Normal aging can produce a loss of explicit memory and executive function, functions dependent upon the integrity of the hippocampus/medial temporal lobe and the prefrontal cortex, respectively. The cognitive domains mediated by the hippocampus and the prefrontal cortex can be measured in rats to provide a functional output against which we can assess the importance of age-related neurobiological changes on memory impairment and the effects of interventions. In the hippocampus and cortex of aged rats and humans, muscarinic M1 and metabotropic glutamate receptor (mGluR) Type 1 coupling to Galphaq/11 and downstream phosphoinositide turnover signaling is blunted. Importantly, the receptor coupling is most blunted in the rats with the most impaired memory, and there is some indication that this is also the case in Alzheimer's disease patients. In vitro and in vivo studies can reproduce the effects of aging on muscarinic receptor/G-protein coupling by two apparently unrelated mechanisms: increasing oxidative stress or removal of cholinergic afferents. Our goal in this project is to determine which mechanism(s) contribute to these effects of aging, and subsequently to intervene and prevent both the mechanistic alterations and cognitive decline. We will combine behavioral assessment with neurobiological analysis to determine if the prevention of receptor coupling deficits via growth hormone/IGF-1 intervention is relevant in the prevention of age-related cognitive decline. The outcome of these experiments will provide new information with regards to the basic mechanisms of age related cognitive decline and reveal if growth hormone administration to aged subjects will prevent the emergence of cognitive decline along with associated alterations in molecular mechanisms. Lay description: This project will determine if certain changes in cell signaling in the brain contribute to a loss of memory in aging and what mechanisms drive these changes. This project will also determine if early intervention with growth hormone will prevent cell signaling changes and the associated age-related cognitive decline.

Public Health Relevance

Thirty percent of individuals aged 65 or older will show signs of cognitive decline ranging from mild cognitive impairment to severe dementia. The rat studies described in this proposal will focus on the mechanistic factors that contribute to the non-pathological loss of memory that occurs as a consequence of normal aging and will provide pre-clinical data aimed at the development of potential therapies to counteract normal, age-related memory decline.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Wise, Bradley C
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Wake Forest University Health Sciences
Internal Medicine/Medicine
Schools of Medicine
United States
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McQuail, Joseph A; Nicolle, Michelle M (2015) Spatial reference memory in normal aging Fischer 344 × Brown Norway F1 hybrid rats. Neurobiol Aging 36:323-33
McQuail, Joseph A; Davis, Kathleen N; Miller, Frances et al. (2013) Hippocampal G?q/?? but not G?o-coupled receptors are altered in aging. Neuropharmacology 70:63-73
McQuail, Joseph A; Banuelos, Cristina; LaSarge, Candi L et al. (2012) GABA(B) receptor GTP-binding is decreased in the prefrontal cortex but not the hippocampus of aged rats. Neurobiol Aging 33:1124.e1-12
Nieves-Martinez, Erasmo; Haynes, Kathryn; Childers, Steven R et al. (2012) Muscarinic receptor/G-protein coupling is reduced in the dorsomedial striatum of cognitively impaired aged rats. Behav Brain Res 227:258-64
McQuail, Joseph A; Riddle, David R; Nicolle, Michelle M (2011) Neuroinflammation not associated with cholinergic degeneration in aged-impaired brain. Neurobiol Aging 32:2322.e1-4
Sergeant, Susan; McQuail, Joseph A; Riddle, David R et al. (2011) Dietary fish oil modestly attenuates the effect of age on diastolic function but has no effect on memory or brain inflammation in aged rats. J Gerontol A Biol Sci Med Sci 66:521-33
Nieves-Martinez, E; Sonntag, W E; Wilson, A et al. (2010) Early-onset GH deficiency results in spatial memory impairment in mid-life and is prevented by GH supplementation. J Endocrinol 204:31-6
Mitschelen, M; Garteiser, P; Carnes, B A et al. (2009) Basal and hypercapnia-altered cerebrovascular perfusion predict mild cognitive impairment in aging rodents. Neuroscience 164:918-28
Zhang, Hai-Yan; Watson, Mona L; Gallagher, Michela et al. (2007) Muscarinic receptor-mediated GTP-Eu binding in the hippocampus and prefrontal cortex is correlated with spatial memory impairment in aged rats. Neurobiol Aging 28:619-26
Shi, Lei; Adams, Michelle M; Long, Ashley et al. (2006) Spatial learning and memory deficits after whole-brain irradiation are associated with changes in NMDA receptor subunits in the hippocampus. Radiat Res 166:892-9

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