Cheryl F. Harding - US grants

This is an application to provide the applicant released time from a heavy load of administrative and teaching duties so that she may further her research career. An award will allow her to devote more time to her federally-sponsored research on hormonal specificity and the activation of behavior and to obtain the additional training in modern biochemical techniques she needs to carry out this research. It will also provide time for additional behavioral research and to explore new areas for future research. Her plans for professional growth during the award period include the establishment of an independent biochemistry lab, continued collaboration with some of the pioneering researchers in behavioral endocrinology and biochemistry, continued research training of students and the addition of postdoctoral training, active participation in federal grant review, and attendance at specialized symposia. The primary goal of her research is to gain a better understanding of the physiological mechanisms underlying hormonal control of behavior. The behavioral actions of androgens such as testosterone appear to be mediated by the interaction of their estrogenic and androgenic metabolites. The major focus of the present research is to determine how these two classes of hormones interact within the brain to elicit such behaviors. Levels and turnover of four monoaminergic neurotransmitters, as well as levels of the enzymes responsible for the synthesis and degradation of a fifth neurotransmitter, acetylcholine, will be monitored in specific brain nuclei known to mediate behavior dependent on the combined actions of estrogens and androgens. Examining the responses of these neurotransmitter systems to treatment with androgens, estrogens, or combined treatment with both hormones should help us to understand how these two classes of hormones interact in the brain to modulate behavior. Interactions of the androgen and estrogen receptor systems in the same nuclei will also be examined. A second line of research investigates whether conversion of androgens to 5 -reduced metabolites is obligatory for the neutral activation of male behavior patterns. A third line of research investigates the importance of estrogenic metabolites in the bloodstream, their biological activity and binding to serum proteins, and examines whether social interactions affect the production rate of estrogenic metabolites from androgens.

The primary goal of this research is to gain a better understanding of the physiological mechanisms underlying the hormonal control of behavior. The behavioral actions of androgens such as testosterone appear to be mediated by the interaction of their estrogenic and androgenic metabolites. Both androgenic and estrogenic metabolites are necessary to activate normal male behavior patterns in a variety of species. The major focus of the present research is to determine how these two classes of hormones interact within the brain to elicit such behaviors. Activity of enzymes responsible for the synthesis and degradation of acetylcholine and monoaminergic neurotransmitters, as well as levels and turnover of serotonin will be monitored in specific brain nuclei known to mediate behavior dependent on the combined actions of estrogenic and androgenic metabolites. Examining the responses of these neurotransmitter systems lo treatment with androgens alone, estrogens alone, or combined treatment with androgens + estrogens should help us to understand how these two classes of hormones interact in the brain to modulate behavior. These hormone treatments have already been shown to affect catecholamine levels and turnover in these nuclei. To further explore this effect, catecholaminergic cell bodies will be located, and the ability of the three hormone treatments to induce de novo synthesis of the rate-limiting enzyme in catecholamine synthesis determined. A second line of research investigates the mechanism underlying the ability of a 5 alpha-reduction blocker to greatly enhance the ability of aromatizable androgens to activate behavior. A third line of research investigates the source of estrogens found in the bloodstream and will determine if plasma estrogen levels measured by RIA are correct. This research on hormone interactions in the central nervous system, the specificity of hormone-sensitive neural mechanisms, and hormone metabolism should increase our understanding of the organization and functioning of endocrine control mechanisms. Hopefully, it will also contribute to the improve management of endocrine function.

[unreadable] DESCRIPTION (provided by applicant): Over the past few years, it has become clear that exposure to mold in water-damaged buildings can have severe adverse effects on human health. As a neuroscientist, I am particularly interested in the effects of mold exposure on neural and cognitive function. Yet despite mounting evidence that mold exposure causes increased anxiety, depression, chronic fatigue, pain, and cognitive problems, no animal research has been published examining how mold exposure causes these problems. The goal of this pilot project is to begin to establish a mouse model to determine how mold exposure affects brain function and behavior. Mold exposure activates an innate immune response. My basic hypothesis is that Innate immune activation caused by mold, like that caused by bacterial infection, initiates "sickness behavior." Many of the problems, including the learning deficits, shown by mold-exposed patients are concordant with the effects of sickness behavior. Mold-exposed patients have difficulties with the types of learning tasks mediated by the hippocampus. Three experiments will be run to determine the effects of different types of mold exposure on sickness behavior: the ability to do a number of hippocampal-dependent cognitive tasks, microglial activation, cytokine and growth factor immunoreactivity, apoptosis and neurogenesis in the hippocampus of C57BI/6 mice. The relationships between these variables will be determined. Determination of the underlying physiological processes will allow the development of more rational therapies to treat mold- induced cognitive problems and possibly those caused by other disease processes which activate the same immune, endocrine, and neural mechanisms. [unreadable] [unreadable] This pilot project serves as a major change in research focus for me. It is structured to provide the mentoring and training I need to master the techniques needed for this research, complete the experiments, publish them in a timely fashion, and secure SC1 or equivalent funding to continue this line of research. [unreadable] [unreadable] [unreadable]