Neural Mechanisms Resetting the Aged Circadian Pacemaker

Aging induces deficits in circadian rhythms in rest-activity, hormone secretion, and other functions. The normal expression of circadian rhythms depends upon the ability of the circadian pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) to respond to timing signals conveyed by several afferent pathways, including serotonergic neurons. During aging, the pacemaker loses its ability to respond appropriately to several timing signals including serotonergic drugs, such as 8-OH-DPAT. Our findings from the previous funding period have shown that this age-related loss of sensitivity is associated with a large loss of specific serotonin7 (5-HT7) receptor binding sites in the dorsal raphe nucleus (DRN). The DRN is a target site for 8-OH-DPAT induction of circadian phase shifts and a source of innervation of two other circadian substrates, the median raphe nucleus (MRN) and the intergeniculate leaflet (IGL), which both communicate with the SCN. The proposed project will test the following working hypothesis: Age-related reduction in 5-HT7 receptors in the DRN attenuates 8-OH-DPAT modulation of neurotransmission within the MRN and IGL. Reduced communication with the MRN and IGL leads to age-related deficits in phase resetting of the circadian pacemaker in the SCN. The specific aims are: 1) To determine the significance of the age-related reduction in 5-HT7 receptors in the DRN for circadian phase shifts, 2) To identify the neurochemical phenotype of 5-HT7 receptor-containing cells in the DRN, 3) To elucidate the role of the IGL and MRN in mediating the phase-shifting effects of 8-OH-DPAT microinjections in the DRN, and 4) To determine the factors responsible for the age-related loss of 5-HT7 receptors in the DRN. These proposed studies focus on the DRN as an important locus of aging of the circadian timing system. The DRN not only communicates with circadian substrates, but also with brain structures, such as the hippocampus and pedunculopontine tegmental nucleus, regulating memory and sleep, respectively. These processes also exhibit deficits with aging, which may reflect age-related changes in the function of the DRN. The proposed project will elucidate whether the 5-HT7 receptors in the DRN are an important target for new pharmacotherapeutic approaches to ameliorate the disrupted circadian rhythms, especially sleep-wake cycles, that disturb the elderly as well as jet travelers and shift workers. Deterioration of circadian rhythms compromises an individual's health by causing chronic fatigue, lowering resistance to disease, impairing cognition and memory, and reducing longevity.