Faculty Profile

Ritchie Edward Brown, PhD

Ritchie Edward Brown, PhD
Associate Professor of Psychiatry, Harvard Medical School
Associate Professor, Department of Psychiatry, VA Boston Healthcare System

See publications


Address

VAMC Brockton, Laboratory of Neuroscience
940 Belmont St. Research 151-C
Brockton, MA 02301
USA

Email ritchie_brown@hms.harvard.edu

Society Memberships

Sleep Research Society
Society for Neuroscience

Research Unit(s)

Head of the in vitro neurophysiology section of the Laboratory of Neuroscience, Department of Psychiatry, VA Boston Healthcare System

Research Interests

The changes in brain physiology which occur over the course of the sleep-wake cycle are controlled by a small number of neurotransmitter systems located in the basal forebrain, hypothalamus and brainstem. These neurotransmitter systems precisely regulate each other as well as the function of the rest of the brain through diffuse and widespread projections. As well as explaining how the sleep-wake cycle operates, investigation of these systems gives insight into mechanisms controlling consciousness, emotion and autonomic function. Drugs which modulate the function of these neurotransmitter systems are widely used for the treatment of many major neurological and psychiatric conditions such as major depression and schizophrenia.

The focus of this investigators’ research program has been to characterize the interactions between these systems and their effects in target regions using in vitro electrophysiological techniques in combination with anatomical and molecular biological methods. Recordings directly from neurons involved in behavioral state control are made using the whole-cell patch-clamp technique in brain slices containing the region of interest. In vitro techniques allow a precise determination of the effects of exogeneously applied neurotransmitters on the membrane potential, ionic currents and firing of the neurons. Furthermore, the receptors, signal transduction mechanisms and effector systems involved can be elucidated. Anatomical techniques can be used in concert with intracellular recording to determine the neurotransmitter identity and morphology of the recorded cells whilst single-cell PCR experiments allow the detection of cloned receptors or effectors for which pharmacological tools are not available.

Current projects:
1) Investigation of mechanisms underlying narcolepsy. Characterization of the effect of orexins/hypocretin on neurons involved in control of the sleep-wake cycle. This neurotransmitter system degenerates in the disease, narcolepsy. Experimental animals lacking orexins or the type II orexin receptor have phenotypes resembling human narcolepsy, with fragmentation of the sleep-wake cycle and periods of behavioural arrest or cataplexy following emotional arousal. Orexins were undetectable in the CSF of many human patients and examination of postmortem narcoleptic brains has provided evidence for degeneration of the orexin neurons.
2) Investigation and characterization of a novel tool for investigation of GABAergic neurons involved in the control of sleep-wake, the GAD67-GFP knock-in mouse. In these mice we are able to selectively target and record from identified GABAergic neurons in the brainstem and basal forebrain for the first time. This allows us to determine their intrinsic electrical properties and their responses to neurotransmitters involved in behavioral state control such as the orexins.
3) Development of an in vitro mouse model of gamma-band EEG abnormalities seen in schizophrenia. Field potential and intracellular recordings from identified GABAergic neurons are made from slices of prefrontal cortex (rodent homologue of the human dorsolateral cortex)  maintained in vitro. Brief focal applications of kainate to the slice are used to generate gamma rhythms. The effects of acute or chronic NMDA receptor blockade (hypothesized to be a trigger for schizophrenia) on the gamma rhythms are being tested.

Trainees

Chun Yang, PhD 2010-present
Serena Franciosi BS 2006-2007
Jaime L. Tartar, PhD 2004-2006
Tatiana Korotkova 2000-2002

Mentor(s)


Research Funding

CURRENT

Competitive Revision supplement of RO1 MH040799 (Neurophysiological studies of schizophrenia; Funded 8/30/07-6/30/12). Supplement funded 10/2009 to 9/2011. 2009-present
In vitro study of gamma oscillations and modulation by NMDA receptors.
Principal Investigator: Robert W. McCarley
Role: Investigator

VA Schizophrenia Center grant, project 3. 2007-present
Modeling Schizophrenic Cortical Circuitry In Vitro: GABA Abnormalities.
Principal Investigator: Robert W. McCarley
Role: Investigator

VA Merit (2007-2011) 2007-present
Orexinergic and GABAergic mechanisms of REM sleep control.
Principal Investigator: Robert W. McCarley
Brainstem control of REM sleep via orexins and GABA.
Role: Investigator

NIMH R37 MH39683 (9/1/1987-4/30/12) 2005-present
Synaptic Basis of Sleep Cycle Control (MERIT Award, fourth 5 year approval)
Principal Investigator: Robert W. McCarley, M.D.
Cholinergic and adenosinergic mechanisms of sleep.
Role: Investigator

PAST

Veterans Administration Merit Review (RO1 equivalent in VA) 2004-2008   
Principal Investigator: Robert Strecker
Adenosine and the Basal Forebrain in the Control of Behavioral State
Rat model of obstructive sleep apnea using concurrent exposure to intermittent hypoxia and sleep fragmentation.
Role: Investigator

