Estrogens and Age-related Memory Decline in Rodents: What Have We Learned and Where Do We Go from Here?

Overview

Journal Horm Behav

Specialties Endocrinology
Psychology
Social Sciences

Date 2008 Oct 7

PMID 18835561

Citations 103

Authors

Karyn M Frick

Affiliations

Soon will be listed here.

Abstract

The question of whether ovarian hormone therapy can prevent or reduce age-related memory decline in menopausal women has been the subject of much recent debate. Although numerous studies have demonstrated a beneficial effect of estrogen and/or progestin therapy for certain types of memory in menopausal women, recent clinical trials suggest that such therapy actually increases the risk of cognitive decline and dementia. Because rodent models have been frequently used to examine the effects of age and/or ovarian hormone deficiency on mnemonic function, rodent models of age-related hormone and memory decline may be useful in helping to resolve this issue. This review will focus on evidence suggesting that estradiol modulates memory, particularly hippocampal-dependent memory, in young and aging female rats and mice. Various factors affecting the mnemonic response to estradiol in aging females will be highlighted to illustrate the complications inherent to studies of estrogen therapy in aging females. Avenues for future development of estradiol-based therapies will also be discussed, and it is argued that an approach to drug development based on identifying the molecular mechanisms underlying estrogenic modulation of memory may lead to promising future treatments for reducing age-related mnemonic decline.

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References

Markham J, Juraska J . Social recognition memory: influence of age, sex, and ovarian hormonal status. Physiol Behav. 2007; 92(5):881-8. PMC: 2151760. DOI: 10.1016/j.physbeh.2007.06.020. View

Bimonte H, Denenberg V . Estradiol facilitates performance as working memory load increases. Psychoneuroendocrinology. 1999; 24(2):161-73. DOI: 10.1016/s0306-4530(98)00068-7. View

Lefevre J, McClintock M . Reproductive senescence in female rats: a longitudinal study of individual differences in estrous cycles and behavior. Biol Reprod. 1988; 38(4):780-9. DOI: 10.1095/biolreprod38.4.780. View

Frick K, Fernandez S . Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice. Neurobiol Aging. 2003; 24(4):615-26. DOI: 10.1016/s0197-4580(02)00138-0. View

Rhodes M, Frye C . ERbeta-selective SERMs produce mnemonic-enhancing effects in the inhibitory avoidance and water maze tasks. Neurobiol Learn Mem. 2005; 85(2):183-91. DOI: 10.1016/j.nlm.2005.10.003. View

Eichenbaum H . Declarative memory: insights from cognitive neurobiology. Annu Rev Psychol. 1997; 48:547-72. DOI: 10.1146/annurev.psych.48.1.547. View

Launer L, Andersen K, Dewey M, Letenneur L, Ott A, Amaducci L . Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups. European Studies of Dementia. Neurology. 1999; 52(1):78-84. DOI: 10.1212/wnl.52.1.78. View

Gresack J, Frick K . Effects of continuous and intermittent estrogen treatments on memory in aging female mice. Brain Res. 2006; 1115(1):135-47. DOI: 10.1016/j.brainres.2006.07.067. View

Maki P . Hormone therapy and cognitive function: is there a critical period for benefit?. Neuroscience. 2006; 138(3):1027-30. DOI: 10.1016/j.neuroscience.2006.01.001. View

10.

Pitha J, Harman S, Michel M . Hydrophilic cyclodextrin derivatives enable effective oral administration of steroidal hormones. J Pharm Sci. 1986; 75(2):165-7. DOI: 10.1002/jps.2600750213. View

11.

Shingo A, Kito S . Estradiol induces PKA activation through the putative membrane receptor in the living hippocampal neuron. J Neural Transm (Vienna). 2005; 112(11):1469-73. DOI: 10.1007/s00702-005-0371-8. View

12.

Wade C, Robinson S, Shapiro R, Dorsa D . Estrogen receptor (ER)alpha and ERbeta exhibit unique pharmacologic properties when coupled to activation of the mitogen-activated protein kinase pathway. Endocrinology. 2001; 142(6):2336-42. DOI: 10.1210/endo.142.6.8071. View

13.

Nilsen J, Brinton R . Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling. Proc Natl Acad Sci U S A. 2003; 100(18):10506-11. PMC: 193591. DOI: 10.1073/pnas.1334098100. View

14.

Mosselman S, Polman J, Dijkema R . ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett. 1996; 392(1):49-53. DOI: 10.1016/0014-5793(96)00782-x. View

15.

Adams M, Fink S, Shah R, Janssen W, Hayashi S, Milner T . Estrogen and aging affect the subcellular distribution of estrogen receptor-alpha in the hippocampus of female rats. J Neurosci. 2002; 22(9):3608-14. PMC: 6758372. DOI: 20026275. View

16.

Frick K, Burlingame L, Arters J, Berger-Sweeney J . Reference memory, anxiety and estrous cyclicity in C57BL/6NIA mice are affected by age and sex. Neuroscience. 2000; 95(1):293-307. DOI: 10.1016/s0306-4522(99)00418-2. View

17.

Warren S, Juraska J . Spatial and nonspatial learning across the rat estrous cycle. Behav Neurosci. 1997; 111(2):259-66. DOI: 10.1037//0735-7044.111.2.259. View

18.

Bimonte-Nelson H, Francis K, Umphlet C, Granholm A . Progesterone reverses the spatial memory enhancements initiated by tonic and cyclic oestrogen therapy in middle-aged ovariectomized female rats. Eur J Neurosci. 2006; 24(1):229-42. DOI: 10.1111/j.1460-9568.2006.04867.x. View

19.

Renner K, Luine V . Analysis of temporal and dose-dependent effects of estrogen on monoamines in brain nuclei. Brain Res. 1986; 366(1-2):64-71. DOI: 10.1016/0006-8993(86)91281-3. View

20.

Packard M, Teather L . Intra-hippocampal estradiol infusion enhances memory in ovariectomized rats. Neuroreport. 1997; 8(14):3009-13. DOI: 10.1097/00001756-199709290-00004. View