I have spent 10 years studying the mechanisms by which estradiol (E2) increases hippocampal dependent learning and memory. Through this exploration I uncovered a novel mechanism whereby E2 increases the magnitude of long-term potentiation (LTP), a cellular substrate of memory acquisition, by enhancing current mediated by NR2B-containing-NMDARs. Moreover, I was able to demonstrate a correlative relationship between a morphological increase in dendritic spine density and LTP magnitude. with E2 This project was extended to an aging model in which I showed that female rats which were hormone deprived for 19 months were unresponsive to E2 therapy using NMDAR transmission, LTP magnitude and spine density as assays, indicating these morphological and functional changes are sensitive to the time spent in reproductive senescence. In 2009 I joined the laboratory of Dr. Robert Greene, a recognized leader in the field of dopamine mediated alterations in hippocampal circuit and functional output, to focus my attention on dopamine dependent alterations in hippocampal circuit function. This has set the stage for an in depth study of the relationship between E2 receptor and dopamine receptor activation. My research in the Greene laboratory is focused on whether dopamine release from noradrenergic, rather than dopaminergic fibers, is responsible for the observed dopaminergic tone in hippocampus and subsequent dopamine mediated increase in synaptic output. Recently, we published this work at the Journal of Neuroscience as a featured article adding to my list of articles in press. I have 7 manuscripts in press including 4 first author manuscripts at the Journal of Neuroscience, 1 of which is a featured article, 1 PNAS manuscript and 1 Psychoneuroendocrinology review. Moreover, the success of my E2 work is represented by receipt of a predoctoral NRSA from NIMH. While I have gained invaluable skills using electrophysiology, immunohistochemistry, confocal microscopy, and stereotactic surgery to address key questions, I have little experience using molecular and biochemical assays. As it is currently expected that investigators will use a broad based approach to address scientific hypotheses, it is critical that I extend my scientific techniques and breadth of knowledge. Drs. Greene and Huber have the combined expertise to direct a project focused on examining the dopamine dependence of the E2-mediated heightened synaptic response. Additional training will be acquired through participation in coursework related to career development and research integrity, delivery of biannual presentations in the weekly "Works in Progress" seminar series and the associated journal club, writing grants and writing manuscripts. Moreover, I will serve as mentor to postdoctoral fellows in the Greene lab and mentor to a summer undergraduate student in the SURF program. It is my intention that through this additional training I will meet my short-term career goals which are to expand my technical expertise, writing skills and mentoring abilities to pursue my long-term career goals of securing a tenure track assistant professor position. Environment: The UT Southwestern Medical Center campus is an environment that promotes translation of research from the bench to bedside by providing state-of-the-art core facilities and by promoting a highly dynamic collaborative atmosphere. The Department of Psychiatry, which houses both basic and clinical research, encourages trainees to integrate cellular physiology with molecular and biochemical approaches. As such, this department has an established track record for medical student, graduate student, and postdoctoral fellow training in translational research. Moreover, the Department of Psychiatry has 2 research cores, a behavioral core under the direction of Dr. Shari Birnbaum and a microscopy core which includes 2 epifluorescent scopes and a confocal microscope under the direction of Dr. Amelia Eisch. Additionally the department houses the Women's Mental Health Center tasked with providing rapid detection and treatment and to direct research centered on mechanisms of mental illness in women which is applicable to this proposal. Research: E2, through two independent mechanisms, can alter hippocampal synaptic response;a slower, nuclear driven, transcriptionally regulated process and a faster, less well characterized, effect. Recent evidence demonstrates that E2, within minutes of application to hippocampal slices, increase glutamate transmission. It is suggested this enhancement results from cooperative activation of the nuclear E2 receptor (ER) ERb, through non-classical, transcription independent mechanisms and the membrane bound Gs-coupled E2 receptor GPR30, which will is the focus of Aim 1 of this proposal. This work will be extended as the downstream mediators of the E2 induced heightened synaptic response are considered. In recent preliminary work I show that activation of the dopaminergic system is required for the E2-induced enhancement in glutamate transmission. Thus, in Aims 2 and 3 I will pursue whether E2 recruits the dopaminergic system through an increase in dopamine release from noradrenergic terminals or through an increase in post-synaptic D1R activation.
Memory loss, a characteristic of neuropsychiatric disorders such as depression, is reversed in women when circulating estrogen levels are elevated. Little is known concerning the mechanisms by which this hormone reverses cognitive deficits. In this project it is proposed that estrogen recruits the dopaminergic system to alter hippocampal circuitry and ultimately learning and memory.