The goal of the proposed work is to provide an understanding the role of chronic inflammation in promoting an early onset memory impairment and progression of cognitive decline during aging. Impaired episodic memory, an early indicator of cognitive decline, is due to a redox-mediated decrease in the function of synaptic NMDA receptors. The mechanism involves reactive oxygen species (ROS), possibly from activated microglia, providing a potential link between inflammation and the emergence of impaired memory.
Aim 1 will test the hypothesis that the onset of cognitive decline is influenced by an inflammation induced increase in oxidative stress, resulting in a redox-mediated decrease in NMDAR function. LPS will be used to induce low- grade systemic inflammation. Studies employ sensitive behavioral tests for different cognitive processes, and can detect changes in motor function or motivation. Impaired cognitive function will be associated with measures of serum and local brain cytokines, oxidative stress, and redox regulation of NMDA receptor function. We predict that inflammatory markers in the serum correlated with the emergence of memory decline and that for specific neural systems, inflammation markers and impaired NMDA receptor function is diagnostic of cognitive impairment phenotypes.
Aim 2 examines the progression of cognitive decline. Systemic inflammation induces long-term effects on microglia and synaptic function that outlast systemic markers. To examine long-term effects we will characterize cognition, redox regulation of NMDA receptors, and RNA sequencing to obtain a picture of the transcriptional profile associated with chronic inflammation and cognitive impairment. Research indicates that decreased activity of synaptic NMDA receptors results in a transcriptional profile similar to that associated with aging and memory impairment suggesting that a decrease in NMDAR synaptic activity, due to chronic inflammation, alters transcription of neurotrophic, neuroprotective, and synapse specific genes. We predict that long-lasting changes due to inflammation involve a redox-mediated decrease in synaptic NMDAR activity resulting in a senescent transcription, which increases cellular vulnerability to age-related stressors, and decreases connectivity in specific neural circuits.
Aim 3 will examine the effect of anti-inflammatory drugs on cognitive and biological changes associated with inflammation.

Public Health Relevance

Systemic inflammation influences the onset and progression of brain aging and neurodegenerative disease. The proposed studies will test a hypothesized mechanism that links inflammation induced oxidative stress with synaptic mechanisms that regulate memory and the transcription of genes that maintain the health of neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG049711-04
Application #
9472274
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wagster, Molly V
Project Start
2015-09-01
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
4
Fiscal Year
2018
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
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
Hernandez, Abbi R; Reasor, Jordan E; Truckenbrod, Leah M et al. (2017) Medial prefrontal-perirhinal cortical communication is necessary for flexible response selection. Neurobiol Learn Mem 137:36-47
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
Guadiana, Sarah M; Parker, Alexander K; Filho, Gileno F et al. (2016) Type 3 Adenylyl Cyclase and Somatostatin Receptor 3 Expression Persists in Aged Rat Neocortical and Hippocampal Neuronal Cilia. Front Aging Neurosci 8:127
Febo, Marcelo; Foster, Thomas C (2016) Preclinical Magnetic Resonance Imaging and Spectroscopy Studies of Memory, Aging, and Cognitive Decline. Front Aging Neurosci 8:158

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