Estrogen administration begun during a critical window near menopause is hypothesized to prevent or delay age-associated cognitive decline. However, due to potential health risks women often limit use of estrogen therapy to a few years to treat menopausal symptoms. The long-term consequences for the brain of short-term use of estrogens are unknown. The long-term goal of the research is to determine the consequences for the female brain and for female cognitive aging of short-term exposure to estrogens during middle-age such as that used by women during the menopausal transition. The central hypothesis to be tested is that lasting changes in levels of estrogen receptor alpha (ER?) and in the insulin-like growth factor-1 (IGF-1) system in the hippocampus resulting from short-term exposure to exogenously administered estradiol in middle-age following the cessation of ovarian function permanently alters the interaction between ER? and the IGF-1 system in the hippocampus of the aging female brain resulting in increases in levels of ER? target genes and proteins and in enhancement of hippocampus-dependent memory. Guided by preliminary data, this hypothesis will be tested by three specific aims: 1) Determine the nature of the interaction between IGF-1 and ER? in hippocampal neurons;2) Determine the respective contributions of ER? and IGF-1 receptors in the ability of short-term estradiol exposure to exert lasting impacts on the hippocampus and on hippocampus-dependent memory;and 3) Determine the extent to which the effects of IGF-1 on the hippocampus and on hippocampus-dependent memory in aged females vary dependent upon previous hormone experience. Experiments under the first aim will use primary hippocampal cell cultures to determine the ability of IGF-1 and its signaling pathways to induce ER?-mediated transcriptional activity from an estrogen response element driven reporter gene and to induce activation on of specific phosphorylation sites on ER?. Experiments under the second aim will assess the impact of pharmacological blockage of brain IGF-1 receptors, ER?, or both on the ability of short-term estradiol exposure in middle-aged ovariectomized rats to exert lasting impacts on ER? target genes and associated proteins in the hippocampus and on hippocampus-dependent memory. Experiments under the third aim will determine effects of centrally administered IGF-1 on hippocampus-dependent memory, IGF-1 associated signal transduction pathways, and ER? target genes and associated proteins in aged ovariectomized rats that have and have not undergone estradiol exposure during middle-age. This research is expected to have a positive impact on the study of female cognitive aging by providing elucidation of mechanisms by which a relatively short-term exposure to exogenously administered estradiol during a critical period following the cessation of ovarian function exerts lasting impacts on the hippocampus and on cognition.

Public Health Relevance

As the population of the United States ages, increased incidence of age-associated dementias will become a major public health issue. Interventions that could delay the onset of cognitive decline by even one or two years would have a major public health impact. These data will help determine the mechanism by which short- term administration of estrogens near the time of menopause could exert lasting benefits to the cognitive health of women as they age.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Wagster, Molly V
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Tulane University
Schools of Arts and Sciences
New Orleans
United States
Zip Code
Pollard, Kevin J; Wartman, Haley D; Daniel, Jill M (2018) Previous estradiol treatment in ovariectomized mice provides lasting enhancement of memory and brain estrogen receptor activity. Horm Behav 102:76-84
Black, Katelyn L; Baumgartner, Nina E; Daniel, Jill M (2018) Lasting impact on memory of midlife exposure to exogenous and endogenous estrogens. Behav Neurosci 132:547-551
Grissom, Elin M; Daniel, Jill M (2016) Evidence for Ligand-Independent Activation of Hippocampal Estrogen Receptor-? by IGF-1 in Hippocampus of Ovariectomized Rats. Endocrinology 157:3149-56
Nelson, Britta S; Black, Katelyn L; Daniel, Jill M (2016) Circulating Estradiol Regulates Brain-Derived Estradiol via Actions at GnRH Receptors to Impact Memory in Ovariectomized Rats. eNeuro 3:
Black, K L; Witty, C F; Daniel, J M (2016) Previous Midlife Oestradiol Treatment Results in Long-Term Maintenance of Hippocampal Oestrogen Receptor ? Levels in Ovariectomised Rats: Mechanisms and Implications for Memory. J Neuroendocrinol 28:
Daniel, Jill M; Witty, Christine F; Rodgers, Shaefali P (2015) Long-term consequences of estrogens administered in midlife on female cognitive aging. Horm Behav 74:77-85
Nelson, Britta S; Springer, Rachel C; Daniel, Jill 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 (Berl) 231:899-907
Witty, Christine F; Foster, Thomas C; Semple-Rowland, Susan L et al. (2012) Increasing hippocampal estrogen receptor alpha levels via viral vectors increases MAP kinase activation and enhances memory in aging rats in the absence of ovarian estrogens. PLoS One 7:e51385