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Normal and Pathological Function of the Dentate Gyrus

Award Number: R01NS082046
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: 09/01/2012
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Normal and Pathological Function of the Dentate Gyrus - The neuronal circuitry within the dentate gyrus is massively disrupted in temporal lobe epilepsy patients and in experimental models of this disorder. This proposal builds upon our laboratory’s previous findings, which demonstrate that the dentate gyrus circuitry within the epileptic hippocampus retains an embedded coding network of dentate granule cells which can reemerge and restore appropriate cognitive function following treatments to suppress degraded pathologic activity. The maintained competence of this embedded dentate granule cell network occurs despite the significant structural pathology which is unaffected by therapeutic interventions. In this proposal, we will build upon this foundation, and examine and manipulate dentate granule cells in both epileptic and control animals to generate a mechanistic understanding of how these epilepsy- associated disruptions to normal circuit functioning can be targeted to restore downstream, emergent properties of the hippocampus, such as learning and memory and emotional behaviors. The CENTRAL HYPOTHESIS of the present proposal is that the epilepsy-associated degradation in coding properties of dentate granule cells contributes significantly to both the cognitive and behavioral comorbidities that constitute key components of the core phenotypes of temporal lobe epilepsy. To test this Central Hypothesis, we propose to conduct a series of experiments centered on 3 SPECIFIC AIMS: Aim 1. Characterize the local circuit properties defining the active dentate granule cell network in epileptic and control mice. Aim 2. Determine the capacity, time course, and extent of long-term dentate gyrus circuit specific intervention strategies to rescue cognitive and behavioral function in epileptic mice. Aim 3. Assess the contribution of dentate granule cell hyperexcitability in epileptic mice to disrupted hippocampal spatial coding. We know little about the mechanisms that mediate the sparse yet deterministic firing properties of neuronal populations in the hippocampal dentate gyrus that are responsible for their role in information coding and plasticity. We know even less about how disease-associated degradation in these critical dentate granule cell properties develop, and in turn how this excitability disruption may erode cognitive and affective functions that the hippocampus normally supports. In addition to the enhanced excitability responsible for seizure generation, patients with epilepsy exhibit severe cognitive comorbidities, including deficits in emotion, mood, and learning and memory, processes typically thought of as limbic system functions. Understanding how epilepsy development alters the basic circuit properties within the limbic system may be important not only in targeting new therapies for seizure amelioration, but also in developing new treatments to reduce comorbid conditions accompanying epilepsy development, a largely unexplored area of therapy development.


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 = $568,054 )
2026	2026	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	3/31/2026	NON-COMPETING CONTINUATION	$568,054
														Subtotal = $568,054

Issue Date FY: 2025 ( Subtotal = $511,249 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	3/26/2025	NON-COMPETING CONTINUATION	$511,249
2025	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	1/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $511,249

Issue Date FY: 2024 ( Subtotal = $551,013 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	12	7/18/2024	NON-COMPETING CONTINUATION	$551,013
2024	2022	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	11/3/2023	COMPETING CONTINUATION	$42,931
2024	2020	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	11/3/2023	NON-COMPETING CONTINUATION	-$42,931
														Subtotal = $551,013

Issue Date FY: 2023 ( Subtotal = $568,054 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	4/7/2023	NON-COMPETING CONTINUATION	$568,054
														Subtotal = $568,054

Issue Date FY: 2022 ( Subtotal = $568,054 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	4/13/2022	COMPETING CONTINUATION	$568,054
2022	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	4/6/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $568,054

Issue Date FY: 2020 ( Subtotal = $367,500 )
2020	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	5/7/2020	NON-COMPETING CONTINUATION	$367,500
														Subtotal = $367,500

Issue Date FY: 2019 ( Subtotal = $367,500 )
2019	2019	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	4/29/2019	NON-COMPETING CONTINUATION	$367,500
														Subtotal = $367,500

Issue Date FY: 2018 ( Subtotal = $367,500 )
2018	2018	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	4/27/2018	NON-COMPETING CONTINUATION	$367,500
														Subtotal = $367,500

Issue Date FY: 2017 ( Subtotal = $367,500 )
2017	2017	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	6	6/22/2017	NON-COMPETING CONTINUATION	$36,750
2017	2017	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	6	4/26/2017	NON-COMPETING CONTINUATION	$330,750
2017	2016	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	1/29/2017	COMPETING CONTINUATION	$63,247
2017	2016	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	4/12/2017	COMPETING CONTINUATION	-$528
2017	2015	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/29/2017	NON-COMPETING CONTINUATION	-$63,247
2017	2015	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	4/12/2017	NON-COMPETING CONTINUATION	$528
														Subtotal = $367,500

Issue Date FY: 2016 ( Subtotal = $367,500 )
2016	2016	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/18/2016	COMPETING CONTINUATION	$367,500
														Subtotal = $367,500

Issue Date FY: 2015 ( Subtotal = $366,406 )
2015	2015	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/31/2015	NON-COMPETING CONTINUATION	$366,406
														Subtotal = $366,406

Issue Date FY: 2014 ( Subtotal = $362,741 )
2014	2014	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/21/2014	NON-COMPETING CONTINUATION	$362,741
														Subtotal = $362,741

Issue Date FY: 2013 ( Subtotal = $353,582 )
2013	2013	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/2/2013	NON-COMPETING CONTINUATION	$353,582
														Subtotal = $353,582

Issue Date FY: 2012 ( Subtotal = $366,406 )
2012	2012	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/31/2012	NEW	$366,406
														Subtotal = $366,406

Grand Total All Awards = $6,053,059

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Normal and Pathological Function of the Dentate Gyrus

Award Number: R01NS082046

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: 09/01/2012

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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