Faculty Profile

Irma Rukhadze, PhD

Irma Rukhadze, PhD
Instructor in Neurology, Harvard Medical School
Systems Neuroscientist, Division of Sleep Medicine, Department of Neurology, Beth Israel Deaconess Medical Center

See publications


Inter-office Mail Address

330 Brookline Ave. E/CLS 7/716

Phone 617-735-3258
Fax 617-735-3249

Email irukhadz@bidmc.harvard.edu

Society Memberships

Sleep Research Society
Federation of European Neuroscience Societies
International Brain Research Organization

Research Unit(s)

Systems Neurobiology Group (Saper)
Beth Israel Deaconess Medical Center, Harvard Medical School

Research Interests

In obstructive sleep apnea (OSA) patients, suppression of upper airway muscles activity during sleep, and especially during rapid-eye-movement (REM) sleep, leads to partial orifice reduction or complete closure of the upper airway. During the resulting hypopneic/apneic episodes, concentration of blood oxygen levels decrease (hypoxia) in parallel with accumulation of CO2 (hypercapnia). The airway obstruction episodes are terminated by awakenings that are mainly caused by the buildup of CO2. Repeated hypoxia and frequent awakenings of OSA patients cause sleep fragmentation/deprivation and a spectrum of morbid cognitive and metabolic disorders.

My research is primarily focused on the neural basis of sleep related hypotonia of upper airway muscles. We found that sleep-related withdrawal of noradrenergic and serotonergic excitatory drive to upper airway muscles is the main cause of upper airway obstructions during sleep. Using anatomic, physiologic and molecular techniques we have determined the origin of the excitatory noradrenergic and cholinergic drive to hypoglossal motoneurons that innervate the genioglossus, the major upper airway dilator muscle. We have determined that A7 neurons are most likely the pontine noradrenergic neurons which control state-dependent activity of hypoglossal motoneurons using an acute rodent model of REM sleep. We have found that chronic intermittent hypoxia, a major component of OSA pathogenesis, increases noradrenergic and to a lesser extent serotonergic terminal density in the ventromedial region of the hypoglossal nucleus, where the genioglossus motoneurons are located. We also determined that the time course of genioglossus electromyographic changes during sleep is quantitatively different from that of the postural muscles in chronically instrumented, behaving rats.

Currently I am investigating neural mechanisms of hypercapnia-mediated respiratory arousal in normal and conditional knockout mice. In these experiments, we employ adeno-associated viral vectors that contain Cre recombinase to delete neurochemically specific populations in cre-dependent knockout mice. Used techniques include stereotaxic microinjections, tract tracing, chronic recordings of sleep and respiratory muscles activity, designer receptors exclusively activated by designer drugs, in situ hybridization, immunohistochemistry.

My research goals are to reveal neuronal mechanisms that underlie both the suppression of upper airway muscles activity during sleep and the hypercapnia-induced arousal. It is my conviction that obtained knowledge will provide a better understanding of the neural mechanisms of OSA pathophysiology that may result in novel and highly effective therapies for OSA patients.

Trainees

Sandra Song, UPenn student, 2005-2006
Xiao Han, UPenn student, 2006-2007
Andrea Price, UPenn, MD candidate 2008-2009
Kimberly Mann, UPenn,VMD, 2008-2009
Julie Kalter, UPenn undergraduate, 2009-2010
Cher Hung, UPenn undergraduate, 2010-2011
Chun-Yu Chen, MD, PhD, Yang-Ming University, 2013
Otari Chipashvili, BA, University of Massachusetts, 2013

Research Funding

Sleep Research Society Foundation, J. Christian Gillin, M.D. Research Grant
(PI: Rukhadze) 09/01/2013-09/01/2014
The role of medullary A1/C1 neurons in control of state-dependent activity of genioglossus muscle in behaving mice.

