(Application abstract) The long-term goal of this research is to determine the cellular and molecular mechanisms in the aging brain that disrupt circadian behaviors. During aging, the circadian pacemaker loses its ability to respond to serotonin, one of the neurotransmitters that shifts the phase of circadian rhythms in locomotor behavior and regulates the expression of vasoactive intestinal peptide (VIP), a neuropeptide which alters the phase of the circadian pacemaker.
The specific aims and methodologies are: (1) to test the hypothesis that aging alters synaptic release of serotonin, by using microdialysis and HPLC, (2) to test the hypothesis that aging leads to a loss of 5HT7 receptors, by using quantitative autoradiography, (3) to test the hypothesis that aging attenuates serotonergic stimulation of cAMP, by using short-term in vitro studies and radioimmunoassays, and (4) to test the hypothesis that aging reduces basal and/or serotonin-stimulated VIP mRNA expression, by using in situ hybridization. The initial studies will focus on the suprachiasmatic nucleus (SCN). Subsequent studies will investigate whether these age-related changes are unique to the SCN or also occur in other brain regions. The findings will provide a rational basis for therapeutic amelioration of the fragmented sleep-wake cycles that occur in the elderly and are especially severe in Alzheimer's patients. Also, because 5HT7 receptors have a high affinity for many anti-psychotic drugs, these studies will benefit the development of treatments for schizophrenia in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013418-04
Application #
6016799
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1996-07-17
Project End
2001-05-31
Budget Start
1999-06-15
Budget End
2000-05-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Sethi, M; Joshi, S S; Webb, R L et al. (2015) Increased fragmentation of sleep-wake cycles in the 5XFAD mouse model of Alzheimer's disease. Neuroscience 290:80-9
Duncan, Marilyn J; Prochot, Jeffrey R; Cook, Daniel H et al. (2013) Influence of aging on Bmal1 and Per2 expression in extra-SCN oscillators in hamster brain. Brain Res 1491:44-53
Duncan, Marilyn J; Smith, J Tyler; Franklin, Kathleen M et al. (2012) Effects of aging and genotype on circadian rhythms, sleep, and clock gene expression in APPxPS1 knock-in mice, a model for Alzheimer's disease. Exp Neurol 236:249-58
Jiang, Peng; Franklin, Kathleen M; Duncan, Marilyn J et al. (2012) Distinct phase relationships between suprachiasmatic molecular rhythms, cerebral cortex molecular rhythms, and behavioral rhythms in early runner (CAST/EiJ) and nocturnal (C57BL/6J) mice. Sleep 35:1385-94
Duncan, Marilyn J; Congleton, Matthew R (2010) Neural mechanisms mediating circadian phase resetting by activation of 5-HT(7) receptors in the dorsal raphe: roles of GABAergic and glutamatergic neurotransmission. Brain Res 1366:110-9
Duncan, Marilyn J; Hester, James M; Hopper, Jason A et al. (2010) The effects of aging and chronic fluoxetine treatment on circadian rhythms and suprachiasmatic nucleus expression of neuropeptide genes and 5-HT1B receptors. Eur J Neurosci 31:1646-54
Legan, Sandra J; Donoghue, Kathleen M; Franklin, Kathleen M et al. (2009) Phenobarbital blockade of the preovulatory luteinizing hormone surge: association with phase-advanced circadian clock and altered suprachiasmatic nucleus Period1 gene expression. Am J Physiol Regul Integr Comp Physiol 296:R1620-30
Duncan, Marilyn J; Bruce-Keller, Annadora J; Conner, Clayton et al. (2008) Effects of chronic expression of the HIV-induced protein, transactivator of transcription, on circadian activity rhythms in mice, with or without morphine. Am J Physiol Regul Integr Comp Physiol 295:R1680-7
Duncan, Marilyn J; Franklin, Kathleen M (2007) Expression of 5-HT7 receptor mRNA in the hamster brain: effect of aging and association with calbindin-D28K expression. Brain Res 1143:70-7
Knoch, Megan E; Siegel, Dustin; Duncan, Marilyn J et al. (2006) Serotonergic mediation of constant light-potentiated nonphotic phase shifting of the circadian locomotor activity rhythm in Syrian hamsters. Am J Physiol Regul Integr Comp Physiol 291:R180-8

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