Faculty Profile

Stephen Thankachan, PhD

S_Thankachan 201705
Instructor in Psychiatry, Harvard Medical School
Research Scientist, Department of Neurology, VA Boston Healthcare System

See publications


Address

VA Medical Center, Research
1400 VFW Parkway, Bldg3, 2B112,
West Roxbury, MA 02132
USA

Email stephen_thankachan@hms.harvard.edu

Society Memberships

Canadian Association of Neuroscience
Sleep Research Society
Society for Neuroscience

Research Unit(s)

Invivo Electrophysiology at Neuroscience Laboratory (Dr. Robert W. McCarley),
Division of Sleep Medicine

Research Interests

My research interest and work so far involved understanding brain neural networks and developing key research strategies (published work) towards identification of neuro-circuits for future target treatment of behavioral and psychiatric disorders mainly in three major areas; motor control, cognition and sleep-wake behaviors. During these investigations, I had employed various specialized invivo electrophysiological recording techniques, such as single-unit (neuronal) recording and juxtacellular recording/labeling of neurons using glass microelectrodes and others with miniaturized microdrive carrying microwires in either anesthetized and/or freely behaving/moving rodents. Lately, I also did head-fixed rodent preparation with plans to doing brain calcium imaging to study neural activity. In addition, research work also involved use of drug application using ionophoretic technique or use of microdialysis in anesthetized or freely behaving rodents, respectively, to study the role of receptors in the control of behavior. More recently, I have combined optogenetic tools and single-neuronal recording in freely behaving animals to study gamma band oscillation (GBO, its deficit seen in schizophrenia patients) and the role of basal forebrain neurons in GBO control.
Highlights of 3 major research work since joining Harvard Medical School: (1). Role of basal forebrain neurons in gamma band oscillation (GBO) control. Deficits in cortical gamma oscillation are particularly evident in mental disorders. Gamma frequency (30-80Hz) act as a binding characteristics of cortical cells in sensory processing of higher level cognitive functions like attention and memory. Their dysfunction can lead to severe mental problems. One such mental disorder that affects ~2.6 million people in the US is Schizophrenia (Sz). Clinical findings showed a deficit in 40Hz cortical gamma in Sz patients. Our research findings showed that optogenetic activation of basal forebrain (BF) parvalbumin (PV) cells cause a strong 40Hz cortical response. PV abnormality has been well documented in Sz. In addition, an external stimulation {acoustic steady state response (ASSR)} induced fine -tuning of the cortical 40Hz is disrupted if the BF PV cells are suppressed. (2). Role of thalamic reticular neurons (TRN) in the generation of sleep spindles. Clinical finding shows an impairment in EEG spindles in Sz patients. Non-REM sleep and spindle deficit are linked to poor memory and cognitive performance. Preliminary findings suggest a gain- & loss-of-function after optogenetic manipulation of the TRN PV cells in the modulation of spindles (number, amplitude) as well as non-REM sleep. (3). Role of brain stem locomotor region neurons in pons in motor control. Motor control dysfunction occur in many neurodegenerative diseases like Parkinson’s, Narcolepsy, motor-neuron diseases etc. We found separate group of pontine cells are activated during cataplexy & REM sleep. Dysfunction of motor tone during active wake causes cataplexy. Results from one such study suggested that brain stem lateral pontine tegmentum cells, possibly glutamatergic, with direct projection to spinal cord that lie within the mesencephalic locomotor region are the principal cells in the control of motor activity. So identifying selective group of neurons and their characterization provides key information to conduct future translational studies for designing therapeutics for motor or sensory related disorders.

Mentor(s)


Research Funding

Active:
Veterans Administration Merit Review (PI: McCarley) 10/1/16- 9/30/21
Objective of this proposal is to understand the control of sleep, sleep spindles and sleep-dependent memory consolidation by the thalamic reticular nucleus (TRN).

Veterans Administration Merit Review (PI: McCarley) 7/1/14-6/30/18
Synaptic Basis of Sleep Cycle Control.
Goal of this project is to study basal forebrain GABA/parvalbumin neurons in control of cortical gamma band oscillations, which are important for coherence of thought and perception and are abnormal in mental disorders, including schizophrenia, where gamma abnormalities have been found to be associated with disordered thinking and hallucinations.

NIH/NHLBI P01HL095491-01A1 (PI: Clif Saper) 7/1/15-6/30/20
PI: Bernat Kocsis = PI, Beth Israel Deaconess Medical Center. Brockton Subcontract Principal Investigators:  Robert W. McCarley.
Mechanisms of Arousal in Sleep Apnea (Project 4 title)
In this project to study the neuronal control mechanisms of the ascending sleep arousal pathway.