NIH/NHLBI PO1 HL-095491 (PI: Chamberlin) 02/01/2010-01/31/2015
“Mechanisms of State Switching in Sleep and Sleep Apnea: Role of the Parabrachial complex in respiratory Arousal (Project 5).”
The goal of this study is to investigate the neuronal circuitry that underlies hypercapnia induced respiratory arousal during sleep.
Role: Investigator

NIH/NHLBI RO1 HL-71097-05 (PI: Kubin) 07/01/2008-05/31/2012
“Hypothalamo-brainstem control of sleepiness and arousal.”
An in-vivo and neuroanatomical study of the role of GABA in the control of hypothalamic neurons important for the regulation of sleep and cardiorespiratory consequences of sleepiness.
Role: Investigator (till 01/31/2012)

NIH/NHLBI RO1 HL-47600-16 (PI: Kubin) 12/01/2004-08/30/2013
“Premotor control of upper airway and REM sleep atonia.”
The goal of the study is to characterize anatomically and neurochemically the pontomedullary network responsible for the REM sleep state-dependent depression of upper airway motor tone.
Role: Investigator (till 01/31/2012)

NIH/NHLBI R21 HL-092962-01  (PI: Kubin) 04/01/2009-03/31/2011
“A rodent model of compromised upper airway.”
A major goal of this project is to determine whether, in rats, a surgical intervention that eliminates muscular support that the genioglossus muscle receives from its synergists results in chronically increased genioglossus muscle tone and begin to investigate the neural basis of this adaptation.
Role: Investigator.

Teaching

Human Systems-Respiratory (IN757.RES) at Harvard Medical School

Selected Publications

Research Articles

Rukhadze I, Kamani H, Kubin L. Quantitative differences among EMG activities of muscles innervated by subpopulations of hypoglossal and upper spinal motoneurons during non-REM sleep - REM sleep transitions: a window on neural processes in the sleeping brain.
Arch Ital Biol. 2011 Dec 1;149(4):499-515. doi: 10.4449/aib.v149i4.1385. [PMID: 22205596]

Mody P, Rukhadze I, Kubin L. Rats subjected to chronic-intermittent hypoxia have increased density of noradrenergic terminals in the trigeminal sensory and motor nuclei.
Neurosci Lett. 2011 Nov 14;505(2):176-9. Epub 2011 Oct 13. [PMID: 22015761]

Rukhadze I, Fenik VB, Benincasa KE, Price A, Kubin L. Chronic intermittent hypoxia alters density of aminergic terminals and receptors in the hypoglossal motor nucleus. Am J Respir Crit Care Med. 2010 Nov 15;182(10):1321-9. Epub 2010 Jul 9. [PMID: 20622040]

Fenik, VB, Rukhadze, I, and Kubin, L. 2009. Antagonism of alpha(1)-adrenergic and serotonergic receptors in the hypoglossal motor nucleus does not prevent motoneuronal activation elicited from the posterior hypothalamus.
Neurosci. Lett. 462: 80-84.

Fenik VB, Rukhadze I, Kubin L. Inhibition of pontine noradrenergic A7 cells reduces hypoglossal nerve activity in rats.
Neuroscience. 2008 Nov 19;157(2):473-82. Epub 2008 Sep 11. [PMID: 18838113]

Rukhadze I, Fenik VB, Branconi JL, Kubin L. Fos expression in pontomedullary catecholaminergic cells following rapid eye movement sleep-like episodes elicited by pontine carbachol in urethane-anesthetized rats.
Neuroscience. 2008 Mar 3;152(1):208-22. [PMID: 18155849]

Volgin DV, Rukhadze I, Kubin L. Hypoglossal premotor neurons of the intermediate medullary reticular region express cholinergic markers.
J Appl Physiol. 2008 Nov;105(5):1576-84. Epub 2008 Sep 4. [PMID: 18772326]

Lu JW, Fenik VB, Branconi JL, Mann GL, Rukhadze I, Kubin L. Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks pontine carbachol-induced REM sleep-like episodes in rats.
J Physiol. 2007 Jul 15;582(Pt 2):553-67. Epub 2007 May 10. [PMID: 17495048]

Rukhadze I, Kubin L. Differential pontomedullary catecholaminergic projections to hypoglossal motor nucleus and viscerosensory nucleus of the solitary tract.
J Chem Neuroanat. 2007 Jan;33(1):23-33. Epub 2006 Nov 28. [PMID: 17134870]

Rukhadze I, Kubin L. Mesopontine cholinergic projections to the hypoglossal motor nucleus.
Neurosci Lett. 2007 Feb 14;413(2):121-5. Epub 2006 Dec 14. [PMID: 17174027]

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