Jill E. Schneider - US grants

Our abilities to see, hear, smell and touch are all mediated by sensory systems in which the stimuli and the receptors are well understood. For example, vision results from light entering the eye and impinging on receptors located in the retina. While it is known that environmental events, such as changes in temperature and food availability, have major effects upon the behavior of mammals, little is known about the stimuli and receptors that mediate these influences on the brain. Dr. Schneider will investigate this important problem. She has found that reproductive, maternal, and temperature regulatory behaviors are controlled by the availability of metabolic energy, or the chemical fuels that derive from sugars and fats. This supply of metabolic fuels is influenced by diet, body fat stores, and the energy required to keep warm, find food and carry out other processes necessary for life. Dr. Schneider will now identify the nature and location of sensory detectors of metabolic energy availability. She will infuse drugs that inhibit specific metabolic pathways to examine effects on neuroendocrine systems controlling each of the three specific regulatory behaviors mentioned above. Her results will provide a broad and integrated view of the relation between metabolic, neural and hormonal signals generated by changes in energy supply and demand. Moreover, these results will have important clinical relevance since they should shed light on phenomena such as infertility in women who limit their energy intake. Infertility is common in professional athletes, ballet dancers and women with eating disorders such as anorexia nervous. It also occurs in normal women who diet and/or participate in recreational sports. Dr. Schneider's work will help elucidate how these changes in fuel availability influence the nervous system to regulate behavioral and physiological responses.

DESCRIPTION (Adapted from applicant's abstract): 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.

This conference of the recently formed Society for Behavioral Neuroendocrinology is one of an annual series. The relatively small meeting is strongly interdisciplinary, with approaches ranging from molecular biology in the lab to behavior in natural environments. This scope gives an integrated view of the field of behavioral neuroendocrinology, and the hormonal mechanisms that regulate behavior. The small size promotes interactions between attendees, fostering active discussions about research outside the formal talks. About a third of the 600 SBN members are student members, so there is substantial impact of this annual conference on advancing the field by promoting interactions among young investigators. This year is the first meeting in the West, to help balance regional representation, and it includes a new initiative to publish student abstracts and to get the best student posters into manuscripts for publication in a major journal. A special panel on 'Balancing Career and Family: Not for Women Only' also will discuss issues important to young investigators.
The promotion of students to attend this conference will have a substantial impact on their careers by exposing them to the latest discoveries and approaches, and making more senior investigators aware of their individual research.

This research will uncover the neural (brain) mechanisms that govern behaviors related to food appetite and the motivation to engage in reproductive activities. A wide variety of chemical substances, such as the fat cell hormone leptin, have been identified as potential satiety signals, despite research from this laboratory showing that leptin is a potent stimulators of reproductive activity. When animals have an unforced choice between foraging for food and mating partners, leptin treatment increases interest in mating partners at doses that fail to decrease food intake. These results are interpreted in light of evolution by natural selection, that is, the idea that traits are maintained in populations over generations if they increase reproductive success. Energy consumption (food intake) is critical for the energetically expensive processes related to reproduction, and so brain processes that increase food intake are directly linked to reproductive success. Similarly, the brain structures that inhibit hunger and ingestive behavior might be most adaptive when these structures cause individuals to stop foraging, hoarding and eating in order to find and court potential mates. This project will be used to study blood fluctuations after food deprivation and re-feeding in leptin, insulin and ghrelin while also examing brain levels of neuropeptide Y, corticotropin releasing hormone, kisspeptin, and gonadotropin inhibiting hormone, the typical chemical messengers that are candidates for mediating the effects of food deprivation on reproduction and eating. It is expected that those peptides that fail to change prior to the changes in behavior will be eliminated as candidates, and this, in turn, will allow focused research on those peptides that change in time to account for changes in behavior. These results will facilitate our understanding of worldwide obesity and the training of both graduate and undergraduate students in our behavioral neuroscience programs.