Gonadal hormones can act to permanently organize the brain and behavior. Traditionally, these actions have been thought to occur during a sensitive period early in development. However, results of recent experiments conducted in Dr. Daniel's lab indicate that administration of a transient period of estradiol, the primary estrogen produced by the ovaries, to middle-age rats at the time of cessation of ovarian function results in lasting enhancements on measures of learning and memory that persist well beyond the period of exposure. Furthermore, these enhancements in performance are associated with permanent increases in levels of a type of receptor for estrogen, estrogen receptor alpha (ERá) in the hippocampus, a brain area important for learning and memory. This project will determine the temporal characteristics of the sensitive period following loss of ovarian function during which transient exposure to estradiol can exert lasting effects on cognition and the hippocampus. The project will also determine if permanent changes in levels of ERá mediate the long-term effects exerted on the hippocampus and associated behaviors as a result of a period of transient exposure to estradiol. Lastly, the project will investigate how estrogen receptors can affect cognition in the absence of ovarian estrogens. These experiments will use behavioral, molecular, and electrophysiological techniques to investigate how and under what conditions a transient period of estradiol exposure in adult mammals can permanently affect the brain and behavior. The activities involved in this project will provide increased research opportunities for undergraduate and graduate students from the state of Louisiana, a geographical region that has traditionally been underrepresented in the sciences.
Intellectual Merit: The goal of the current study was to understand how exposure to estrogens in middle-age following the loss of ovarian function can permanently enhance cognition and impact the hippocampus, a brain area important for memory. Results of work in Dr. Daniel’s lab indicate that administration of a transient period of estradiol, the primary estrogen produced by the ovaries, to middle-age rats at the time of ovariectomy results in lasting enhancements on measures of learning and memory and also leads to lasting increases in level of estrogen receptor α (ERα) in the hippocampus, effects that persist well beyond the period of estradiol exposure. Results indicate that these permanent changes in levels of ERα mediate the long-term effects exerted on the hippocampus and associated behaviors as a result of a period of transient exposure to estradiol. Furthermore, results indicate a mechanism by which ERα can impact memory and the hippocampus in the absence of ovarian estrogens. The data demonstrate an interaction between ERα and the hormone insulin-like growth factor-I in the hippocampus. Insulin-growth factor-I can act to activate ERα in a ligand-independent manner. Thus, increased levels of ERα can lead to enhanced cognition in aging females through novel mechanisms independent of estradiol actions. Collectively results indicate that middle-age represents a sensitive period during which the nervous system can be permanently altered by a short-term presence of exogenously administered estrogens. Broader Impacts: The activities supported by these funds provided increased research opportunities for students from the state of Louisiana, a geographical region that has traditionally been underrepresented in the sciences. Among other research activities, qualified undergraduates attending universities in Louisiana participated in Tulane University’s Neuroscience Summer Research Program and served as undergraduate research assistants in the Daniel lab. Last Modified: 06/05/2014 Submitted by: Jill M Daniel Publications Produced as a Result of this Research: Daniel, J.M. (2013). Estrogens, estrogen receptors and female cognitive aging: Impact of timing. Invited review in Special Issue, Hormones & Neurotrauma,Hormones and Behavior, 63: 231-237. Nelson, B.S, Springer, R.C. & Daniel, J.M. (2014). Antagonism of brain insulin-like growth factor-1 receptors blocks estradiol effects on memory and levels of hippocampal synaptic proteins in ovariectomized rats. Psychopharmacology, 231: 899-907.