NHLB (2 P50 HLO60292) 2003-2008
Harvard Center on Sleep Neurobiology and Sleep Apnea
Principal Investigator: Clif Saper, MD
Project 2: Behavioral & Neurobiological Consequences of Obstructive Sleep Apnea
Principal Investigator: Robert Strecker
Role: Investigator

NIMH R01 MH62522 (03/01/01 - 02/28/06). 2002-2006
Orexin and the Control of Sleep and Wakefulness.
Principal Investigator: Robert W. McCarley
Physiological and pharmacological mechanisms by which orexin modulates behavioral state.
Role: Investigator

Research Committee of the Heinrich-Heine University, Duesseldorf. 2000-2002
Grant 9772 111
Role: Principal Investigator
"Plasticity of Glutamatergic Synaptic Transmission in the Dorsal Raphe Nucleus"

Selected Publications

Chen L, McKenna JT, Leonard MZ, Yanagawa Y, McCarley RW, Brown RE. GAD67-GFP knock-in mice have normal sleep-wake patterns and sleep homeostasis.
Neuroreport. 2010 Jan 4. [Epub ahead of print] [PMID: 20051926]

Tartar JL, McKenna JT, Ward CP, McCarley RW, Strecker RE, Brown RE. Sleep fragmentation reduces hippocampal CA1 pyramidal cell excitability and response to adenosine.

Neurosci Lett. 2009 Nov 13. [Epub ahead of print] [PMID: 19914331]

Brown RE, McKenna JT, Winston S, Basheer R, Yanagawa Y, Thakkar MM, McCarley RW. Characterization of GABAergic neurons in rapid-eye-movement sleep controlling regions of the brainstem reticular formation in GAD67-green fluorescent protein knock-in mice.

Eur J Neurosci. 2008 Jan;27(2):352-63. [PMID: 18215233]

Brown RE, Winston S, Basheer R, Thakkar MM, McCarley RW. Electrophysiological
characterization of neurons in the dorsolateral pontine rapid-eye-movement sleep
induction zone of the rat: Intrinsic membrane properties and responses to carbachol and orexins.

Neuroscience. 2006 Dec;143(3):739-55. Epub 2006 Sep 26. [PMID: 17008019]

Korotkova TM, Brown RE, Sergeeva OA, Ponomarenko AA, Haas HL. Effects of arousal- and feeding-related neuropeptides on dopaminergic and GABAergic neurons in the ventral tegmental area of the rat.

Eur J Neurosci. 2006 May;23(10):2677-85. Erratum in: Eur J Neurosci. 2006 Jun;23(12):3407. [PMID: 16817870]

Tartar JL, Ward CP, McKenna JT, Thakkar M, Arrigoni E, McCarley RW, Brown RE,  Strecker RE. Hippocampal synaptic plasticity and spatial learning are impaired in a rat model of sleep fragmentation.

Eur J Neurosci. 2006 May;23(10):2739-48.[PMID: 16817877]

Basheer R, Brown R, Ramesh V, Begum S, McCarley RW. Sleep deprivation-induced
protein changes in basal forebrain: implications for synaptic plasticity.

J Neurosci Res. 2005 Dec 1;82(5):650-8. [PMID: 16273548]

Selbach O, Doreulee N, Bohla C, Eriksson KS, Sergeeva OA, Poelchen W, Brown RE, Haas HL. Orexins/hypocretins cause sharp wave- and theta-related synaptic plasticity in the hippocampus via glutamatergic, gabaergic, noradrenergic, and cholinergic signaling. Neuroscience. 2004;127(2):519-28. [PMID: 15262340]


Sergeeva OA, Korotkova TM, Scherer A, Brown RE, Haas HL. Co-expression of non-selective cation channels of the transient receptor potential canonical family in central aminergic neurones.
J Neurochem. 2003 Jun;85(6):1547-52. [PMID: 12787073]


Korotkova TM, Sergeeva OA, Eriksson KS, Haas HL, Brown RE. Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins.
J Neurosci. 2003 Jan 1;23(1):7-11. [PMID: 12514194]


Brown RE, Sergeeva OA, Eriksson KS, Haas HL. Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline).
J Neurosci. 2002 Oct 15;22(20):8850-9.
[PMID: 12388591]

Korotkova TM, Eriksson KS, Haas HL, Brown RE. Selective excitation of GABAergic neurons in the substantia nigra of the rat by orexin/hypocretin in vitro.
Regul Pept. 2002 Mar 15;104(1-3):83-9. [PMID: 11830281]


Korotkova TM, Haas HL, Brown RE. Histamine excites GABAergic cells in the rat substantia nigra and ventral tegmental area in vitro.
Neurosci Lett. 2002 Mar 8;320(3):133-6. [PMID: 11852180]


Eriksson KS, Sergeeva O, Brown RE, Haas HL. Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus.
J Neurosci. 2001 Dec 1;21(23):9273-9. [PMID: 11717361]


Doreulee N, Brown RE, Yanovsky Y, Godecke A, Schrader J, Haas HL. Defective hippocampal mossy fiber long-term potentiation in endothelial nitric oxide synthase knockout mice.
Synapse. 2001 Sep 1;41(3):191-4. [PMID: 11391779]


