Faculty Profile

Paul A. Rosenberg, MD, PhD


Associate Professor of Neurology, Harvard Medical School
Senior Associate in Neurology, Department of Neurology, Children's Hospital Boston
Staff Physician, Department of Neurology, Beth Israel Deaconess Medical Center

Administrative Title(s)

Assistant Director, Neurobiology Program, Department of Neurology, Children’s Hospital

See publications


Address

300 Longwood Ave
Boston, MA 02115
USA

Inter-office Mail Address

Enders 349
Department of Neurology
Children’s Hospital

Phone 617-355-6962
Fax 617-730-0243

Email paul.rosenberg@childrens.harvard.edu

Society Memberships

Sleep Research Society
Society for Neuroscience
International Society for Neurochemistry
Society of General Physiologists
American Society for Cell Biology
American Society for Biochemistry and Molecular Biology

Research Interests

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.

Trainees

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-

Research Funding

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)

Selected Publications

Kabakov AY, Rosenberg PA. Evidence for change in current-flux coupling of GLT1 at high glutamate concentrations in rat primary forebrain neurons and GLT1a-expressing COS-7 cells.
Eur J Neurosci. 2009 Jul;30(2):186-95. Epub 2009 Jul 9. [PMID: 19614985]

Li J, Wang H, Rosenberg PA. Vitamin K prevents oxidative cell death by inhibiting activation of 12-lipoxygenase in developing oligodendrocytes.
J Neurosci Res. 2009 Jul;87(9):1997-2005. [PMID: 19235890]

Gerstner B, Lee J, DeSilva TM, Jensen FE, Volpe JJ, Rosenberg PA. 17beta-estradiol protects against hypoxic/ischemic white matter damage in the neonatal rat brain.
J Neurosci Res. 2009 Jul;87(9):2078-86. [PMID: 19224575]

DeSilva TM, Kabakov AY, Goldhoff PE, Volpe JJ, Rosenberg PA. Regulation of glutamate transport in developing rat oligodendrocytes.
J Neurosci. 2009 Jun 17;29(24):7898-908. [PMID: 19535601]

Li J, Ramenaden ER, Peng J, Koito H, Volpe JJ, Rosenberg PA. Tumor necrosis factor alpha mediates lipopolysaccharide-induced microglial toxicity to developing oligodendrocytes when astrocytes are present.
J Neurosci. 2008 May 14;28(20):5321-30. [PMID: 18480288]

Desilva TM, Billiards SS, Borenstein NS, Trachtenberg FL, Volpe JJ, Kinney HC, Rosenberg PA. Glutamate transporter EAAT2 expression is up-regulated in reactive astrocytes in human periventricular leukomalacia.
J Comp Neurol. 2008 May 10;508(2):238-48. [PMID: 18314905]

van Leyen K, Arai K, Jin G, Kenyon V, Gerstner B, Rosenberg PA, Holman TR, Lo EH. Novel lipoxygenase inhibitors as neuroprotective reagents.
J Neurosci Res. 2008 Mar;86(4):904-9. [PMID: 17960827; [Central PMCID: PMC2759176]

Gerstner B, DeSilva TM, Genz K, Armstrong A, Brehmer F, Neve RL, Felderhoff-Mueser U, Volpe JJ, Rosenberg PA. Hyperoxia causes maturation-dependent cell death in the developing white matter.
J Neurosci. 2008 Jan 30;28(5):1236-45. [PMID: 18234901]

Bassan M, Liu H, Madsen KL, Armsen W, Zhou J, Desilva T, Chen W, Paradise A, Brasch MA, Staudinger J, Gether U, Irwin N, Rosenberg PA. Interaction between the glutamate transporter GLT1b and the synaptic PDZ domain protein PICK1.
Eur J Neurosci. 2008 Jan;27(1):66-82. [PMID: 18184314]

Lu Y, Rosenberg PA. NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors.
Brain Res. 2007 Jun 25;1155:116-24. Epub 2007 May 4. [PMID: 17509540]

Gerstner B, Sifringer M, Dzietko M, Schüller A, Lee J, Simons S, Obladen M, Volpe JJ, Rosenberg PA, Felderhoff-Mueser U. Estradiol attenuates hyperoxia-induced cell death in the developing white matter.
Ann Neurol. 2007 Jun;61(6):562-73. [PMID: 17427919]

Desilva TM, Kinney HC, Borenstein NS, Trachtenberg FL, Irwin N, Volpe JJ, Rosenberg PA. The glutamate transporter EAAT2 is transiently expressed in developing human cerebral white matter.
J Comp Neurol. 2007 Apr 20;501(6):879-90. [PMID: 17311320]

Redman PT, He K, Hartnett KA, Jefferson BS, Hu L, Rosenberg PA, Levitan ES, Aizenman E. Apoptotic surge of potassium currents is mediated by p38 phosphorylation of Kv2.1.
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3568-73. Epub 2007 Feb 20. [PMID: 17360683]

Deng W, Neve RL, Rosenberg PA, Volpe JJ, Jensen FE. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit composition and cAMP-response element-binding protein regulate oligodendrocyte excitotoxicity.
J Biol Chem. 2006 Nov 24;281(47):36004-11. Epub 2006 Sep 21. [PMID: 16990276]

Arrigoni E, Rosenberg PA. Nitric oxide-induced adenosine inhibition of hippocampal synaptic transmission depends on adenosine kinase inhibition and is cyclic GMP independent.
Eur J Neurosci. 2006 Nov;24(9):2471-80. [PMID:17100836]

Kalinchuk AV, Lu Y, Stenberg D, Rosenberg PA, Porkka-Heiskanen T. Nitric oxide production in the basal forebrain is required for recovery sleep.
J Neurochem. 2006 Oct;99(2):483-98. [PMID: 17029601]

Kalinchuk AV, Stenberg D, Rosenberg PA, Porkka-Heiskanen T. Inducible and neuronal nitric oxide synthases (NOS) have complementary roles in recovery sleep induction.
Eur J Neurosci. 2006 Sep;24(5):1443-56. [PMID: 16987226]

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]

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]

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]

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]

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]

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]

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.

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

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

Reviews

Zhang Y, Aizenman E, DeFranco DB, Rosenberg PA. Intracellular zinc release, 12-lipoxygenase activation and MAPK dependent neuronal and oligodendroglial death.
Mol Med. 2007 Jul-Aug;13(7-8):350-5. Review. [PMID: 17622306]

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

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