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.
| Gledhill, Richard F; Bartel, Peter R; Yoshida, Yasushi et al. (2004) Narcolepsy caused by acute disseminated encephalomyelitis. Arch Neurol 61:758-60 |
| Ko, Emily M; Estabrooke, Ivy V; McCarthy, Marie et al. (2003) Wake-related activity of tuberomammillary neurons in rats. Brain Res 992:220-6 |
| Scammell, Thomas E (2003) The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 53:154-66 |
| Chou, Thomas C; Scammell, Thomas E; Gooley, Joshua J et al. (2003) Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms. J Neurosci 23:10691-702 |
| Llewellyn-Smith, I J; Martin, C L; Marcus, J N et al. (2003) Orexin-immunoreactive inputs to rat sympathetic preganglionic neurons. Neurosci Lett 351:115-9 |
| Scammell, Thomas E; Arrigoni, Elda; Thompson, Margaret A et al. (2003) Focal deletion of the adenosine A1 receptor in adult mice using an adeno-associated viral vector. J Neurosci 23:5762-70 |
| Chou, Thomas C; Bjorkum, Alvhild A; Gaus, Stephanie E et al. (2002) Afferents to the ventrolateral preoptic nucleus. J Neurosci 22:977-90 |
| Scammell, T E; Gerashchenko, D Y; Mochizuki, T et al. (2001) An adenosine A2a agonist increases sleep and induces Fos in ventrolateral preoptic neurons. Neuroscience 107:653-63 |
| Estabrooke, I V; McCarthy, M T; Ko, E et al. (2001) Fos expression in orexin neurons varies with behavioral state. J Neurosci 21:1656-62 |
| Chou, T C; Lee, C E; Lu, J et al. (2001) Orexin (hypocretin) neurons contain dynorphin. J Neurosci 21:RC168 |
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