THYROID-HORMONE AND ESTROGEN INTERACT TO REGULATE BEHAVIOR

Environmental perturbations that increase plasma thyroid hormone (T-3) concentrations also profoundly affect female reproductive behavior an d physiology, We explored whether these effects were mediated by inter actions between T-3 receptor (TR) and estrogen receptor (ER). This hyp othesis was of interest because the half-site of a consensus T-3 respo nse element DNA sequence is identical to an ER response element (ERE), and TRs bind to a consensus ERE. Molecular data presented in the acco mpanying paper [Zhu, Y.-S., Yen, P. M,, Chin, W, W, & Pfaff, D, W, (19 96) Proc, Natl. Acad, Sci. USA 93, 12587-12592] demonstrate that TRs a nd ERs are both present in rat hypothalamic nuclear extracts and that both can bind to the promoter the hypothalamic gene preproenkephalin a nd that interations between liganded TRs and ERs affect preproenkephal in transcription, In this paper, we show that molecular interactions b etween TRs and ERs are sufficient to mediate environmental effects on estrogen-controlled reproductive behavior, Ovariectomized (OVX) rats t reated with high doses of T-3 showed significantly lower levels of lor dosis behavior in response to estradiol benzoate (EB) compared with OV X females treated with EB alone, Conversely, thyroidectomized/OVX fema les treated with EB showed significantly greater levels of lordosis be havior compared with OVX females treated with EB, showing the effect o f endogenous T-3. Thyroid hormone interference with EB-induced behavio r could not be explained by a reduction in plasma E(2) concentrations or by a general reduction in responsiveness of EB-sensitive tissues. M oreover, numbers of hypothalamic EB-immunoreactive cells increased dra matically following T-3 treatment. These data suggest that T-3 may red uce EB-dependent sexual behavior through interactions between TR and E R in the nuclei of behaviorally relevant hypothalamic neurons, envisio ning for the first time a functional consequence of interactions betwe en two nuclear hormone receptors in brain. These results also open up the possibility of molecular interactions on DNA encoding environmenta l signals, a new field for the study of neuronal integration.