SIDS most likely involves a disorder of sleep or arousal, from a disruption of sleep development. Since the circadian system has a profound influence on both the distribution of sleep states and the coupling of sleep to regulated systems, disruptions of the developing human circadian system that result in its delayed or impaired maturation will have a deleterious effect on sleep and physiological integration and could thereby place an infant at increased risk for SIDS. We hypothesize that SIDS risk will be decreased if the development of the circadian system and its coupling to other regulated systems is optimized. Impairments of the circadian system may result from a deficit in the input pathways to the circadian pacemaker, the pacemaker itself, or the outputs from the pacemaker. it is therefore critical to understand the normal function of the infant circadian system, its responses to light and other entraining stimuli, and its interaction with other physiological systems. The experiments in this component are designed to address the development of each of these three aspects of the circadian system in the rat and attempt to provide analogous information for the human infant. Particular emphasis will be placed on the maturation of neurotransmitter receptors within the suprachiasmatic nucleus (SCN) that may mediate entrainment of endogenous circadian rhythms to the light/dark cycle. A developmental timeline will be established for the ability of photic and non-photic stimuli transmitted to the circadian system through release of a glutamate-like excitatory amino acid (EAA) at terminals immediate early genes (IEGs) in the presence or absence of EAA antagonists such as MK-801. We will also determine the developmental expression of glutamate receptor subunit mRNAs in the SCN of rats by in situ hybridization. Since serotonergic stimulation of the SCN in vitro has been shown to phase-shift the circadian rhythm of SCN single-unit activity in a circadian phase-dependent manner, we will conduct neurophysiological studies of the SCN in vitro to determine the development of this response and in situ hybridization studies with cDNA probes to the 5HT1a and 5HT1c receptors to delineate 5HT receptor ontogenesis in the SCN. We will also determine the ontogeny of mRNAs encoding these receptors in the developing human circadian system through in situ hybridization studies of post-mortem tissue. Lastly, we will determine when outputs from the circadian pacemaker are first functional by (1) examining the ontogeny of light- induced stimulation of SCN neuropeptide mRNAs and (2) determining the development of the circadian rhythm of c-fos mRNA in extra-SCN brain regions.
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