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Hippobellum: Cerebellar influence on the hippocampus and temporal lobe seizures

Award Number: R01NS112518
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: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Hippobellum: Cerebellar influence on the hippocampus and temporal lobe seizures - PROJECT SUMMARY Decades ago, the cerebellum was explored as a potential target for the epilepsies. Mixed results ultimately reduced enthusiasm, but we have now shown that with the correct stimulation parameters, electrical stimulation of the cerebellar cortex can provide robust seizure control in a mouse model of temporal lobe epilepsy. During the previous funding period, we also demonstrated that optogenetic excitation of excitatory neurons in the cerebellar fastigial nucleus with projections to the central lateral thalamus (but not other populations of fastigial neurons) was able to inhibit hippocampal seizures. The fastigial nucleus may make a better target for deep brain stimulation than the cerebellar cortex. Unfortunately, it is not yet known if optimization of stimulation parameters can allow for robust seizure control when targeting the cerebellar nucleus (rather than cerebellar cortex) with on-demand electrical stimulation. In healthy animals, we further demonstrated that optogenetic stimulation of the cerebellum can cause a transient inhibition of CA1 pyramidal cells, and mixed, but structured, effects on CA1 interneurons. How cerebellar intervention in epilepsy impacts CA1 excitatory and inhibitory neuronal populations is unknown. Importantly, not only can the cerebellum impact seizures, but also seizures can impact the cerebellum, suggesting bidirectional functional modulation. In this proposal, we therefore examine 1) the impact of on-demand cerebellar stimulation on CA1 principle and inhibitory interneuron populations in chronically epileptic animals, 2) the impact of seizures on cerebellar fastigial and central lateral thalamic neurons, and the impact of on-demand optogenetic intervention targeting the fastigial nucleus on the central lateral nucleus, and 3) if, with Bayesian optimization, electrical stimulation of the fastigial nucleus can be an effective strategy, if this outperforms targeting of a different cerebellar nucleus (the dentate nucleus), and if targeting the downstream central lateral nucleus can also be an effective approach. Collectively, this data will significantly improve our understanding of temporal lobe seizure networks (extending far beyond the temporal lobe), improve our understanding of how cerebellar modulation may result in seizure inhibition, and ultimately identify potential new intervention strategies.


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 = $593,514 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	2/20/2026	NON-COMPETING CONTINUATION	$593,514
														Subtotal = $593,514

Issue Date FY: 2025 ( Subtotal = $593,514 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	5/27/2025	COMPETING CONTINUATION	$593,514
2025	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	6/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $593,514

Issue Date FY: 2024 ( Subtotal = $424,133 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/16/2023	NON-COMPETING CONTINUATION	$393,525
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/3/2024	NON-COMPETING CONTINUATION	$30,608
														Subtotal = $424,133

Issue Date FY: 2023 ( Subtotal = $437,250 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	2/1/2023	NON-COMPETING CONTINUATION	$43,725
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/2/2022	NON-COMPETING CONTINUATION	$393,525
														Subtotal = $437,250

Issue Date FY: 2022 ( Subtotal = $437,250 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/12/2022	NON-COMPETING CONTINUATION	$43,725
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/18/2021	NON-COMPETING CONTINUATION	$393,525
														Subtotal = $437,250

Issue Date FY: 2021 ( Subtotal = $435,605 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/24/2020	NON-COMPETING CONTINUATION	$392,043
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/11/2021	NON-COMPETING CONTINUATION	$43,562
														Subtotal = $435,605

Issue Date FY: 2020 ( Subtotal = $434,429 )
2020	2020	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/28/2020	NEW	$434,429
														Subtotal = $434,429

Grand Total All Awards = $3,355,695

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Hippobellum: Cerebellar influence on the hippocampus and temporal lobe seizures

Award Number: R01NS112518

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: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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