NEURAL STEROIDOGENIC ENZYMES AND BRAIN FUNCTION

University Of California Los Angeles, Los Angeles CA

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Abstract

DESCRIPTION (applicant's abstract): Steroids have profound effects on the development and function of the brain. Traditionally, the brain is viewed as a target for action of sex steroids synthesized in the gonads, or to a lesser degree the adrenals, since each of these organs express all the enzymes that catalyze the conversion of cholesterol into the active sex steroids. In the last two decades, evidence has emerged indicating that some steroidogenic enzymes could be found in the central nervous system, suggesting that the brain itself could synthesize the active steroidal signaling molecules. Nevertheless, despite their identification in brain tissue, there is little evidence confirming a functional role for these enzymes in brain. We believe that steroids synthesized in brain may contribute to the organization and activation of specific behaviors in songbirds. Behavioral and neuroanatomical studies show that some steroid-dependent functions occur in songbirds in the absence of detectable steroid signaling from the periphery. These functions may be activated by a local, non-systemic steroidal signal. We have obtained support for this hypothesis in that we have found neural expression and/or activity of all 4 steroidogenic enzymes (CYP11A1, 3B-HSD, CYP17, and CYP19) required for the conversion of cholesterol to progestins, androgens, and estrogens in adult zebra finches, including expression of all enzymes in cerebellar Purkinje cells. The goal of these studies is to explore this hypothesis more fully by determining 1) if mRNA for each steroidogenic enzyme in brain is translated into functional protein, especially in Purkinje cells of adult zebra finches; 2) if neural expression of steroidogenic enzymes is associated with the organization of the neural song control circuit and with song learning in developing zebra finches and song sparrows, and 3) if neural expression of steroidogenic enzymes is associated with the activation of sex steroid-dependent behavioral functions when circulating steroids are basal in adult song sparrows. We believe these studies will contribute significantly to our understanding of the steroidogenic capability of the brain, and expand concepts of steroids as neural signaling molecules.