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Neurophysiology of Breathing Behavior in Mice

Award Number: R01HL104127
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2010
PERIOD OF PERFORMANCE END DATE: 04/30/2020

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Neurophysiology of Breathing Behavior in Mice - ¿ DESCRIPTION (provided by applicant): This R01 renewal project aims to explain the neural origins of breathing behavior at the cellular and synaptic level. It advances understanding of the brainstem pre-Bötzinger complex (preBötC), which is acknowledged to be the principal site driving respiration in humans and all terrestrial mammals so far studied. Also, this project examines interneurons of the intermediate reticular formation, adjacent to the preBötC, which may give rise to respiratory premotor neurons. The intellectual driving force for this project is te discovery by the PI's team - and French colleagues - that the key rhythmogenic preBötC interneurons in perinatal mice are derived from embryonic precursors that express transcription factor Dbx1 (i.e., Dbx1 preBötC neurons). This project exploits this new knowledge and by coupling Dbx1 Cre-driver mice with six different flox-STOP reporter strains to perform a spectrum of experiments in vivo and in vitro such as patch-clamp recordings, cell-specific laser ablations with physiological monitoring, and optogenetic manipulations that interrogate network properties. Aim 1 uses juvenile and adult mice (in vivo and in vitro) to examine whether Dbx1 preBötC neurons are rhythmogenic beyond embryonic and neonatal stages of development. Aim 2 uses embryonic and neonatal mice in vitro in conjunction with cell-specific laser ablation methods to test whether preBötC neurons with bursting-pacemaker properties are obligatory for respiratory rhythm generation, offering a fresh approach to a 24-year-old unsolved problem regarding `pacemaker' driven preBötC rhythms. Aim 3 uses perinatal mice in vitro to characterize synaptic interconnections among Dbx1 neurons and quantify the input-output relationship. These experiments elucidate recurrent synaptic excitation in Dbx1 preBötC neurons, which is also putatively rhythmogenic. Aim 4 uses perinatal through adult mice (in vivo and in vitro) to examine whether Dbx1 neurons in the adjacent intermediate reticular formation serve as the first layer of premotor neurons for respiratory movements of the tongue (genioglossus) and pharynx. Dysfunctions in respiratory control circuits cause significant health problems including obstructive and central apneas, as well as respiratory failure and death. These conditions afflict premature infants, children, adults, and patients with neurodegenerative disorders. This project is significant because it characterizes the cellular and synaptic mechanisms that animate the key genetic class of neurons (i.e., Dbx1) at the core of the respiratory oscillator, which represents a transformative advance in our understanding that would inform new prevention and treatment strategies to combat respiratory pathologies. The PI is the ideal scientist for this job because of his track record as a leader in respiratory neurobiology, who - with French colleagues - first characterized the role of Dbx1 neurons in the preBötC and now is poised to further discover their detailed properties and downstream premotor counterparts. If this project succeeds, neuroscience would finally know the cellular and synaptic origins of a significant central pattern- generating circuit in a mammal and the point of origin for an important behavior, breathing.


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: 2021 ( Subtotal = $0 )
2021	2018	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	National Center on Sleep Disorders Research	000	9	11/18/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	National Center on Sleep Disorders Research	000	9	8/2/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $329,136 )
2018	2018	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	National Center on Sleep Disorders Research	000	9	4/23/2018	NON-COMPETING CONTINUATION	$329,136
														Subtotal = $329,136

Issue Date FY: 2017 ( Subtotal = $329,248 )
2017	2017	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	National Center on Sleep Disorders Research	000	8	6/14/2017	NON-COMPETING CONTINUATION	$329,248
														Subtotal = $329,248

Issue Date FY: 2016 ( Subtotal = $329,350 )
2016	2016	COLLEGE OF WILLIAM & MARY	P.O. BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	National Center on Sleep Disorders Research	000	7	4/20/2016	NON-COMPETING CONTINUATION	$329,350
														Subtotal = $329,350

Issue Date FY: 2015 ( Subtotal = $329,444 )
2015	2015	COLLEGE OF WILLIAM & MARY	P.O. BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	National Center on Sleep Disorders Research	000	6	7/9/2015	COMPETING CONTINUATION	$329,444
														Subtotal = $329,444

Issue Date FY: 2014 ( Subtotal = $285,125 )
2014	2014	COLLEGE OF WILLIAM & MARY	P.O. BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	National Center on Sleep Disorders Research	000	5	6/23/2014	NON-COMPETING CONTINUATION	$285,125
														Subtotal = $285,125

Issue Date FY: 2013 ( Subtotal = $278,380 )
2013	2013	COLLEGE OF WILLIAM & MARY	P.O. BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	National Center on Sleep Disorders Research	000	4	6/28/2013	NON-COMPETING CONTINUATION	$196,629
2013	2013	COLLEGE OF WILLIAM & MARY	P.O. BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	Cardiovascular Diseases Research	001	4	8/15/2013	SUPPLEMENT FOR EXPANSION	$82,307
2013	2013	COLLEGE OF WILLIAM & MARY	P.O. BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	Cardiovascular Diseases Research	002	4	8/27/2013	SUPPLEMENT FOR EXPANSION	-$556
														Subtotal = $278,380

Issue Date FY: 2012 ( Subtotal = $212,355 )
2012	2012	COLLEGE OF WILLIAM & MARY	P.O. BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	National Center on Sleep Disorders Research	000	3	6/30/2012	NON-COMPETING CONTINUATION	$212,355
														Subtotal = $212,355

Issue Date FY: 2011 ( Subtotal = $214,157 )
2011	2011	COLLEGE OF WILLIAM & MARY	P.O. BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	National Center on Sleep Disorders Research	000	2	6/29/2011	NON-COMPETING CONTINUATION	$214,157
														Subtotal = $214,157

Issue Date FY: 2010 ( Subtotal = $245,892 )
2010	2010	COLLEGE OF WILLIAM & MARY	P.O. BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	National Center on Sleep Disorders Research	000	1	6/15/2010	NEW	$245,892
														Subtotal = $245,892

Grand Total All Awards = $2,553,087

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Neurophysiology of Breathing Behavior in Mice

Award Number: R01HL104127

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2010

PERIOD OF PERFORMANCE END DATE: 04/30/2020

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