Faculty Profile

Adenosine is an important endogenous regulator of behavioral state, and we have been motivated to understand how extracellular levels of adenosine are regulated at a biochemical and molecular level by the idea that if we come to understand how extracellular adenosine is regulated, we will gain important insight into the basic cellular, biochemical and molecular mechanisms underlying the control of sleeping and waking.  We observed that nitric oxide evokes extracellular adenosine accumulation in cultured forebrain neurons, generating the hypothesis that nitric oxide is released in the basal forebrain from local nitric oxide synthase containing neurons as well as projections from the laterodorsal tegmental nucleus, an important wake and REM active nucleus known to express high levels of neuronal nitric oxide synthase, causing the accumulation of adenosine in waking that leads to the drive to sleep.

In collaboration with Dr. Tarja Porkka-Heiskanen, we tested the role of nitric oxide (NO) in sleep homeostasis by using in vivo microdialysis to administer compounds into the rat basal forebrain that increase or decrease concentrations of NO.  Consistent with our hypothesis, we found that nitric oxide production is required for the production of NREM recovery sleep following sleep deprivation.  However, using specific inhibitors of nitric oxide synthases, we found that iNOS rather than nNOS produced the nitric oxide involved in homeostatic sleep regulation.  The generation of NREM recovery sleep was tightly associated with increases in adenosine levels in the BF: when adenosine concentration was not elevated, recovery sleep was not induced while all cases of recovery sleep induction were preceded by adenosine increases.  These results suggest that the elevation of NO in the BF during prolonged wakefulness is a specific mechanism for producing NREM recovery sleep.  We are now interested in the cellular sources of nitric oxide activated by sleep deprivation, the mechanisms of their activation, and the cellular and molecular targets of nitric oxide generated in response to sleep deprivation.

Bassan Merav, PhD, 2001- ; Baud Olivier, MD, 2002-2003; Boll Michael, PhD, 2002-2003 Chen Li, PhD, 2003- ; Chen Weizhi, MD, 1997-2002; Andreeva Svetlana, PhD, 1999-2002 Chung Hye Joo, PhD, 1996-1997;  DeSilva Tara, PhD, 2001-; Kabakov Anatolii, PhD, 2001-

P50 HL60292  (P.I.: Clif Saper) 9/1/03-8/31/08
NIH/NHLBI (Harvard Center on Sleep Neurobiology and Sleep Apnea)
Project 3: Nitric oxide and the Regulation of Behavioral State (P.I. Rosenberg)   
This is one of 6 projects in a SCOR.  The aim of this project is to study the role of nitric oxide in the regulation of behavioral state, using in vivo microdialysis, neuroanatomical methods, and electrophysiology.
Neuron-glial interactions (quarter course; with Gabriel Corfas)

Rosenberg, P.A., and Dichter, M.A. Extracellular cAMP accumulation and degradation in rat cerebral cortex in dissociated cell culture.
J Neurosci 1989. 9: 2654-2663. [PMID: 2549217]

Rosenberg, P.A., Knowles, R., Knowles, K.P., and Li Y. Beta-adrenergic receptor mediated regulation of extracellular adenosine in cerebral cortex in culture.
J Neurosci 1994; 14: 2953-2965. [PMID: 8182451]

Rosenberg, P.A. and Li, Y. Adenylyl cyclase activation underlies intracellular cyclic AMP accumulation, cyclic AMP transport, and extracellular adenosine accumulation evoked by  beta-adrenergic receptor stimulation in mixed cultures of neurons and astrocytes derived from cerebral cortex. 
Brain Res 1995; 692: 227-232. [PMID: 8548307]

Rosenberg, P.A. and Li, Y. 1995. Vasoactive intestinal peptide regulates extracellular adenosine levels in rat cortical cultures.
Neurosci Lett 1995; 200: 93-96. [PMID: 8614571]

Rosenberg, P.A., and Li, Y.  Forskolin evokes extracellular adenosine accumulation in rat cortical cultures. 
Neurosci Lett 1996; 211: 49-52. [PMID: 8809845]

Pawlikowska, L., Cottrell, S.E., Harms, M.B., and Rosenberg, P.A. Extracellular synthesis of cyclic adenosine diphospho-ribose from NAD by rat cortical astrocytes in culture.
J Neurosci 1996; 16: 5372-5381.

Wang, T.F., Rosenberg, P.A., and Guidotti, G. Characterization of brain ecto-apyrase: evidence for only one ecto-apyrase (CD39) gene.
Mol Brain Res 1997; 47: 295-302. [PMID: 9221928]

Rosenberg, P.A., Zhang, Y., Li, Y., and Le, M. Nitric oxide stimulated increase in extracellular adenosine accumulation in rat forebrain neurons in culture is associated with ATP hydrolysis and inhibition of adenosine kinase activity.
J Neurosci  2000; 20: 6294-6301. [PMID: 10934281]

Andreeva, S.G., Dikkes, P., Epstein, P.M., and Rosenberg, P.A. Expression of cGMP specific phosphodiesterase 9a mRNA in the rat brain.
J Neurosci 2001; 21: 9068-9076. [PMID: 11698617]

Lu, Y., Chung, H. J., Li, Y., and Rosenberg, P. A. NMDA receptor-mediated extracellular adenosine accumulation in rat forebrain neurons in culture is associated with inhibition of adenosine kinase.
Eur J Neurosci 2003; 17: 1213-1222. [PMID: 12670309]

Lu, Y., Li, Y., Herin, G. A., Aizenman, E., Epstein, P. M., and Rosenberg, P. A. Elevation of intracellular cAMP evokes activity-dependent release of adenosine in cultured rat forebrain neurons.
Eur J Neurosci 2004; 19:2669-2681. [PMID: 15147301]

Le, M. Li, Y. Greene, R.W. Epstein, P.M. Rosenberg, P.A. Zaprinast stimulates extracellular adenosine accumulation in rat pontine slices.
Neurosci Lett 2004;371:12-17. [PMID: 15500958]

Kalinchuk, A.V., Lu, Y., Stenberg, D., Rosenberg, P.A., Porkka-Heiskanen, T. Nitric oxide production in the basal forebrain is required for recovery sleep.
J Neurochem; accepted, June, 16, 2006. [PMID: 17029601]

Kalinchuk, A.V., Lu, Y., Stenberg, D., Rosenberg, P.A., Porkka-Heiskanen, T. Inducible and neuronal nitric oxide have complementary roles in homeostatic sleep regulation.
Eur J Neurosci; accepted, June 26, 2006.

Reviews

Rosenberg, P.A. 1992. Functional significance of cyclic AMP secretion in cerebral cortex.
Brain Research Bulletin. 29: 315-318. [PMID: 1327421]