Tuesday, July 1, 2025 7/1/2025

Remote effects of focal hippocampal seizures on neocortical function

Award Number: R01NS066974
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: 02/01/2011
PERIOD OF PERFORMANCE END DATE: 11/30/2026

Group Awards By:

View Award Description

Remote effects of focal hippocampal seizures on neocortical function - PROJECT SUMMARY / ABSTRACT Seizures have both local and remote effects on nervous system function. Temporal lobe epilepsy is a common and debilitating neurological disorder, characterized by focal seizures arising from limbic structures, including the hippocampus. Interestingly, focal temporal lobe seizures often cause functional deficits such as impaired consciousness, which is not expected from local hippocampal impairment alone. Human focal temporal lobe seizures with impaired consciousness show slow waves on electro-encephalography (EEG) and decreased cerebral blood flow in the neocortex, distant from the hippocampus. The mechanisms by which focal seizures in the hippocampus cause depressed function in the neocortex are not known. Our previous work in a rat model with focal limbic seizures reproduced the human findings and suggested that decreased subcortical arousal produces impaired consciousness during seizures. Importantly, neurostimulation of subcortical arousal systems was capable of restoring cortical function and behavioral responses during seizures, offering hope for restored arousal in human epilepsy. Therefore, our central hypothesis is that focal limbic seizures decrease subcortical arousal, causing cortical slow waves and impaired consciousness. However, the fundamental mechanisms of these changes have not been determined. We recently developed a novel awake head-fixed mouse model of focal limbic seizures, providing unique opportunities to investigate network, neurotransmitter and neuronal mechanisms in relation to behavior. We found that both increased inhibition and decreased excitation may contribute in parallel to depressed subcortical arousal in limbic seizures. In addition, depressed arousal in multiple neurotransmitter systems may contribute to impaired cortical function. We now plan to capitalize on strengths of the awake mouse model to employ techniques including high field fMRI, genetically encoded fluorescent neurotransmitter sensors, optogenetics, single cell electrophysiology and behavioral testing to fully investigate the mechanisms of impaired arousal in seizures. Therefore, our aims are to first investigate the network mechanisms of impaired arousal in focal limbic seizures in the awake mouse model. We will map cortical and subcortical networks by fMRI, followed by direct electrophysiological recordings, stimulation and disconnection experiments to identify key network nodes. Second, we will analyze the neurotransmitter changes in depressed cortical function. We will use genetically encoded fluorescent indicators and optogenetics to determine the roles of increased inhibition and decreased excitation in depressed subcortical arousal; and will investigate which arousal neurotransmitters contribute to impaired cortical function and behavior. Third, we will relate the activity of single neurons to behavior in focal limbic seizures, using juxtacellular recordings of identified subcortical arousal neurons and whole cell recordings of cortical neurons. The integration of information across these levels in the awake model will have important translational value to guide development of new treatments aimed at restoring consciousness during and following seizures.


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 = $416,894 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	11/20/2024	NON-COMPETING CONTINUATION	$416,894
														Subtotal = $416,894

Issue Date FY: 2024 ( Subtotal = $458,038 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	12	5/10/2024	NON-COMPETING CONTINUATION	$33,055
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	11/10/2023	NON-COMPETING CONTINUATION	$424,983
														Subtotal = $458,038

Issue Date FY: 2023 ( Subtotal = $475,756 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	11/24/2022	NON-COMPETING CONTINUATION	$428,180
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	1/31/2023	NON-COMPETING CONTINUATION	$47,576
														Subtotal = $475,756

Issue Date FY: 2022 ( Subtotal = $483,346 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	10	8/17/2022	COMPETING CONTINUATION	$8,720
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	12/14/2021	COMPETING CONTINUATION	$483,346
2022	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	12/7/2021	NON-COMPETING CONTINUATION	$0
2022	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	9	8/17/2022	NON-COMPETING CONTINUATION	-$8,720
														Subtotal = $483,346

Issue Date FY: 2020 ( Subtotal = $363,878 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	8/17/2020	NON-COMPETING CONTINUATION	$363,878
														Subtotal = $363,878

Issue Date FY: 2019 ( Subtotal = $363,934 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	8/5/2019	NON-COMPETING CONTINUATION	$363,934
														Subtotal = $363,934

Issue Date FY: 2018 ( Subtotal = $362,376 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	7/26/2018	NON-COMPETING CONTINUATION	$362,376
														Subtotal = $362,376

Issue Date FY: 2017 ( Subtotal = $364,939 )
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	8/15/2017	NON-COMPETING CONTINUATION	$364,939
														Subtotal = $364,939

Issue Date FY: 2016 ( Subtotal = $361,844 )
2016	2016	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	9/1/2016	COMPETING CONTINUATION	$361,844
														Subtotal = $361,844

Issue Date FY: 2014 ( Subtotal = $360,577 )
2014	2014	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/14/2014	NON-COMPETING CONTINUATION	$32,780
2014	2014	YALE UNIVERSITY	47 College Street	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/30/2014	NON-COMPETING CONTINUATION	$327,797
														Subtotal = $360,577

Issue Date FY: 2013 ( Subtotal = $351,032 )
2013	2013	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/24/2013	NON-COMPETING CONTINUATION	$23,646
2013	2013	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/17/2013	NON-COMPETING CONTINUATION	$327,386
														Subtotal = $351,032

Issue Date FY: 2012 ( Subtotal = $356,913 )
2012	2012	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/27/2012	NON-COMPETING CONTINUATION	$356,913
														Subtotal = $356,913

Issue Date FY: 2011 ( Subtotal = $353,434 )
2011	2011	YALE UNIVERSITY	PO BOX 208250	NEW HAVEN	CT	06520	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/31/2011	NEW	$353,434
														Subtotal = $353,434

Grand Total All Awards = $5,072,961

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Remote effects of focal hippocampal seizures on neocortical function

Award Number: R01NS066974

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: 02/01/2011

PERIOD OF PERFORMANCE END DATE: 11/30/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer