Neural Mechanisms Resetting the Aged Circadian Pacemaker

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 (SCN), 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 CA 1 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 extension,a 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 non photic 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.