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Role of adenosinergic inhibition of serotonin neurons in seizure induced respiratory arrest

Award Number: F32NS117792
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/23/2022
PERIOD OF PERFORMANCE END DATE: 05/22/2025

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Role of adenosinergic inhibition of serotonin neurons in seizure induced respiratory arrest - Project Summary Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature death in persons with epilepsy who do not have satisfactory seizure control. SUDEP results in more years of potential life lost than any other neurological condition with the exception of stroke. There are no known ways of reliably preventing SUDEP. Convergent lines of evidence suggest that respiratory dysfunction is a critical component of SUDEP pathophysiology. There are several potential mechanistic explanations for the respiratory arrest seen in SUDEP. (1) Serotonin signaling is important for stable breathing and increasing serotonergic tone may be protective against seizure-induced respiratory arrest. Unfortunately, seizures disrupt serotonergic neurotransmission. There is a gap in knowledge as to the mechanism responsible for seizure-induced disruption of serotonergic neurotransmission. (2) Seizures also cause a surge in extracellular adenosine throughout the brain. Increases in adenosine levels suppress breathing and inhibit neural activity. Excessive adenosine signaling has been implicated in the respiratory dysfunction seen in SUDEP; however, the mechanism by which adenosine affects breathing after seizures is unknown. (3) Slow moving (2-5 mm/min) waves of spreading depolarization are sometimes triggered by seizures. Spreading depolarization transiently inactivates the brain tissue. Under certain circumstances spreading depolarization can travel into the brainstem where it halts neural activity in nuclei necessary for cardiorespiratory function and causes death. Brainstem spreading depolarization is a potential cause of SUDEP. Spreading depolarization also causes an increase in extracellular adenosine. It is not known whether the increase in adenosine due to spreading depolarization contributes to seizure-induced death. The goal of this proposal is to integrate the serotonergic, adenosinergic, and spreading depolarization explanations of SUDEP etiology by testing the central hypothesis that adenosine surging as the result of seizure activity and spreading depolarization disrupts serotonergic neurotransmission thereby potentiating respiratory failure. In the first aim, adenosine signaling will be augmented in the serotonergic raphe nuclei during seizures to determine if this alters respiratory responsiveness to CO2 and the likelihood of respiratory failure. In the second aim, brainstem spreading depolarization will be induced in mice in which adenosine signaling has been pharmacologically or genetically altered in the raphe nuclei. The proposed experiments will generate compelling evidence for or against the hypothesized interaction between serotonin and adenosine while providing the training in writing, mentorship, and quantitatively rigorous hypothesis-testing necessary for a career in science.


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	2021	RUTGERS, THE STATE UNIVERSITY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/23/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $65,380 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	3	2/27/2024	NON-COMPETING CONTINUATION	$2,712
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	2/19/2024	NON-COMPETING CONTINUATION	$69,080
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	3	5/10/2024	NON-COMPETING CONTINUATION	$4,964
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	2/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	1/5/2024	NEW	$0
2024	2021	RUTGERS, THE STATE UNIVERSITY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/28/2023	NEW	-$11,376
														Subtotal = $65,380

Issue Date FY: 2023 ( Subtotal = $69,080 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/7/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$68,684
2023	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	6/16/2023	NEW	$396
														Subtotal = $69,080

Issue Date FY: 2021 ( Subtotal = $65,994 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/23/2021	NEW	$65,994
														Subtotal = $65,994

Grand Total All Awards = $200,454

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Role of adenosinergic inhibition of serotonin neurons in seizure induced respiratory arrest

Award Number: F32NS117792

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/23/2022

PERIOD OF PERFORMANCE END DATE: 05/22/2025

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