Aging leads to deficits in many functions,including circadian timekeeping, which has been the focus of our on-going research. Circadian rhythm disruption is associated with increased risk of cardiovascular disease and cancer as well as impaired memory. Our previous studies revealed age-related changes in serotonergic regulation of the suprachiasmatic nucleus (SON), the site of the master circadian pacemaker, and the dorsal raphe nucleus (DRN), which also regulates circadian rhythms. We expanded our studies to include the hippocampus, which regulates memory, and observed aging changes in serotonergic regulation of this structure as well. In the SCN, aging increases serotonin transporter sites and decreases VIP mRNA expression. VIP is a key peptide involved in circadian rhythm generation, phase resetting, and transmission of circadian output. We propose to investigate if the increase in transporter sites causes the age-related decrease in VIP mRNA, since serotonin depletion attenuates VIP mRNA levels. Our previous studies also showed that aging decreases 5-HT7 receptors in the DRN and hippocampus. The age-related loss of 5-HT7 receptors in the DRN attenuates phase shifts to serotonergic drugs. We propose to investigate the neural pathways mediating DRN 5-HT7 receptor induction of phase shifts, by exploring the role of the GABAergic and glutamatergic neurotransmission, which are modulated by DRN 5-HT7 receptors in vitro. Finally, the age-related loss of 5-HT7 receptors in the hippocampal CA1 may be related to age-related memory loss, because genetic deletion of 5-HT7 receptors induces memory deficits. Exciting new studies of hippocampal neurons in vitro show that activation of 5-HT7 receptors stimulates neurite extensions critical process for synaptic connectivity. Decreased dendritic length is associated with memory impairments during aging and neurodegenerative diseases. Therefore, we propose to further investigate the intriguing but relatively little explored effect of 5-HT7 receptor stimulation of neurite length.
The specific aims are to investigate: 1) the role of age-related changes in serotonin transporter sites in regulating SCN VIP and GRP expression, 2) the mechanisms by which 5-HT7 receptors in the dorsal raphe, which are decreased with aging, mediate nonphotic circadian phase shifts and 3) the effect of 5-HT7 receptors on neurite length in the hippocampus, SCN and DRN and whether this effect decreases during aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013418-14
Application #
7916637
Study Section
Special Emphasis Panel (ZRG1-IFCN-D (03))
Program Officer
Mackiewicz, Miroslaw
Project Start
1996-07-17
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
14
Fiscal Year
2010
Total Cost
$291,375
Indirect Cost
Name
University of Kentucky
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
939017877
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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