Brown RE, Sergeeva O, Eriksson KS, Haas HL. Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat.
Neuropharmacology. 2001 Mar;40(3):457-9. [PMID: 11166339]


Doreulee N, Yanovsky Y, Flagmeyer I, Stevens DR, Haas HL, Brown RE. Histamine H(3) receptors depress synaptic transmission in the corticostriatal pathway.
Neuropharmacology. 2001;40(1):106-13. [PMID: 11077076]


Brown RE, Haas HL. On the mechanism of histaminergic inhibition of glutamate release in the rat dentate gyrus.
J Physiol. 1999 Mar 15;515 ( Pt 3):777-86. [PMID: 10066904]


Wilson RI, Godecke A, Brown RE, Schrader J, Haas HL. Mice deficient in endothelial nitric oxide synthase exhibit a selective deficit in hippocampal long-term potentiation.
Neuroscience. 1999;90(4):1157-65. [PMID: 10338286]


Manahan-Vaughan D, Reymann KG, Brown RE. In vivo electrophysiological investigations into the role of histamine in the dentate gyrus of the rat.
Neuroscience. 1998 Jun;84(3):783-90. [PMID: 9579783]


Selbach O, Brown RE, Haas HL. Long-term increase of hippocampal excitability by histamine and cyclic AMP.
Neuropharmacology. 1997 Nov-Dec;36(11-12):1539-48. [PMID: 9517424]


Fedorov NB, Brown RE, Reymann KG. Fast increases of AMPA receptor sensitivity following tetanus-induced potentiation in the CA1 region of the rat hippocampus.
Neuroreport. 1997 Jan 20;8(2):411-4. [PMID: 9080418]


Brown RE, Reymann KG. Histamine H3 receptor-mediated depression of synaptic transmission in the dentate gyrus of the rat in vitro.
J Physiol. 1996 Oct 1;496 ( Pt 1):175-84. [PMID: 8910206]


Brown RE, Reymann KG. Class I metabotropic glutamate receptor agonists do not facilitate the induction of long-term potentiation in the dentate gyrus of the rat in vitro.
Neurosci Lett. 1995 Dec 29;202(1-2):73-6. [PMID: 8787834]


Brown RE, Reymann KG. Metabotropic glutamate receptor agonists reduce paired-pulse depression in the dentate gyrus of the rat in vitro.
Neurosci Lett. 1995 Aug 18;196(1-2):17-20. [PMID: 7501246]


Brown RE, Fedorov NB, Haas HL, Reymann KG. Histaminergic modulation of synaptic plasticity in area CA1 of rat hippocampal slices.
Neuropharmacology. 1995 Feb;34(2):181-90. [PMID: 7617144]


Brown RE, Rabe H, Reymann KG. (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) does not block theta burst-induced long-term potentiation in area CA1 of rat hippocampal slices.
Neurosci Lett. 1994 Mar 28;170(1):17-21. [PMID: 8041499]

Reviews, Books, and Chapters

McKenna, Brown RE, McCarley RW. Neuroanatomy and neurobiology of sleep and wakefulness. Chapter X
In: Foundations of Psychiatric Sleep Medicine. Plante DT, Winkelman J (Eds.), 2010. Cambridge University Press, UK. In press

Chen L, Brown RE, McKenna JT, McCarley RW. Animal models of narcolepsy.
CNS Neurol Disord Drug Targets. 2009 Aug;8(4):296-308. [PMID: 19689311]

Brown RE, McCarley RW. Neuroanatomical and neurochemical basis of wakefulness and REM sleep systems. Chapter 2 (pp23-58)

In: Neurochemistry of Sleep and Wakefulness. Monti JM, Pandi-Perumal SR, Sinton CM (Eds.), 2008, Cambridge University Press, Cambridge, UK. ISBN 978-0-521-86441-1.

Brown RE, McCarley RW. Neurotransmitters, Neuromodulators and Sleep. Chapter 3 (pp 45-75)

In: The Physiological Nature of Sleep. Parmeggiani PL, Velluti RA (Eds.), 2005. Imperial College Press, London, UK. ISBN 1-86094-557-0.

Korotkova TM, Ponomarenko AA, Brown RE, Haas HL. Functional diversity of ventral midbrain dopamine and ABAergic neurons.
Mol Neurobiol. 2004 Jun;29(3):243-59. Review. [PMID: 15181237]

Brown RE. Involvement of hypocretins/orexins in sleep disorders and narcolepsy.
Drug News Perspect. 2003 Mar;16(2):75-9. Review. [PMID: 12792667]

Stevens DR, Eriksson KS, Brown RE, Haas HL. The mechanism of spontaneous firing in histamine neurons.
Behav Brain Res. 2001 Oct 15;124(2):105-12. Review. [PMID: 11640962]

Brown RE, Stevens DR, Haas HL. The physiology of brain histamine.
Prog Neurobiol. 2001 Apr;63(6):637-72. Review. [PMID: 11164999]


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