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Ion Channel Mechanisms of Inspiratory Breathing Movements in Mice

Award Number: R01NS107296
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: 03/15/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Ion Channel Mechanisms of Inspiratory Breathing Movements in Mice - PROJECT SUMMARY Our goal is to explain the neurophysiology of breathing. Breathing refers to periodic movements of the chest and airways that ventilate the lungs. To breathe, the brain must:  Generate a rhythm,  Produce a spatiotemporal pattern for breathing muscles,  Integrate sensory feedback. Here we focus on jobs 1 and 2, discovering the ionic mechanisms underlying the rhythm and motor pattern. The brainstem preBötzinger complex (preBötC) generates the inspiratory breathing rhythm. Its core rhythmogenic interneurons are derived from Dbx1-expressing progenitors (i.e., Dbx1 neurons). Because we know the site (preBötC) and the canonical cell-class (Dbx1) at the point of origin for breathing, we are well equipped to discover which ion channels influence normal inspiration (eupnea), ‘sighs’, and gasps in hypoxia. We manipulate ion channels using genetic technologies. We assess breathing phenotypes in intact adult mice. We explain the biophysics of these phenotypes via patch-clamp recordings from adult Dbx1 preBötC neurons. Three types of ion channels are implicated in preBötC function: (1) Na+ channels that engender persistent Na+ current (INaP), (2) Transient receptor potential (Trp) channels that mediate Ca2+-activated nonspecific cationic current (ICAN), and (3) K+ channels that give rise to transient outward K+ current (i.e., A-current, IA). Specific aim 1 evaluates the role of INaP in Dbx1 preBötC neurons. A rhythmogenic role for INaP has been suspected for 27 years. We use intersectional mouse genetics and short-hairpin RNA (shRNA) to knockout or knock-down Na+ channel genes that give rise to INaP and evaluate its role in eupnea, sighing, and gasping. Specific aim 2 evaluates the role of ICAN in Dbx1 preBötC neurons. ICAN is a major charge carrier for inspiratory bursts. Next-generation RNA Seq technology provides us with a suite of Trp channel targets that we will acutely attenuate using shRNA to test the role of ICAN in eupnea, sighing, and gasping. Specific aim 3 evaluates the role of IA in Dbx1 preBötC neurons. IA-expressing preBötC neurons feature other key rhythmogenic properties so they may be specialized. We use intersectional mouse genetics and shRNA to knockout or knock-down K+ channel genes for IA to evaluate its role in eupnea, sighing, and gasping. Then we selectively kill the 56% of IA-expressing Dbx1 preBötC neurons to test whether they serve a specialized rhythmogenic role. The success of this project would be a watershed in terms of understanding the ion channel-level origins of real behavior. The new knowledge could be applicable to treatment and prophylaxis of respiratory pathologies with a central etiology. The new knowledge may provide general insights regarding the neural origins of motor rhythms.


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: 2024 ( Subtotal = $0 )
2024	2022	COLLEGE OF WILLIAM AND MARY	1314 S MOUNT VERNON AVE	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	COLLEGE OF WILLIAM AND MARY	1314 S MOUNT VERNON AVE	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $278,392 )
2022	2022	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/18/2022	NON-COMPETING CONTINUATION	$250,552
2022	2022	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/24/2022	NON-COMPETING CONTINUATION	$27,840
														Subtotal = $278,392

Issue Date FY: 2021 ( Subtotal = $278,447 )
2021	2021	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/19/2021	NON-COMPETING CONTINUATION	$278,447
														Subtotal = $278,447

Issue Date FY: 2020 ( Subtotal = $309,516 )
2020	2020	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/3/2020	NON-COMPETING CONTINUATION	$309,516
														Subtotal = $309,516

Issue Date FY: 2019 ( Subtotal = $278,544 )
2019	2019	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/15/2019	NEW	$278,544
														Subtotal = $278,544

Grand Total All Awards = $1,144,899

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Ion Channel Mechanisms of Inspiratory Breathing Movements in Mice

Award Number: R01NS107296

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: 03/15/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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