Aging of the mammalian brain is accompanied by reduced expression of neuronal nicotinic acetylcholine receptors (nAChR), and decreased control of pro-inflammatory mechanisms. Our previous findings identified age-related and mouse strain-specific changes in nAChR expression by hippocampal interneurons (and astrocytes) and identified interactions with either the inflammatory mediator cyclooxygenase 2 (Cox2), or the RXR co-transcription factor, PPARgamma. We will now focus on genetic and cellular mechanisms contributing to these interactions. Completion of these studies will identify genetic mechanisms and possible therapeutic strategies for interventions that will promote stability of nAChR expression into advanced age.
SPECIFIC AIM 1. Hypothesis: Interneuron subtypes, as defined by differential nAChR, somatostatin and Cox2/PPARgamma2 expression, vary in their relative susceptibility to age-related decline. Differential nAChR expression defines at least 4 interneuron subclasses in hippocampal CA1, but there are additional subtypes whose relative susceptibility to age-related loss will be determined.
SPECIFIC AIM 2. Hypothesis: Intracellular pathways that signal neuronal responses to either nicotine or NSAIDs contribute to regulating nAChR expression in the aged brain, but converge to become antagonistic. Long-term NSAID administration promotes retention of nAChR expression into old age, but this is antagonized by co-administration of nicotine. A primary neuronal tissue culture model system will be used to define intracellular signaling pathways where these agents converge to produce antagonism.
SPECIFIC AIM 3. Hypothesis: The efficacy of long-term administration of nicotine, Cox2 antagonists, and/or PPARgamma agonists on retaining nAChRalpha4 expression in aged animals is determined by strain-specific genetic background. Using newly generated congenic mouse lines, the importance of nAChR expression by astrocytes versus other components of the genetic background will be measured to identify strain-specific components of the nicotine and NSAID interaction, and determine if NSAIDs, working as PPARgamma agonists, promote retention of nAChRalpha4 expression in the aging brain.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Petanceska, Suzana
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University of Utah
Schools of Medicine
Salt Lake City
United States
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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
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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

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