Genomic and Non-Genomic Effects of Steroid Hormones on Social Behavior

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DESCRIPTION (provided by applicant): The regulation of social interactions is of fundamental importance to both basic scientists and to clinicians interested in the etiology of mental illness. Such studies can produce general principles that will facilitate insights into the etiology and pathophysiology of mental disorders. This endeavor is a major goal of the NIMH and of this research program. The activation of social behaviors involves not only an individual being in the presence of an appropriate stimulus but also being in the appropriate motivational state. The steroid hormone testosterone is a pro-hormone that can be metabolized via the enzyme aromatase to an estrogen such as estradiol. In the preoptic area, the conversion of testosterone to estradiol is critical for the activation of both sexual motivation and performance. Estradiol ca act in two modes, a slow mode that involves binding to intracellular receptors and the induction of gene expression and a fast mode that involves interactions with the cell membrane and the activation of second messenger systems. Our recent work has shown that the fast actions of estrogens produced by brain aromatase are important for the activation of appetitive sexual behavior (motivational aspects) while the slower genomic actions are important for the activation of copulatory performance. In addition to the preoptic area, aromatase is widely distributed in brain nuclei of the social behavior network. One goal of the current proposal (Aim I) is to investigate in both males and females the function of estrogen production in other nuclei of the social behavior network besides the preoptic area and the effects of estrogens on motivational aspects of other social behaviors besides sexual behavior. Another goal (Aim II) is to study the rapid non-genomic effects of steroid hormones on male sexual motivation and whether these effects are specific to sexual motivation or extend to other motivated responses. We will also assess the neuroanatomical target sites of these effects. Subsequent studies in Aim III will address some the cellular mechanisms of these effects. For example, there is evidence that estrogen receptors embedded in the cell membrane interact with receptors for the excitatory amino acid receptor glutamate. The anatomical pattern of such interactions and the role they play in motivation will be investigated. Finally in the last aim (IV) the rapid regulation of the enzyme, aromatase, that converts androgens to estrogens will be studied. We will assess how behavioral situations that modulate motivation might also modulate aromatase that in turn will affect how much estradiol is available in specific brain areas related to behavioral activation.