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Synaptic Modulation of Mesopontine Cholinergic Neurons

Award Number: R01NS027881
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/1991
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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View Award Description

Synaptic Modulation of Mesopontine Cholinergic Neurons - Chronic or intermittent sleep disorders including narcolepsy, REM behavior disorder, sleep apnea, and insomnia afflict nearly 50-70 million people in the United States. Yet the neural mechanisms controlling both normal sleep and its pathologies remain poorly understood. Considerable evidence indicates that mesopontine cholinergic neurons and serotonergic dorsal raphe neurons along with other neurons at the mesopontine junction are critical for this control and that their dysregulation is involved with numerous disorders including narcolepsy, REM behavior disorder, Parkinson's disease, supranuclear palsy and depression. The long term goal of this project is to understand the mechanisms regulating activity of these neurons and their functions in regulating normal homeostatic brain functions including sleep and sleep pathologies. Compelling evidence indicates that disruption of the Hypocretin/Orexin (Hcrt/Orx) peptide system results in narcolepsy - a sleep disorder characterized by excessive daytime sleepiness, sleep fragmentation and the intrusion of rapid eye movement sleep behaviors into wakefulness. Building on the findings from the previous funding period, which discovered a novel mechanism by which orexin alters the intrinsic properties of mesopontine cholinergic neurons and dorsal raphe serotonergic neurons, we will investigate the hypothesis that Hcrt/Orx peptides have pleiotropic actions which in the short term tune somatic and dendritic excitability to enhance phasic synaptic inputs while attenuating tonic synaptic inputs and in the long-term regulate the strength of synaptic inputs and circuit function. To do so we will 1) Identify the ion channels underlying the new class of orexin actions on the post-spike afterhyperpolarization in mesopontine cholinergic neurons and dorsal raphe serotonergic neurons. 2) Determine the role of these novel actions on modulating the dendrites of mesopontine cholinergic neurons and dorsal raphe serotonergic neurons. 3) Investigate the hypothesis that orexin regulates the strength of synaptic inputs to 5-HT and GABA neurons in the LDT and DR and that the orexin-enhanced AHP and noisy orexin conductance preferentially boost high frequency synaptic inputs arising from prefrontal cortex and that these processes are perturbed in narcolepsy. These experiments will use whole-cell patch clamp recording, calcium imaging and dynamic clamp methods in brain slices from normal and orexin receptor knockout mice and will utilize focal uncaging of glutamate and optogenetic stimulation methods in normal and narcoleptic mice. Collectively, these results will advance our understanding of the molecular, cellular and circuit mechanisms underlying sleep regulation and its pathology.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	26	9/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	26	5/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $481,274 )
2022	2022	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	26	5/30/2022	NON-COMPETING CONTINUATION	$481,274
														Subtotal = $481,274

Issue Date FY: 2021 ( Subtotal = $481,274 )
2021	2021	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	5/28/2021	NON-COMPETING CONTINUATION	$481,274
														Subtotal = $481,274

Issue Date FY: 2020 ( Subtotal = $481,274 )
2020	2020	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	24	5/20/2020	NON-COMPETING CONTINUATION	$481,274
														Subtotal = $481,274

Issue Date FY: 2019 ( Subtotal = $481,274 )
2019	2019	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	23	5/27/2019	NON-COMPETING CONTINUATION	$481,274
														Subtotal = $481,274

Issue Date FY: 2018 ( Subtotal = $428,052 )
2018	2018	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	22	9/17/2018	COMPETING CONTINUATION	$428,052
2018	2016	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	8/8/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $428,052

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	4/24/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $352,188 )
2016	2016	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	1/27/2016	EXTENSION WITH OR WITHOUT FUNDS	$352,188
														Subtotal = $352,188

Issue Date FY: 2015 ( Subtotal = $352,188 )
2015	2015	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	3/20/2015	NON-COMPETING CONTINUATION	$352,188
														Subtotal = $352,188

Issue Date FY: 2014 ( Subtotal = $348,666 )
2014	2014	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	19	3/14/2014	NON-COMPETING CONTINUATION	$31,697
2014	2014	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	2/7/2014	NON-COMPETING CONTINUATION	$316,969
														Subtotal = $348,666

Issue Date FY: 2013 ( Subtotal = $338,844 )
2013	2013	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	18	4/19/2013	COMPETING CONTINUATION	$338,844
2013	2011	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	17	4/17/2013	NON-COMPETING CONTINUATION	$0
2013	2011	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	1/23/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $338,844

Issue Date FY: 2011 ( Subtotal = $338,713 )
2011	2011	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	12/28/2010	NON-COMPETING CONTINUATION	$311,063
2011	2011	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	17	6/7/2011	NON-COMPETING CONTINUATION	$27,650
														Subtotal = $338,713

Issue Date FY: 2010 ( Subtotal = $396,760 )
2010	2010	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	1/18/2010	NON-COMPETING CONTINUATION	$342,170
2010	2010	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	8/23/2010	SUPPLEMENT FOR EXPANSION	$54,590
														Subtotal = $396,760

Issue Date FY: 2009 ( Subtotal = $414,475 )
2009	2009	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	15	4/6/2009	NON-COMPETING CONTINUATION	$34,562
2009	2009	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Trans-NIH Recovery Act Research Support	002	15	9/17/2009	SUPPLEMENT FOR EXPANSION	$68,850
2009	2009	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	12/22/2008	NON-COMPETING CONTINUATION	$311,063
														Subtotal = $414,475

Issue Date FY: 2008 ( Subtotal = $345,625 )
2008	2008	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	2/4/2008	NON-COMPETING CONTINUATION	$345,625
														Subtotal = $345,625

Issue Date FY: 2007 ( Subtotal = $335,983 )
2007	2007	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	2/5/2007	COMPETING CONTINUATION	$335,983
														Subtotal = $335,983

Issue Date FY: 2006 ( Subtotal = $290,362 )
2006	2006	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	1/26/2006	NON-COMPETING CONTINUATION	$290,362
														Subtotal = $290,362

Issue Date FY: 2005 ( Subtotal = $297,350 )
2005	2005	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	1/14/2005	NON-COMPETING CONTINUATION	$297,350
														Subtotal = $297,350

Issue Date FY: 2004 ( Subtotal = $297,350 )
2004	2004	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	1/27/2004	NON-COMPETING CONTINUATION	$297,350
														Subtotal = $297,350

Issue Date FY: 2003 ( Subtotal = $297,350 )
2003	2003	NEW YORK MEDICAL COLLEGE	ADMINISTRATION BUILDING	VALHALLA	NY	10595	WESTCHESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9		NON-COMPETING CONTINUATION	$297,350
														Subtotal = $297,350

Grand Total All Awards = $7,549,088

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Synaptic Modulation of Mesopontine Cholinergic Neurons

Award Number: R01NS027881

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/1991

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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