Aged individuals and individuals suffering from Alzheimer's disease typically have significant cognitive impairment. Similarly aged animals are also known to have profound deficits in learning and memory. However, it is only recently that significant progress has been made in understanding the molecular and cellular substrates of cognitive functioning. Thus an understanding of the cellular and molecular bases of age related-learning deficits is just beginning to emerge. Long-term potentiation (LTP) is a form of synaptic plasticity that has been widely touted as a cellular building block of learning and memory. During the previous grant period the P.I. demonstrated clear deficits in LTP induction in the CA1 area of aged Fischer 344 rats. Molecular correlates of LTP were also a major focus of previous work. The P.I. has shown that LTP-inducing stimuli produce an increase in the phosphorylation of synapsin a synaptic vesicle-associated phosphoprotein and has also shown that aged animals have significant deficits in synapsin phosphorylation. Moreover, The P.I. and his colleagues have recently developed the immunological reagents required to study the NMDA and kainate/AMPA receptors. These receptors are thought to play critical role in LTP and they appear to be defective in old animals. in the current proposal previous work on age-related deficits in LTP mechanisms will be extended and new studies of NMDA and kainate/AMPA receptors are planned. Second, the P.I. proposes to test whether treatments (caloric restriction an antioxidant therapy) which have been reported to ameliorate cognitive and other deficits seen with age may limit or eliminate age-related deficits in specific LTP mechanisms. These studies will involve both cellular and molecular analyses. The specific foci will be in four areas. First, the P.I. will test the hypothesis that aged animals will exhibit deficits in LTP induction in the dentate and CA3 regions of the hippocampus. The P.I. will then test the hypothesis that antioxidant treatment and/or caloric restriction may ameliorate age related-deficits in LTP induction. Second, the P.I. proposes to test the hypothesis that aged animals have deficits in symapsin phosphorylation induced by electrophysiological stimulation. When deficits are found it is proposed that antioxidant treatment and/or caloric restriction be tested for their ability to ameliorate these deficits. The P.I. proposes to test the hypothesis that NMDA and/or kainate/AMPA receptor function, expression and/or phosphorylation are altered in aged animals. If age related deficits in either of these receptors is selected, the P.I. will test the hypothesis that caloric restriction and/or antioxidant treatment may ameliorate these deficits. In the final aim of this proposal, the P.I. will test the hypothesis that kinase activation following LTP induction may be deficient in old animals. In addition, the P.I. also proposed to collaborate with Projects 1, 2 and 4. Purified kinases and antibodies will be provided for collaborative studies of GABAA-R and Ca2+ channel function in collaborative experiments with Projects 1 and 2 respectively. Lastly, synapsin I expression will be assayed as a measure of transplant development in collaboration with Project #4.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Bickford, Paula C; Flowers, Antwoine; Grimmig, Bethany (2017) Aging leads to altered microglial function that reduces brain resiliency increasing vulnerability to neurodegenerative diseases. Exp Gerontol 94:4-8
Grimmig, Bethany; Kim, Seol-Hee; Nash, Kevin et al. (2017) Neuroprotective mechanisms of astaxanthin: a potential therapeutic role in preserving cognitive function in age and neurodegeneration. Geroscience 39:19-32
Tajiri, Naoki; Acosta, Sandra A; Shahaduzzaman, Md et al. (2014) Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats. J Neurosci 34:313-26
Lee, Daniel C; Ruiz, Claudia R; Lebson, Lori et al. (2013) Aging enhances classical activation but mitigates alternative activation in the central nervous system. Neurobiol Aging 34:1610-20
Lee, D C; Rizer, J; Hunt, J B et al. (2013) Review: experimental manipulations of microglia in mouse models of Alzheimer's pathology: activation reduces amyloid but hastens tau pathology. Neuropathol Appl Neurobiol 39:69-85
Ross, Jaime M; Stewart, James B; Hagström, Erik et al. (2013) Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501:412-5
Shahaduzzaman, Md; Golden, Jason E; Green, Suzanne et al. (2013) A single administration of human umbilical cord blood T cells produces long-lasting effects in the aging hippocampus. Age (Dordr) 35:2071-87
Olson, Linus; Faulkner, Stuart; Lundströmer, Karin et al. (2013) Comparison of three hypothermic target temperatures for the treatment of hypoxic ischemia: mRNA level responses of eight genes in the piglet brain. Transl Stroke Res 4:248-57
Morganti, Josh M; Nash, Kevin R; Grimmig, Bethany A et al. (2012) The soluble isoform of CX3CL1 is necessary for neuroprotection in a mouse model of Parkinson's disease. J Neurosci 32:14592-601
Li, Qingyou; Lebson, Lori; Lee, Daniel C et al. (2012) Chronological age impacts immunotherapy and monocyte uptake independent of amyloid load. J Neuroimmune Pharmacol 7:202-14

Showing the most recent 10 out of 317 publications