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Overview Development of the Character of the Lab Analysis of Thirst Mechanisms Significance of Program to Study of Pathological Processes Cardiovascular-Behavioral Interactions

Overview
The major research direction of this laboratory deals with the elucidation of neural and hormonal mechanisms involved in the maintenance of body fluid homeostasis. The regulation of body fluids involves both the determination of overall hydromineral balance and the control of appropriate distribution of salt and water in the body. The processes providing for the consistency of body fluid evoke behavioral, humoral, and cardiovascular effector systems. The unique character for which our laboratory has become widely recognized is its rigorous analysis of the role of behavior as a control of body fluid homeostasis and for studies which focus on the interaction of hormonal and cardiovascular systems with motivated (primary) behaviors. Specifically, we have a major emphasis on the role of ingestive behaviors (thirst, or the drinking of water; and sodium appetite, or the ingestion of sodium) which are important for the determination of overall fluid balance, and we study the interactions of environmental stimuli and the study of ongoing behaviors (e.g., ingestion; aggression, defense, etc.) with the cardiovascular system (i.e., heart rate, blood pressure, regional blood flow).

Our current research thrust evolved from an interest in the neuropsychology of thirst and salt appetite. The conceptual model which we adopted for the physiological analysis of this motivational process is analogous to that employed by sensory systems (e.g., vision, audition, etc.). That is, the types of questions that we ask are: (1) What are the effective stimuli which produce thirst and mobilize drinking behavior? In the case of classic sensory systems the stimuli are well known, but in our problem area much effort is directed at defining the nature of intrinsic (i.e., internal) stimuli that stimulate drinking. (2) What type of receptors is stimulated by such internal stimuli? (3) Where are these receptors located? (4) What are the biophysical and biochemical mechanisms involved in signaling pathways in these receptors? (5) What neuroanatomical pathways are activated when such receptors are stimulated?, and (6) What neurotransmitter systems are involved in mediating the communication between neurons within this motivational system? More specifically, we have conducted experiments designed to evaluate when the internal stimuli of increased osmolality and increased circulating levels of the hormone angiotensin II would serve as adequate stimuli for the induction of thirst. Our lab has played a major role in the definition of what critical regions within the central nervous system house receptors for these physiological stimuli. We have significant steps in elucidating the projections of nerve tracks issuing from putative receptor sites. Finally, our group has made strides in evaluating the role of various transmitter and modulator systems associated with thirst and salt appetite.

The stimuli responsible for the induction of thirst (i.e., increased angiotensin II levels and increased body fluid osmolality) act not only to increase water intake but also activate hormonal systems responsible for water retention as well. Thus, it became apparent to us that the model and techniques which we adopted for the analysis of salt and water intake could be applied to the analysis of these other complimentary physiological systems. Our decision to begin concurrent studies on the neural control of fluid retention as well as on the cardiovascular system is important for three reasons. First, basic alterations in either one of these intrinsic physiological systems can modify the behaviors of interest to us. For example, if fluid retention mechanisms are activated and the animal does not excrete as much water, drinking behavior is likely to be suppressed. The mechanism for the suppression or inhibition becomes an important consideration for our analyses. The second reason to study these parallel physiological processes is that under normal conditions it has been consistently demonstrated that fluid retention and distribution systems are mobilized when thirst is activated. Thus, it becomes possible to test whether an observation made in the process of conducting experiments on thirst is "physiologically valid" by examining the effects of the same manipulations on the complimentary physiological processes. The third reason for investigating the neural control of these complimentary physiological processes is that a working hypothesis can frequently be tested more easily (for example, under anesthesia) by studying either hormonal or cardiovascular endpoints because they are often easier to measure in a surgically manipulated animal in which behavior might be compromised. Therefore, results obtained from studying such physiological processes serve as a source of hypotheses that promote or encourage the development of better methods (e.g., surgical technique) that permit the development of more reliable techniques for collecting behavioral data. Thus, the study of complimentary physiological processes along with behavior increases our experimental and conceptual leverage and enhances our understanding of both behavior and physiology.

Over the past 25 years, our experiments investigating thirst, sodium appetite, the neuroendocrinology of water retention, and the central control of the cardiovascular system have stimulated interest among scientists of many disciplines because both behavioral and physiological processes are recognized to be significant in conditions where there is disordered regulation of body fluid balance or blood distribution, e.g., hypertension. From our basic studies attempting to localize and characterize receptors for dipsogenic (thirst) stimuli, we hypothesized that the same regions of the central nervous system may house receptors on which the identical stimuli act to promote body fluid expansion and to increase vasomotor tone. In collaboration with members of The University of Iowa Cardiovascular Center, we have been able to demonstrate that the major regions of the central nervous system, which we had implicated in the control of thirst, are necessary for the production and maintenance of many forms of experimental hypertension. Animals in which the receptive area for angiotensin is destroyed are "protected" against high blood pressure. This observation has provoked the development of a major research program to further elucidate the mechanisms and the basic neurobiology associated with this protection.

As a result of our developing interest in hypertension, we have directed a significant amount of our research interest over the past twelve to thirteen years to exploring the nature of interactions between the cardiovascular system and behavior in both normal and pathological states. In particular, we have been interested in exploring the neural and physiological mediators in models of hypertension in which high blood pressure is induced or exacerbated by exposing animals to physical or psychosocial stimuli which have been characterized as stressors. Second, we are pursuing experiments studying the effects of stressors administered early in life on the development of the autonomic controls of the circulatory system, adult behaviors (e.g., open field activity) and the level of adult blood pressure. Third, we are currently applying methodologies that will permit the characterization of several cardiovascular parameters in conjunction with ongoing behaviors. The ultimate aim of these latter experiments is to provide us a means to determine how the central nervous system functions to couple somatic (behavioral) and visceral (cardiovascular) responses and to determine whether repetitive activation of the neural substrates or the dissociation of the somatic and visceral responses can contribute to pathological conditions such as hypertension. Fourth, at the present time we are heavily involved in investigating brain mechanisms involved in states of orthostatic intolerance and shock. These last four experimental areas require an application of both refined behavioral and physiological techniques. These later research directions represent an emerging new discipline, experimental behavioral medicine, one in which we believe our laboratory is playing a significant and defining role.