agonists. Other proposed studies will clarify the behavioral conditions in which the basal forebrain cholinergic system is operative, and will test hypotheses concerning the ascending components of the model. These include an examination of the role of visceral afference in modulating behavioral and autonomic reactivity in anxiogenic contexts, by means of subdiaphragmatic vagotomy and other approaches. The proposed studies bear on the fundamental nature of anxiety and the underlying neural mechanisms that link behavioral processes and autonomic functions. These are important issues given the prevalence of anxiety disorders, and the fact that anxiolytic benzodiazepine receptor agonists are the most widely prescribed psychopharmacological agents worldwide. Because anxiety disorders are often associated with abnormal autonomic regulation, they represent a clear risk factor for cardiovascular disease and sudden cardiac death.
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