Our goal is to understand the decline in cholinergicneurotransmission associated with age and to determine if intervention with exogenous aaents such as cholinergic agonists or anti-inflammatories modifies this age-related process. The overall hypothesis to be tested is: Long-term oral administration of nicotine and/or non-steroidal anti-inflammatories to adult CBA/J mice provides protection against age-related loss and/or changes in nicotinic cholinergic receptor expression and function. We have developed a mouse model (Rogers et al., J. Neurosci. 18:4825-4832, 1998) that reliably reflects age-related decline in neuronal nicotinic acetylcholine receptor (nAChR) expression (i.e., nAChRa4 subunit) and shown that long-term (1 year) oral nicotine delivery slows this decline. No data are available regarding other nAChR subunit expression in the aging mouse brain, or how the brain may compensate for the changes. Notably, the nAChRa4 expressing cholinergic neurons in CAl that are diminished in the aged brain also constitutively express cyclooxygenase-2 (COX2), a target of non-steroidal anti-inflammatories (NSAIDs) that have been suggested to be neuroprotective. The focus of this proposal is to examine the influence of long-term (1-year) oral nicotine, Cox-2 preferring NSAIDs or both on the process of age-related change in nAChA expression and function in the CBA mouse brain through answering three basic questions.
Specific Aim 1 : Do age-related changes in the expression of multiple nicotinic acetyicholine receptor (nAChR) subunits occur and are these changes modified by long-term nicotine administration? Specific Aim 2: Does inhibition of cyclooxygenase 2 by non-steroidal anti-inflammatory drugs (NSA!Ds) impact age-related alterations in nAChR subunit expression? Finally, since aging influences many cellular functions including the ability to respond to inflammatory agents, we will ask in Specific Aim 3 using microarray chip analysis; Do these treatments contribute to maintaining normal transcriptional responses by the brain?

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Wise, Bradley C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Utah
Schools of Medicine
Salt Lake City
United States
Zip Code
Rothermel, Markus; Wachowiak, Matt (2014) Functional imaging of cortical feedback projections to the olfactory bulb. Front Neural Circuits 8:73
Gahring, Lorise C; Enioutina, Elena Y; Myers, Elizabeth J et al. (2013) Nicotinic receptor alpha7 expression identifies a novel hematopoietic progenitor lineage. PLoS One 8:e57481
Rogers, Scott W; Gahring, Lorise C (2012) Nicotinic receptor Alpha7 expression during tooth morphogenesis reveals functional pleiotropy. PLoS One 7:e36467
Rogers, Scott W; Tvrdik, Petr; Capecchi, Mario R et al. (2012) Prenatal ablation of nicotinic receptor alpha7 cell lineages produces lumbosacral spina bifida the severity of which is modified by choline and nicotine exposure. Am J Med Genet A 158A:1135-44
Gahring, Lorise C; Osborne, Amber V; Reed, Michelle et al. (2010) Neuronal nicotinic alpha7 receptors modulate early neutrophil infiltration to sites of skin inflammation. J Neuroinflammation 7:38
Gahring, Lorise C; Rogers, Scott W (2010) Nicotinic receptor subunit alpha5 modifies assembly, up-regulation, and response to pro-inflammatory cytokines. J Biol Chem 285:26049-57
Gahring, Lorise C; Vasquez-Opazo, Gustavo A; Rogers, Scott W (2010) Choline promotes nicotinic receptor alpha4 + beta2 up-regulation. J Biol Chem 285:19793-801
Albuquerque, Edson X; Pereira, Edna F R; Alkondon, Manickavasagom et al. (2009) Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 89:73-120
Gahring, Lorise C; Rogers, Scott W (2008) Nicotinic acetylcholine receptor expression in the hippocampus of 27 mouse strains reveals novel inhibitory circuitry. Hippocampus 18:737-49
Rogers, Scott W; Weis, Janis J; Ma, Ying et al. (2008) Mouse chromosome 11 harbors genetic determinants of hippocampal strain-specific nicotinic receptor expression. Hippocampus 18:750-7

Showing the most recent 10 out of 18 publications