(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.
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