: These multi-disciplinary studies target the long-sought physiological link between blood pressure variability and blood pressure regulation. The proposed link involves neural plasticity and explains why blood pressure stability is improved by regular exercise, and is impaired by inactivity, bed rest or exposure to micro-gravity. Classical conditioning, the most studied neural plasticity, is involved in drug tolerance, digestion, and quantitative adjustment of critical visual tracking reflexes. Conditioning occurs when a weak or conditioned stimulus (CS) is repeatedly followed by a stronger unconditioned stimulus (US); eventually the CS begins to produce the same reflex effects as the US. The baro-receptor reflexes of the carotid sinus and aortic arch are crucial to blood pressure stabilization. The applicants have shown (1) that the depressor effects of the aortic baroreflex can be classically conditioned, and (2) formulated mathematical models that predict that the conditioning can adjust the reflex, and improve its effectiveness. The proposed studies extend these results, to a special 'homotopic' form of conditioning, which is hypothesized to be a mechanism for continuous recalibration of the baroreflex sensitivity. In ordinary conditioning, the CS and US are in entirely different sensory modes: for example, in Pavlov's original experiments, the CS was a bell, and the US, acid irritation of the mouth. In contrast, for homotopic conditioning, CS and US are both applied to the same sensory mode: for example, in learning to avoid being burned by a hot object: both the CS (warmth) and US (pain) sensations are thermal stimuli on the same fingertip. For conventional baroreflex conditioning, a sound repeatedly (CS) preceded stimulation of the aortic nerve (US), and eventually, the sound by itself, caused BP to decrease. In the homotopic baroreflex conditioning Hypothesis, the initial phase of a BP rise activates low threshold receptors (CS) and the subsequent peak of the rise activates high pressure receptors (US); these events occur in the course of normal BP variability patterns, which fit well to the temporal constraints of classical conditioning. The counterbalanced within subject studies, are to be done in a special CNS intact rat preparation, and the conditioning procedures will use differential activation of A or A+C aortic nerve fibers; or differential carotid sinus dilatation, as the CS and US. Scientifically, these basic experiments will extend the empirical mechanisms and theoretical concepts of traditional baroreflex physiology to include classical conditioning, and will determine whether there could be a fundamental and implicit role for conditioning in normal blood pressure regulation. Clinically, they will help explain how the action of blood pressure regulatory reflexes becomes tailored to the needs of an individual's anatomy, constitution and life experience; understanding that, will open new avenues for the treatment of hypertension, vascular disease, and stroke.
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