The recent controversial Women's Health Initiative Memory Study (WHIMS) implies that long-term treatment with estrogen and progestin significantly increases the risk of cognitive decline and dementia in menopausal women. These data sharply contrast with studies in women and rodents that have demonstrated a clear ability of estrogen to alleviate age- and hormone-related memory loss. The WHIMS finding that progestin is detrimental to memory is even more surprising because estrogen and progesterone treatment have been shown to be beneficial to memory in laboratory animals. The proposed studies were designed to clarify whether progesterone attenuates the beneficial effects of estrogen and to identify the neural mechanisms underlying the effects of estrogen and progesterone on memory consolidation. Because adverse side effects of hormone replacement such as increased risks of breast cancer and stroke make it impractical to conduct these studies in women, the proposed studies will utilize a female mouse model.
The specific aims are as follows: 1) To pinpoint if estrogen and progesterone, alone or in combination, enhance memory consolidation and alter MAP kinase signaling in the hippocampus in young and aging females, 2) To determine if the mnemonic and hippocampal response to estrogen and progesterone is influenced by environmental factors, and 3) To compare the mnemonic and neural effects of estrogen and progesterone treatments that vary in duration (short- vs. long-term) and type (sustained vs. cyclic). To achieve these aims, ovariectomized female C57BL/6 mice (4, 17, and 24 months old) will be used in a series of nine experiments. Spatial memory will be tested in a spatial water maze task and non-spatial memory will be tested in an object recognition task. The goal of this research is to clarify the findings of WHIMS, a study which has greatly impacted the treatment of millions of menopausal women. WHIMS was a limited study, focusing on an older, highly educated population receiving treatment that was not cyclic and included a detrimental type of progestin. Establishing how factors such as age at treatment, degree of cognitive stimulation, type of progestin, and type of treatment (i.e., cyclic vs. sustained) influence the mnemonic and neural response to hormones will be critical to future use of hormone replacement. Our mouse model will enable a more controlled study of these factors than is possible with women. Elucidation of these issues may ultimately lead to the development of safer and more effective treatments to prevent cognitive decline and dementia in women

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Wagster, Molly V
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Yale University
Schools of Arts and Sciences
New Haven
United States
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Frick, Karyn M; Kim, Jaekyoon; Koss, Wendy A (2018) Estradiol and hippocampal memory in female and male rodents. Curr Opin Behav Sci 23:65-74
Frick, Karyn M; Tuscher, Jennifer J; Koss, Wendy A et al. (2018) Estrogenic regulation of memory consolidation: A look beyond the hippocampus, ovaries, and females. Physiol Behav 187:57-66
Sheppard, P A S; Koss, W A; Frick, K M et al. (2018) Rapid actions of oestrogens and their receptors on memory acquisition and consolidation in females. J Neuroendocrinol 30:
Frick, Karyn M; Kim, Jaekyoon (2018) Mechanisms underlying the rapid effects of estradiol and progesterone on hippocampal memory consolidation in female rodents. Horm Behav :
Choleris, Elena; Galea, Liisa A M; Sohrabji, Farida et al. (2018) Sex differences in the brain: Implications for behavioral and biomedical research. Neurosci Biobehav Rev 85:126-145
Galea, Liisa A M; Frick, Karyn M; Hampson, Elizabeth et al. (2017) Why estrogens matter for behavior and brain health. Neurosci Biobehav Rev 76:363-379
Frick, Karyn M; Kim, Jaekyoon; Tuscher, Jennifer J et al. (2015) Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents. Learn Mem 22:472-93
Tuscher, Jennifer J; Fortress, Ashley M; Kim, Jaekyoon et al. (2015) Regulation of object recognition and object placement by ovarian sex steroid hormones. Behav Brain Res 285:140-57
Frick, Karyn M (2015) Molecular mechanisms underlying the memory-enhancing effects of estradiol. Horm Behav 74:4-18
Benoit, Jamie D; Rakic, Pasko; Frick, Karyn M (2015) Prenatal stress induces spatial memory deficits and epigenetic changes in the hippocampus indicative of heterochromatin formation and reduced gene expression. Behav Brain Res 281:1-8

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