INTEGRATIVE RESPONSES TO AMINO ACID DEFICIENCY

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Adequate amino acid (AA) nutrition is essential for the health and well being of humans and animals alike. Because AAs have no storage pool, the development of an indispensable amino acid (IAA) deficiency can occur rapidly, particularly if a mild state of protein deficiency already exists. AA deficiencies have been shown to compromise growth and any bodily function that depends on protein synthesis, such as wound healing. In addition, IAA imbalance leads to a well-described anorectic response. Since AA supplements have become fashionable, especially among "health food" faddists, dieters, and athletes, IAA imbalance should be recognized as a potential health hazard. Moreover, many human diseases are complicated by IAA disproportion. Given the importance of AA nutrition, it is imperative to gain a better understanding of the basic mechanisms by which the responses to IAA deficiency are integrated by the brain. The long term goals of the work in this laboratory are to understand how IAA deficiency is recognized by the body and how this deficiency causes the depression of food intake. The IAA imbalanced diet (1MB) is an excellent nutritional model for these studies, as the biochemical and behavioral responses are robust, rapid and well described. The anterior piriform cortex (APC) of the brain appears to be the chemosensor for IAA deficiency; however, the APC cannot act alone to cause the anorectic response. Thus, the signals generated by the APC must be integrated with other brain areas, likely in the anterior forebrain, to change eating behavior. The goals of this proposal are to determine the circuitry and mechanisms by which the brain integrates the initial response to 1MB. We propose to achieve these goals through the following: Specific Aim 1, to identify the neural circuit within the forebrain that integrates the sensory signals from the APC and activates other brain areas to initiate the anorectic responses to TMB; Specific Aim 2, to determine the neurochemical mechanisms that mediate the response to 1MB; and Specific Aim 3, to determine the order of activation in this neural circuit and the signaling mechanisms.