Energy availability is the most important of all environmental factors that control reproduction. Decreased food intake, body fat content, and increased exercise have dramatic effects on fertility, ovulatory cycles and sex behavior in virtually every female mammal studied, including women. The general goal of the proposed research is to understand the sensory system that monitors cellular energy availability and inhibits reproduction. The specific goals are to better understand the nature of metabolic stimuli, the anatomical location of their detectors, and the neural pathways from the detectors to brain areas controlling reproductive cycles and behavior. To get a picture of the brain areas involved, the investigators will examine the effects of various metabolic treatments on neural activation (as measured by FOS-like immunoreactivity) throughout the brain. Areas of particular interest will be examined for their dose response to pharmacological inhibitors of glucose utilization. To examine the functional significance of these areas, nuclei or subnuclei that show significant changes in neural activation in response to metabolic inhibitors will be lesioned to see whether the absence of these areas attenuate or prevent the effects of metabolic inhibitors on estrous cyclicity (lordosis and the vaginal discharge). Standard methods of tract tracing will be used to determine the neural pathways from the caudal brain stem to the hypothalamic neurons suspected to be involved in pulsatile GnRH secretion in Syrian hamsters. Another set of experiments will examine the nature of metabolic signals by comparing the ability of different metabolic substrates infused intracerebroventricularly to overcome 2-DG-induced anestrus. The above experiments involve techniques that are published and up-and-running in the PI's laboratory. The last experiments in this proposal will take the first stems toward examining the actual neuroendocrine effects of specific metabolic pulsatile LH secretion and/or neural activation in GnRH neurons. Understanding metabolic effects on behavior has broad clinical significance. For example, infertility is consistently associated with excessive body weight loss in women. An understanding of all of the above phenomena will be facilitated by research focused on the links among body weight, nutrition, exercise and fertility. However, the interaction of metabolic fuels with the nervous system has implications that reach far beyond the link between body weight and fertility. Although we know almost nothing of the stimuli and detectors for metabolic sense, it appears that this sensory system influences virtually every category of behavior including sex, eating, aggression, maternal behavior and learning and the physiological processes that insure caloric homeostasis. In addition, metabolic effects on the nervous system might underlie behavioral and mood disorders such as Alzheimer, anxiety and depression. The proposed experiments will be an important step toward understanding the basic biology that underlies these phenomena.
