Age-related changes in circadian rhythms
Circadian (24-hour) rhythms govern a wide array of physiological and behavioral processes in virtually all organisms, including humans. By coordinating these processes with internal and external timing signals, circadian rhythms enable us to anticipate and prepare for daily changes in our environment. Robust, well synchronized circadian rhythms are essential for health and optimal physical and mental performance. Attenuation or disruption of circadian rhythms, especially sleep-wake rhythms, impairs cognition and memory and lowers resistance to disease. My research is directed at understanding the neural mechanisms leading to impairments in circadian rhythms during normal aging and in pathological conditions such as Alzheimer’s disease, obesity, and diabetes. Towards this end, we have identified age- and disease-related alterations in expression of clock genes and neuropeptides, at several levels of the circadian timing system, including the master circadian pacemaker in the suprachiasmatic nucleus (SCN) of the brain and in regions that provide input to the SCN and/or contain local oscillators (“clocks”). With aging, the SCN becomes less sensitive to several timing signals, including the neurotransmitter, serotonin. Our findings have shown that aging alters the expression of several types of serotonin receptors and transporters in the SCN and in other regions. Other studies have focused on the disruptive effects of acute arousal or high-fat diet on circadian rhythms, hormone secretion, and/or metabolism. Alterations in sleep-wake rhythms and their possible role in cognitive deficits are being investigated in rodent models of AD. These studies utilize a variety of experimental techniques, including behavioral studies (assessment of locomotor rhythms, sleep-wake rhythms, and memory), neurochemical procedures (immunohistochemistry, receptor autoradiography, and in situ hybridization), and drug administration. This research will provide a rational basis for novel treatments of circadian rhythm and sleep disorders in the elderly population, as well as in shift-workers and jet travelers.
1. Duncan, M.J., J. M. Hester, J.A. Hopper, K.M. Franklin (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. 31:1646-1654. PMCID: PMC2957648
2. Legan, S.J., X-L. Peng, K.M. Franklin, and M.J. Duncan (2010) Novel wheel running blocks the preovulatory luteinizing hormone (LH) surge as well as advances the hamster circadian pacemaker. J. Biol. Rhythms 25:450-459. PMCID: PMC3013354
3. Duncan, M.J., M.R. Congleton (2010) Neural mechanism mediating circadian phase resetting by activation of 5-HT7 receptors in the dorsal raphe: Role of GABAergic and glutamatergic neurotransmission, Brain Research 1366:110-119. PMCID: PMC2993770
4. Su, W.; Z. Xie, Z. Guo, M.J. Duncan, J. Lutshumba, M.C. Gong (2012) Altered clock gene expression and vascular smooth muscle diurnal contractile variations in Type2 diabetic db/db mice. Am. J. Physiol. Heart Circul. Physiol. 302:H621-H633. PMCID: PMC335796
5. Duncan, M.J., J.T. Smith, K.M. Franklin, M.P. Murphy, D. St. Clair, M. Striz, and B.F. O’Hara (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. Expt. Neurol. 236:249-258. PMCID:
6. Jiang,P., K.M. Franklin, M.J. Duncan, B.F. O’Hara, and J.P. Wisor (2012) Distinct phase relationships between suprachiasmatic molecular rhythms, cerebral cortex molecular rhythms and behavioral rhythms in early runner (CAST/EiJ) and nocturnal (C57Bl6) mice. Sleep 35:1385-1394. PMCID: PMC34437665
7. Duncan, M.J., J.R. Prochot, D.H. Cook, J.T. Smith, K.M. Franklin (2013) Influence of aging on Bmal1 and Per2 expression in extra-SCN oscillators in hamster brain. Brain Research: 1491:44-53. PMCID: PMC3530017
8. Wolff, G., M.J. Duncan, and K.A. Esser (2013) Chronic phase advance alters circadian physiological rhythms and peripheral molecular clocks. J. Appl. Physiol. 115:373-382.
9. Duncan, M.J, X-L. Peng, C. Yun, K.M. Franklin, and S.J. Legan (2014) Circadian rhythm disruption by a novel running wheel: Roles of exercise and arousal in blockade of the surge of luteinizing hormone (LH). Physiol. Behav. 131:7-16. PMCID: PMC4091821
10. Sethi, M., S.S. Joshi, R.L. Webb, T.L. Beckett, K.D. Donohue, M. P. Murphy, B.F. O’Hara, M.J. Duncan (2015) Increased fragmentation of sleep-wake cycles in the 5XFAD mouse model of Alzheimer’s disease. Neuroscience 290:80-89. PMCID: PMC4361816
11. Legan, S.J., X-L Peng, C. Yun, K.M Franklin, M.J. Duncan (2015) Effect of arousing stimuli on circulating corticosterone and the circadian rhythm of luteinizing hormone (LH) surges and locomotor activity in estradiol-treated ovaraiectomized (ovx+EB) hamsters. Hormones and Behavior 72:28-38. PMCID: PMC4466083
12. Duncan, M.J., J.T. Smith, Bustle, L.; Narbaiza, J.N.; Mueez, F., C. Fieseler, Legan, S.J. (2016) Restricting feeding to the active phase in middle-aged mice attenuates adverse metabolic effects of a high-fat diet, Physiol. Behav. 167:1-9.