The proposed research addresses the clinical goal of increasing our understanding of the etiology of mental health disorders that are more prevalent in women than men. The overall goal of the proposed studies is to identify the underlying etiology of reproductive dysfunction in the psychiatric disorders of anorexia and bulimia nervosa and functional hypothalamic amenorrhea (FHA). Little is known about the etiology of any of these disorders or why women appear to be so much more susceptible to them than men. It is clear, however, that patients with these diseases are exposed, at least to some extent, to a similar constellation of physiological stresses, including nutritional stress, exercise stress and psychosocial stress. To gain a better understanding of how these three forms of stress impact on hypothalamic function, and in particular the central hypothalamic control of the reproductive axis, we have developed nonhuman primate models for examining the physiological consequences of these three stresses using female and male rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) monkeys. A central goal of our studies is to understand the neural mechanisms by which these three stresses cause a dysfunction in the hypothalamic drive to the reproductive axis. To address this goal, specific experiments are designed to (1) identify the neural systems whose activities change in response to these stresses by measuring the transient expression of cFos and FRAs (Fos Related Antigens) in identified neuronal populations and by determining changes in gene expression in central neural systems using in situ hybridization techniques, (2) determine if the neural systems whose activities change in response to these three stresses play a causal role in the stress-induced hypothalamic dysfunction of the reproductive axis, (3) determine whether the neural mechanisms influencing the hypothalamic drive to the reproductive axis are similar or dissimilar in metabolic versus nonmetabolic stresses, (4) determine whether differences in steroid hormone milieu make females more susceptible than males to various stress-induced reproductive dysfunctions, and (5) determine whether there are differences during development in susceptibility to these stresses.
