DESCRIPTION (provided by applicant): Estrogens are a class of steroid hormones that can aid recovery from brain injury and reduce the impact of certain neurological disorders. Recently, the central nervous system of humans and other animals has been shown capable of generating its own local supply of estrogens, providing new opportunities for the targeted treatment of brain diseases. Historically, the clinical use of estrogens has produced mixed success, possibly because estrogenic drug treatments are designed to mimic long term actions of estrogens (days-weeks) whereas cognitive function may depend critically on the short-term actions of estrogens (seconds-minutes). Indeed, treating neurological disorders with systemic doses of estrogens is associated with adverse side effects and reduced patient compliance. The goal of this research program is to characterize the mechanisms for rapid estrogen production and action ('rapid estrogen signaling') within discrete brain regions, and to understand the consequences of these events for sensorimotor integration and behavior. Taking advantage of recent methodological advances, these studies will combine sensitive real-time measures of brain estrogen concentrations, acute recordings of identified neurons, and contemporary behavioral assessments to understand the functional significance of rapid estrogen signaling in brain circuits. This work will address a fundamental gap in our understanding of how estrogen production within the brain guides complex behavior, and will ultimately inform the development of highly-targeted estrogen therapies for cognitive and neurological disorders.

PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because discoveries about how rapid estrogen signaling can guide higher brain function will yield new information about the way estrogens can be optimized for the prevention and/or treatment of neurological disorders that have been linked to dysfunction in estrogen actions, such as Alzheimer's, Parkinson's, dementia and stroke. Thus, the long-term goal of this research is consistent with the NIH mission to translate basic biomedical research outcomes into viable treatment strategies that can benefit millions of patients suffering from neurological disorders.