ADENOSINE AND THE PREOPTIC REGULATION OF SLEEP

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Abstract

DESCRIPTION (adapted from applicant's abstract): This development award will enable Dr. Scammell to become an independent researcher in sleep, thoroughly skilled in basic sleep neurobiology and clinical sleep medicine. The research proposal focuses heavily on training Dr. Scammell in new techniques of neuroanatomy and sleep physiology. In addition, he will become increasingly independent in clinical sleep medicine, and he will take coursework in molecular neurobiology and statistical methodology that will complement the research plan. Little is understood about the neural structures that regulate sleep, but accumulating evidence suggests that the neuromodulator adenosine (AD) may be an important somnogen. The long-term goal of this research is to identify the neural pathways through which AD produces sleep. To evaluate this model, the investigator will determine the distribution and neurochemical phenotype of neurons producing AD receptor mRNA in the pre-optic area and basal forebrain (POA/BF) of rat brain using in situ hybridization histochemistry combined with immunohistochemistry for neurotransmitter-specific markers. To establish whether AD-responsive neurons directly project to the VLPO, he will combine injection of retrograde tracer into the VLPO with in situ hybridization histochemistry for AD receptor mRNA. He then will determine where in the POA/BF AD acts to produce sleep by micro-injecting adenosine agonists into sites known to produce AD receptors and polysomnographically recording sleep. He will examine the PO/BF using Fos as a marker of neuronal activation to determine if micro-injection of adenosine agonists activates the VLPO or other sleep-active populations. Finally, he will micro-inject AD antagonists into AF-sensitive sites to determine whether POA/BF AD is necessary mediator of normal sleep. These studies will provide important insights into the pre-optic and basal forebrain sites and mechanisms through which AD induces sleep.