Sleep and wakefulness are regulated for the most part by circadian and homeostatic processes. The homeostatic process is more powerful and can override circadian influences. The nature of the homeostatic process is unknown, but might be molecular in nature. Recent studies with the immediate-early gene, c-fos, have shown that this gene is expressed differentially in discrete brain regions in response to sleep and wakefulness. These findings have led to the hypothesis that c-fos might be representative of a molecular cascade that transduces a signal involving sleep. If this cascade is compromised, as with the application of c-fos antisense (which blocks new c-Fos protein synthesis), or in animals lacking the c-fos gene (null c-fos), then there should be less sleep. Our recent findings support this hypothesis. The proposed studies will examine whether the diminished sleep in aging might, in part, result from a decline in c-fos to AP-1 binding.
Four specific aims will directly test this hypothesis.
Specific aim 1 will test the hypothesis that old rats (24 months) show less sleep and slow wave activity (0.3-4.0 Hz) for a given amount of prior wakefulness compared to young rats (2 months). Rats will be kept awake (by gentle handling) for various time periods (0, 6, 12 hr) and then allowed recovery sleep. The investigators predict that young rats will have more sleep, including increased slow wave activity (0.3-4 Hz), compared to old rats.
Specific aim 2 will test the hypothesis that old (24 months) rats have reduced c-Fos and AP-1 binding in wake-active populations in the basal forebrain in response to wakefulness compared to young (2 months) rats. Rats will be kept awake as in Specific aim 1 and killed following 6, 12 hr of wakefulness. Immunohistochemistry and western blot assays will qualify c-fos levels. Gel-shift assays will examine the AP-1 complex in young vs. old rats.
Specific aim 3 will test the hypothesis that old rats demonstrate a reduced response to adenosine in the basal forebrain compared to young rats. Adenosine will be dialyzed in the basal forebrain in young and old rats and the increase in sleep will be measured. The investigators predict that for the same dose of adenosine, older rats will show less sleep compared to young.
Specific aim 4 will test the hypothesis that adenosine induces c-fos expression and resultant AP-1 binding in the basal forebrain. The investigators predict that the c-fos induction and AP-1 binding are much stronger in young versus old rats. Their preliminary results indicate that somnogens such as adenosine induce c-Fos (measured using immunohistochemistry and on tissue slices, and via western blot analysis of basal forebrain tissue homogenate) and AP-1.
| Blanco-Centurion, Carlos; Xu, Man; Murillo-Rodriguez, Eric et al. (2006) Adenosine and sleep homeostasis in the Basal forebrain. J Neurosci 26:8092-100 |
| Gerashchenko, D; Blanco-Centurion, C A; Miller, J D et al. (2006) Insomnia following hypocretin2-saporin lesions of the substantia nigra. Neuroscience 137:29-36 |
| Blanco-Centurion, C A; Shiromani, P J (2006) Beneficial effects of regular exercise on sleep in old F344 rats. Neurobiol Aging 27:1859-69 |
| Arias-Carrion, Oscar; Murillo-Rodriguez, Eric; Xu, Man et al. (2004) Transplantation of hypocretin neurons into the pontine reticular formation: preliminary results. Sleep 27:1465-70 |
| Shiromani, Priyattam J; Xu, Man; Winston, Elizabeth M et al. (2004) Sleep rhythmicity and homeostasis in mice with targeted disruption of mPeriod genes. Am J Physiol Regul Integr Comp Physiol 287:R47-57 |
| Gerashchenko, Dmitry; Chou, Thomas C; Blanco-Centurion, Carlos A et al. (2004) Effects of lesions of the histaminergic tuberomammillary nucleus on spontaneous sleep in rats. Sleep 27:1275-81 |
| Gerashchenko, Dmitry; Shiromani, Priyattam J (2004) Effects of inflammation produced by chronic lipopolysaccharide administration on the survival of hypocretin neurons and sleep. Brain Res 1019:162-9 |
| Blanco-Centurion, Carlos; Gerashchenko, Dmitry; Salin-Pascual, Rafael J et al. (2004) Effects of hypocretin2-saporin and antidopamine-beta-hydroxylase-saporin neurotoxic lesions of the dorsolateral pons on sleep and muscle tone. Eur J Neurosci 19:2741-52 |
| Gerashchenko, Dmitry; Shiromani, Priyattam J (2004) Different neuronal phenotypes in the lateral hypothalamus and their role in sleep and wakefulness. Mol Neurobiol 29:41-59 |
| Desarnaud, Frank; Murillo-Rodriguez, Eric; Lin, Ling et al. (2004) The diurnal rhythm of hypocretin in young and old F344 rats. Sleep 27:851-6 |
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