application) The carotid and aortic barorefleces of the cardiovascular system are crucial to blood pressure stabilization. The proposed experiments will determine whether a mechanism of neural plasticity, known as classical conditioning, important to drug tolerance, digestion, and critical visual tracking reflexes, is also involved in activation and calibration of the baroreflexes. Classical conditioning is simply a repeating sequence of a weak (conditioned) stimulus followed by a stronger (unconditioned) stimulus. It has been known, since Pavlov, that eventually, the weaker stimulus produces reflex effects closely resembling those of the stronger stimulus. Newly formulated mathematical models predict that classical conditioning can significantly augment the effectiveness of innate and life experience. The applicants recently established that the vascular sympathoinhibitory and cardiac depressor effects of the baroreflex could be conditioned, and that the conditioned responses satisfy the assumptions of the models. The present experiments use a unique, economical, long-term rat model to 1) accurately determine the cardiac and detailed regional vascular resistance effects of the unconditioned baroreflex; 2) verify and extend the analysis of the mechanism and properties of the conditioned baroreflex; 3) study a special form of conditioning, especially relevant to natural calibration of the baroreflex, wherein the weaker and stronger conditioning stimuli are both applied to the baroreceptors; and 4) rigorously test the biological assumptions and predictive accuracy of the mathematical models of regulation. The project has the following implications for improving health and treating disease: a) In a social setting, cardiovascular responses to stress, such as blood pressure elevation, are often inappropriate to the physiological needs of impending behavior; with time, these vestigial emergency responses may increase the risk of an acute cardiovascular event. An anticipatory conditioned baroreflex, which develops with repeated exposures to stress, may ameliorate the stress effects; understanding it can help explain why for some people compensatory cardiovascular responses to stress fail to develop in a normal manner, and also suggest better behavioral or pharmacological interventions to facilitate more appropriate responses. B) Basic studies will extend the empirical mechanics and theoretical concepts of traditional baroreflex physiology to include classical conditioning, and determine whether there is a fundamental and implicit role of conditioning in normal blood pressure regulation.
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