The long-term objective of this work is to learn about the role of insulin signaling in the brain as it relates to neuroendocrine function. Insulin receptors are particularly abundant in the hypothalamus, a brain region involved in neuroendocrine function. Our past work identified that insulin signaling in the brain is necessary for normal neuroendocrine function. Moreover, infusion of small amounts of insulin directly into the hypothalamus of diabetic female rats was sufficient to reverse all diabetes-induced neuroendocrine abnormalities. In addition, our recent collaborative work describes a technique for generating selective insulin resistance in specific brain sites (IR-KD). This technique will be used to explore the role of insulin signaling in specific brain sites as it relates to neuroendocrine function. The specific aims of this proposal are: Aim 1: Use IR-KD to test the hypothesis that a reduction in brain insulin signaling in the neural structures surrounding the third ventricle leads to a loss of neuroendocrine function as well as a loss in the ability of insulin to rescue neuroendocrine function in diabetes. Aim 2: Explore the role of brain insulin signaling in the preoptic area and ventromedial hypothalamus in the control of luteinizing hormone surges and hormone-facilitated reproductive behavior, respectively. Aim 3: By utilizing stereotaxic implantation of cannulae to administer antagonists of PI3 kinase and/or MAP kinase directly to the third ventricle or specific brain sites (if warranted) determine whether these are critical enzyme(s) that link hypothalamic insulin action to the maintenance of neuroendocrine function. Aim 4: Will attempt to answer the question: Does insulin signaling in the brain enable neuroendocrine function by maintaining estrogen receptor levels in key brain sites? If warranted, we will determine the ER subtype specificity and neuroanatomical specificity within the hypothalamus of putative insulin effects. The utility of our model is that it enables us to study the consequences of brain site selective insulin resistance. Hypothalamic insulin resistance may prove to be a major factor in diseases such as polycystic ovary syndrome and diabetes.