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Theta Phase-Locked Stimulation of Entorhinal-Hippocampal Inputs in Healthy and Epileptic Mice

Award Number: F31NS134301
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: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Theta Phase-Locked Stimulation of Entorhinal-Hippocampal Inputs in Healthy and Epileptic Mice - Project Summary Epilepsy is a debilitating neurological disorder characterized not only by spontaneous recurrent seizures, but also severe cognitive deficits that present a significant detriment to quality of life. Changes in synchrony within and across brain regions have been implicated in temporal lobe epilepsy (TLE), but it is unclear how these changes contribute to memory deficits. Electrophysiological recordings from the Shuman lab have shown that coherence between the hippocampus and medial entorhinal cortex (MEC) is disrupted in a mouse model of TLE. This synchronization between hippocampus and MEC has been theorized to be important for spatial memory by allowing efficient information transfer at distinct phases of theta. However, there have been few causal studies on the impact of synchronization due in part to limited technical methods to manipulate the timing of inputs in behaving mice. Thus, investigating the causal nature of altered synchrony in cognitive dysfunction requires the application of novel tools to precisely manipulate the timing neural activity. To address this gap, I have developed a closed-loop optogenetic system that can stimulate neural populations at distinct phases of endogenous theta oscillations. In this proposal, I will use this system to test the hypothesis that the timing of MECII and MECIII inputs relative to endogenous theta oscillations controls memory performance in both healthy and epileptic mice. I will employ a head-fixed virtual reality task to test the effect of altered input timing on spatial memory performance and will investigate the role of this timing on other measures of synchrony including interregional coherence. I hypothesize that mistiming MEC inputs in healthy mice will impair memory performance and disrupt coherence, while restoring proper timing in epileptic mice will improve performance and increase coherence. Furthermore, I will use a layer specific viral approach to restrict optogenetic stimulation to afferents arriving to the hippocampus from MEC layer II or layer III and determine the distinct role of each of these inputs into hippocampus. Together, the results of these experiments will determine how the timing of inputs into the hippocampus impacts spatial processing in both health and disease and will pave the way for future therapeutic targets in epilepsy.


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: 2026 ( Subtotal = $29,010 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/23/2026	NON-COMPETING CONTINUATION	$28,770
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/31/2026	NON-COMPETING CONTINUATION	$240
														Subtotal = $29,010

Issue Date FY: 2025 ( Subtotal = $47,938 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	9/8/2025	NON-COMPETING CONTINUATION	$564
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/14/2025	NON-COMPETING CONTINUATION	$47,374
														Subtotal = $47,938

Issue Date FY: 2024 ( Subtotal = $47,374 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	5/7/2024	NEW	$1,280
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	3/29/2024	NEW	$0
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/29/2024	NEW	$46,094
														Subtotal = $47,374

Grand Total All Awards = $124,322

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Theta Phase-Locked Stimulation of Entorhinal-Hippocampal Inputs in Healthy and Epileptic Mice

Award Number: F31NS134301

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: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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