Abstract

Evidence points to a positive influence of estrogen for memory processes that depend on the hippocampus, including postponement of age-related memory impairments. However, estrogen effects are diverse and the challenge remains to determine which biological mechanisms are important for estradiol (E2) effects on cognition. The discovery of several different nuclear estrogen receptors (ERs) and emerging evidence for rapid nongenomic influences on second messenger signaling cascades makes this challenge more formidable. Our long-term goal is to understand mechanisms of estrogen action on the hippocampus, which influence memory over the life span. E2 rapidly influences physiological processes in a manner opposite that observed during aging. However, E2 responsiveness decreases with advanced age possibly due to a loss of ERalpha associated transcription. The current study will determine which hippocampal genes are linked to ERalpha activity. It is hypothesized that ERalpha-linked genes regulate the responsiveness of rapid E2 effects and a decrease in activity is associated with functional brain aging and memory decline.
Specific aim 1 will test the hypotheses that E2 influences transcription of functionally associated genes involved in brain aging using microarray technology.
Specific aim 2 will employ ER knockout mice to test the hypothesis that ERalpha is important in the regulation of genes associated with aging and memory function.
Specific aim 3 will test the hypothesis that ERalpha contributes to E2 responsiveness for second messenger signaling pathways using electrophysiology and second messenger assays to compare responses in wildtype and knockout mice.
Specific aim 4 will use viral vector-based gene delivery to restore ERalpha function in the hippocampus in vivo. ERalpha may be a good test case for examining the function of a specific gene in memory since ERalpha knockout mice exhibit a gene dose impairment in memory function such that delivery would be expected to have a dramatic consequences on memory.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH059891-06
Application #
6819361
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (03))
Program Officer
Winsky, Lois M
Project Start
1999-12-15
Project End
2010-02-28
Budget Start
2005-03-05
Budget End
2006-02-28
Support Year
6
Fiscal Year
2005
Total Cost
$324,713
Indirect Cost

  Institution

Name
University of Florida
Department
Neurosciences
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611

  Publications

Scheinert, Rachel B; Asokan, Aditya; Rani, Asha et al. (2015) Some hormone, cytokine and chemokine levels that change across lifespan vary by cognitive status in male Fischer 344 rats. Brain Behav Immun 49:216-32
Zeier, Zane; Madorsky, Irina; Xu, Ying et al. (2011) Gene expression in the hippocampus: regionally specific effects of aging and caloric restriction. Mech Ageing Dev 132:8-19
Jackson, Travis C; Verrier, Jonathan D; Semple-Rowland, Susan et al. (2010) PHLPP1 splice variants differentially regulate AKT and PKC? signaling in hippocampal neurons: characterization of PHLPP proteins in the adult hippocampus. J Neurochem 115:941-55
Aenlle, Kristina K; Foster, Thomas C (2010) Aging alters the expression of genes for neuroprotection and synaptic function following acute estradiol treatment. Hippocampus 20:1047-60
Bodhinathan, Karthik; Kumar, Ashok; Foster, Thomas C (2010) Redox sensitive calcium stores underlie enhanced after hyperpolarization of aged neurons: role for ryanodine receptor mediated calcium signaling. J Neurophysiol 104:2586-93
Kumar, Ashok (2010) Carbachol-induced long-term synaptic depression is enhanced during senescence at hippocampal CA3-CA1 synapses. J Neurophysiol 104:607-16
Bodhinathan, Karthik; Kumar, Ashok; Foster, Thomas C (2010) Intracellular redox state alters NMDA receptor response during aging through Ca2+/calmodulin-dependent protein kinase II. J Neurosci 30:1914-24
Jackson, Travis C; Foster, Thomas C (2009) Regional Health and Function in the hippocampus: Evolutionary compromises for a critical brain region. Biosci Hypotheses 2:245-251
Aenlle, Kristina K; Kumar, Ashok; Cui, Li et al. (2009) Estrogen effects on cognition and hippocampal transcription in middle-aged mice. Neurobiol Aging 30:932-45
Zeier, Z; Kumar, A; Bodhinathan, K et al. (2009) Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome. Gene Ther 16:1122-9

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