Within the cardiovascular system the baroreflexes of the carotid sinus and aortic arch are crucial to blood pressure stabilization. The experiments proposed will determine whether a mechanism of neural plasticity, known as classical conditioning, which is involved in drug tolerance, digestive secretion, and setting the gain of critical visual tracking reflexes, is also involved in calibration of the baroreflexes. Classical conditioning itself is simply a repeating sequence of a weak (conditioned) stimulus followed by a stronger (unconditioned) stimulus. It has been known since Pavlov that with this procedure eventually the weaker stimulus produces reflex effects resembling those of the stronger stimulus. Recent mathematical models describe how classical conditioning can significantly augment the effectiveness of innate regulatory reflexes and in various ways tailor them to the needs of an individual's anatomy, constitution and life experience. The human cardiac baroreflex can be classically conditioned, and preliminary studies in rats show that the vascular sympathoinhibitory effect of the baroreflex can also be readily conditioned. The proposed experiments all use the same unique long-term behavioral-physiological rat model to (1) determine if a widely observed, but poorly understood phenomenon, shock conditioned vagal bradycardia, is in reality a case of implicit baroreflex conditioning; (2) verify and extend preliminary evidence that the vascular baroreflex can be classical conditioned; (3) examine and analyze a distinctive 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 mathematical models of regulation using actual carotid sinus cul de sac pressures as the conditioning stimuli. The proposed project has the following implications for improving health and treating disease: (a) In a conventional social setting the cardiovascular responses to stress, such as blood pressure elevation, are frequently inappropriate to the physiological needs of impending behavior. With time, repetition of these unnecessary """"""""emergency"""""""" responses may contribute to increased risk of an acute cardiovascular event. Conditioned bradycardia that develops with repeated exposures to stress may itself be, or be a useful model for, an important homeostatic function; understanding its basis may help explain why for some people compensatory cardiovascular responses to stress fail to develop in a normal manner, and suggest behavioral or pharmacological interventions to facilitate more appropriate responses. (b) Basic studies extending the experimental model and control theory concepts of traditional baroreflex physiology to include classical conditioning, will show how conditioning plays an important role in natural cardiovascular adjustments. By thus highlighting a novel and unappreciated mechanism of cardiovascular regulation, this work could open unexplored, potentially fruitful, avenues for research on the control of blood pressure.
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