Even in the absence of dementia, a dichotomy remains between successful and unsuccessful cognitive aging. The long range goal is to provide interventions to delay, prevent, or treat cognitive decline associated with unsuccessful aging in order to improve the health and well- being of older Americans. The overall hypothesis for the proposed work is that memory consolidation deficits are an early marker of cognitive decline. It is hypothesized that memory deficits result from impaired activation of NMDA receptor (NMDAR) signaling cascades that direct the expression of genes for maintaining hippocampal function. The studies will examine signaling cascades in two fields of the hippocampus (CA1 and the dentate gyrus) of rats at different ages in order to distinguish when and where changes associated with memory deficits first emerge.
Specific aim 1 will combine behavioral characterization, in vitro electrophysiology, protein and gene expression analyses to tests the hypothesis that memory consolidation deficits result from a decreased ability to activate signaling cascades that are important for memory. Preliminary data indicates that NMDAR synaptic responses and the activity of ERK is decreased in middle-aged and aged animals with memory consolidation deficits relative to aged-matched, unimpaired rats. Examination of brain tissue supports the idea that deficits are associated with a reduction in experience induced changes in chromatin structure (histone acetylation) and the expression of genes related to synaptic activity.
Specific aim 2 will test the hypothesis that neural inflammation contributes to the decline in the signaling cascade and cognitive decline. It is predicted that non-steroidal anti-inflammatory drugs (NSAIDs) will reverse the decrease in NMDAR activated signaling cascade activity and improve memory in aging animals. The same techniques and measures will be used to examine control and NSAID treated animals. Preliminary data indicates that memory impaired animals exhibit markers of neuroinflammation observed as enhanced expression of cytokines and genes related to cellular stress and memory consolidation deficits associated with neuroinflammation can be reversed by NSAID treatment.

Public Health Relevance

Even in the absence of dementia, a dichotomy remains between successful and unsuccessful cognitive aging. The long range goal is to provide interventions to delay, prevent, or treat cognitive decline associated with unsuccessful aging in order to improve the health and well- being of older Americans

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG036800-08
Application #
9266698
Study Section
Special Emphasis Panel (NSS)
Program Officer
Wagster, Molly V
Project Start
2010-09-30
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Florida
Department
Neurosciences
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Kumar, Ashok; Foster, Thomas C (2018) Alteration in NMDA Receptor Mediated Glutamatergic Neurotransmission in the Hippocampus During Senescence. Neurochem Res :
Kumar, Ashok; Yegla, Brittney; Foster, Thomas C (2018) Redox Signaling in Neurotransmission and Cognition During Aging. Antioxid Redox Signal 28:1724-1745
Kumar, Ashok; Rani, Asha; Scheinert, Rachel B et al. (2018) Nonsteroidal anti-inflammatory drug, indomethacin improves spatial memory and NMDA receptor function in aged animals. Neurobiol Aging 70:184-193
Ianov, Lara; Riva, Alberto; Kumar, Ashok et al. (2017) DNA Methylation of Synaptic Genes in the Prefrontal Cortex Is Associated with Aging and Age-Related Cognitive Impairment. Front Aging Neurosci 9:249
Ianov, Lara; De Both, Matt; Chawla, Monica K et al. (2017) Hippocampal Transcriptomic Profiles: Subfield Vulnerability to Age and Cognitive Impairment. Front Aging Neurosci 9:383
Foster, T C; Kyritsopoulos, C; Kumar, A (2017) Central role for NMDA receptors in redox mediated impairment of synaptic function during aging and Alzheimer's disease. Behav Brain Res 322:223-232
Rani, Asha; O'Shea, Andrew; Ianov, Lara et al. (2017) miRNA in Circulating Microvesicles as Biomarkers for Age-Related Cognitive Decline. Front Aging Neurosci 9:323
McGuiness, James A; Scheinert, Rachel B; Asokan, Aditya et al. (2017) Indomethacin Increases Neurogenesis across Age Groups and Improves Delayed Probe Trial Difference Scores in Middle-Aged Rats. Front Aging Neurosci 9:280
Ianov, Lara; Kumar, Ashok; Foster, Thomas C (2017) Epigenetic regulation of estrogen receptor ? contributes to age-related differences in transcription across the hippocampal regions CA1 and CA3. Neurobiol Aging 49:79-85

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