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CRH Dysregulation of Brainstem Autonomic Circuits Increases SUDEP Risk

Award Number: R01NS102937
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: 12/09/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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CRH Dysregulation of Brainstem Autonomic Circuits Increases SUDEP Risk - Project Summary The overarching objective of this proposal is to investigate a novel mechanism for sudden unexpected death in epilepsy (SUDEP). Our laboratory recently made the unexpected discovery that mice genetically engineered for hyperactive stress circuits exhibit an increased incidence of SUDEP, a finding that was verified to be translationally relevant from observed neuroendocrine abnormalities in patients that died of confirmed or suspected SUDEP. Given that both stress and SUDEP link to disruption of central circuits responsible for the regulation of cardiorespiratory function, we propose that exaggerated activity of central stress circuits on downstream brainstem autonomic control centers represents a novel mechanism contributing to increased SUDEP risk. Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are at the apex of the stress axis and project directly to brainstem regions critical for autonomic regulation, including the nucleus of the solitary tract (PVN-NTSCRH). PVN-NTSCRH has a well-established role in integrating cardiorespiratory responses to stress, making them a likely driver of cardiorespiratory dysfunction related to central stress axis hyperexcitability and, potentially, SUDEP. In fact, our preliminary data demonstrate that chemogenetic activation of PVN-NTSCRH increases SUDEP incidence. The current application will build on the expertise of, Drs. Jamie Maguire and Carie Boychuk, to test the hypothesis that HPA axis hyperexcitability in chronically epileptic mice increases the risk for SUDEP through increased PVN-NTSCRH drive, exaggerating cardiac vagal output during homeostatic challenges. We will investigate this hypothesis by examining whether there is increased PVN-NTSCRH drive associated with SUDEP risk and whether excessive activation of this pathway is sufficient to increase SUDEP incidence. We will interrogate potential, novel pathophysiological mechanisms mediating the impact of hyperactive stress circuits on SUDEP risk by examining the impact on cardiac vagal output. Finally, we will investigate whether environmental factors associated with hyperactive stress circuits, such as chronic stress, can impact cardiac vagal function and SUDEP risk. This application has the potential to uncover a novel mechanism contributing to SUDEP risk, which may also be relevant to other forms of sudden death.


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 = $548,575 )
2025	2025	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	11/29/2024	NON-COMPETING CONTINUATION	$548,575
														Subtotal = $548,575

Issue Date FY: 2024 ( Subtotal = $609,921 )
2024	2024	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	11/30/2023	SUPPLEMENT FOR EXPANSION	$19,166
2024	2024	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	11/28/2023	NON-COMPETING CONTINUATION	$548,123
2024	2024	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	4/15/2024	NON-COMPETING CONTINUATION	$42,632
														Subtotal = $609,921

Issue Date FY: 2023 ( Subtotal = $663,760 )
2023	2023	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	12/7/2022	COMPETING CONTINUATION	$620,309
2023	2023	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	3/28/2023	SUPPLEMENT FOR EXPANSION	$43,451
														Subtotal = $663,760

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/15/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $360,938 )
2021	2021	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/18/2021	NON-COMPETING CONTINUATION	$360,938
														Subtotal = $360,938

Issue Date FY: 2020 ( Subtotal = $360,938 )
2020	2020	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/18/2020	NON-COMPETING CONTINUATION	$360,938
														Subtotal = $360,938

Issue Date FY: 2019 ( Subtotal = $360,938 )
2019	2019	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/12/2019	NON-COMPETING CONTINUATION	$360,938
														Subtotal = $360,938

Issue Date FY: 2018 ( Subtotal = $360,938 )
2018	2018	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/19/2018	NON-COMPETING CONTINUATION	$324,844
2018	2018	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/8/2018	NON-COMPETING CONTINUATION	$36,094
														Subtotal = $360,938

Issue Date FY: 2017 ( Subtotal = $360,938 )
2017	2017	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/25/2017	NEW	$360,938
														Subtotal = $360,938

Grand Total All Awards = $3,626,946

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CRH Dysregulation of Brainstem Autonomic Circuits Increases SUDEP Risk

Award Number: R01NS102937

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: 12/09/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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