The mammalian brain is highly responsive to estrogen; neuroendocrine, reproductive, and autonomic function and behavior are powerfully controlled by this hormone. Specific neurons in the brain of both the male and female contain estrogen receptors (Ers) that, when bound to estrogen, interact with the genome to alter gene transcription. Estrogen receptive neurons in a highly sexually dimorphic part of the brain, the preoptic area, play a pivotal role in estrogen-regulates function and behavior. However, very little is known about these critical transducers of the endocrine environment. Specifically, mush has yet to be learned about the types of neurons that contain Ers and their synaptic inputs. Thus, with the use of light-level double-label immunocytochemistry, the neurochemical systems that contain Ers will be compared in the male and female rat brain, with the aim being to identify dimorphisms that could account for sex-related differences in estrogen-dependent function. Also, since many different neuroactive compounds have profound effects on estrogen-dependent function, the possibility exists that afferent input of these neurochemical systems to ER-positive neurons could be of great functional significance. Thus, the neurochemical systems that provide afferent input to ER-positive cells will be determined by ultrastructural investigation of tissue double-immunostained for Ers and neuroactive compounds. Using the same ultrastructural double- immunostaining technique, potential synaptic input to ER-positive neurons by axons arising in the suprachiasmatic nucleus will be studied, potentially identifying an important pathway through which circadian control of estrogen-dependent function could be imparted. Finally, it is now becoming clear that marked synaptic plasticity may occur in the brain under natural conditions, as well as in response to injury. Over the course of the estrous cycle it is known that there is marked synaptic plasticity in the hypothalamic arcuate nucleus. The possibility that comparable estrous cycle-related synaptic plasticity occurs in the preoptic area, potentially with ER-positive neurons as critical nodal sites for this plasticity, will also be studied with immunocytochemistry at the ultrastructural level. These studies could potentially set the stage for many future investigations of the mechanisms underlying natural synaptic plasticity. Thus, collectively, the experiments proposed in this application will increase our understanding of the preoptic area, a highly complex region known to control neuroendocrine, reproductive, autonomic, and behavioral functions. In light of the fact that a large segment of the US female population is exposed to estrogens for contraceptive purposes, postmenopausal replacement therapy, and for other medical reasons, these studies are significant because they will increase our understanding of the neural circuitry and mechanisms through which estrogen can effect brain function.