Completed:
Veterans Administration Merit Review (PI: McCarley) 10/1/11- 9/30/15
Basal Forebrain Cellular Mechanisms of Cortical Activation
To investigate the neuronal circuitry regulating cortical activation especially electroencephalographic (EEG) oscillations in the gamma range (30-120 Hz), using optogenetic, and in vivo electrophysiology techniques.

NIH/NHLBI P01HL095491-01A1 (PI: Clif Saper) 3/1/10-2/28/2015
PI: Bernat Kocsis = PI, Beth Israel Deaconess Medical Center. Brockton Subcontract Principal Investigators:  Robert W. McCarley.
Mechanisms of state switching in sleep and sleep apnea (Project 4 title)

NIDNS NS062727 (PI: Jun Lu) 2/1/2009 – 1/31/2014                                 
The goal of this project is to delineate the pontine neural circuits regulating motor behavior and its links with the basal ganglia.
Role: Co-Investigator

Selected Publications

Yang C, Thankachan S, McCarley RW, Brown RE. The menagerie of the basal forebrain: How many (neural) species are there, what do they look like, how do they behave and who talks to whom? Curr. Opinion Neurobiol. 2017 (in press).

Tae K, Thankachan S*, McKenna JT, McNally JM, Yang C, Choi JH, Chen L, Kocsis B, Deisseroth K, Strecker RE, Basheer R, Brown RE, RW. McCarley. Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations. Proc.Natl.Acad.Sci (USA). 2015. 112:3535-3540. [PMID: 25733878]. * Co-first author.

Thankachan S, Fuller PM, Lu J. Movement– and behavioral state- dependent activity of pontine reticulospinal neurons. Neuroscience. 2012. 221:125-29. [PMID: 22796072].

Kaur S, Thankachan S, Begum S, Blanco-Centurion C, Shiromani PJ. Hypocretin-2 saporin lesions of the ventrolateral periaquaductal gray (vlPAG) increase REM sleep in Hypocretin-null mice. PlosOne. 2009. 4 (7): 1-19. [PMID: 19623260].

Thankachan S, Kaur S, Shiromani PJ. Activity of pontine neurons during sleep and cataplexy in hypocretin knockout mice. J. Neurosci. 2009. 29(5): 1580-1585. [PMID: 19193905].

Kaur S, Thankachan S, Begum S, Blanco-Centurion S, Sakurai T, Yanagisawa M, Shiromani PJ. Entrainment of temperature and activity rhythms to restricted feeding in orexin knock out mice. Brain Res. 2008.1205: 47–54. [PMID: 18343358].

Liu M, Thankachan S, Kaur S, Begum S, Blanco-Centurion C, Sakurai T, Yanagisawa M, Neve R, Shiromani PJ. Orexin (Hypocretin) gene transfer diminishes narcoleptic sleep behavior in mice. Eur J Neurosci. 2008. 28(7):1382-93. [PMID: 18973565].

Zhang S, Lin L, Kaur S, Thankachan S, Blanco-Centurion C, Yanagisawa M, Mignot E, Shiromani PJ. The development of hypocretin (OREXIN) deficiency in hypocretin/ataxin-3 transgenic rats. Neuroscience.2007. 148(1):34-435. [PMID: 17618058].

Thankachan S, Rusak B. Juxtacellular recording/labeling analysis of physiological and anatomical characteristics of rat intergeniculate leaflet (IGL) neurons. J. Neurosci. 2005. 25(40):9195-9204. [PMID: 16207879].

Mallick BN, Thankachan S, Islam F. Influence of hypnogenic brain areas on wakefulness- and rapid-eye-movement sleep-related neurons in the brainstem of freely moving cats. J. Neurosci. Res. 2005. 75:133–142. [PMID: 1468956].

Thankachan S, Islam F, Mallick BN. Role of wake inducing brain stem area on rapid eye movement sleep regulation in freely moving behaving cats. Brain Res. Bull.2001. 55(1): 43-49. [PMID: 11427336].

Thankachan S, Islam F, Mallick BN. Adrenergic and cholinergic modulation of spontaneous and brain stem reticular formation stimulation induced desynchronization of the cortical EEG in freely moving behaving cats. Sleep and Hypnosis.1999. 1; 14-21. PMID: not available.

Mallick BN, Thankachan S, Islam F. Differential responses of brain stem neurons during spontaneous and stimulation induced desynchronization of the cortical EEG in freely moving cats. Sleep Res. Online 1998. 1(4); 132-146. http://www.sro.org/1998/Mallick/132/. [PMID: 11382870].

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