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Mild traumatic brain injury alters interneuron structure and function

Award Number: R01NS077675
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: 09/01/2011
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Mild traumatic brain injury alters interneuron structure and function - Project Summary This proposal seeks to better understand the contribution of cortical inhibitory interneuron subtypes to network dysfunction after mild traumatic brain injury (mTBI) utilizing a well controlled and characterized mouse model, the central fluid percussion injury. Our group has identified significant and differential dysfunction in neocortical interneuron subtypes after mTBI in this model. Parvalbumin interneurons (PV) modulate gamma oscillations recorded from EEG that is critical for sensory perception. The PV are particularly vulnerable after injury, with 10% being axotomized and the output from PV to local pyramidal neurons being significantly reduced. In contrast somatostatin-containing interneurons (SOM) show little axotomy and have an increased output onto local pyramidal neurons. In other disease models the link between the ratio of PV:SOM and altered gamma levels has been well established. We hypothesize that injury also alters this ratio and that alteration underlies the increase in resting gamma and the decrease in evoked gamma that we and others have observed. We will test that here using chemogenetics and mutant mice with altered PV:SOM ratios. In addition we will test the link of that altered gamma to an increased sensitivity to touch and lowered pain threshold. We further hypothesize that the reason PV are vulnerable is due to the activation of microglia which subsequently degrade the perineuronal nets (PNN) that normally surround the PV. Once the PNN are removed PV function is likely reduced due to reactive oxygen species. Each aspect of these hypotheses will be tested by depleting microglia and by treating the oxidative stress with N-Acetylcysteine. Outcome measures will include the power of the gamma recorded from EEG, pain threshold via von Frey filaments, whisker nuisance test score, the percent of axotomized PV and SOM interneurons, the intracellularly recorded function of the PV and SOM and the level of output from PV and SOM. These studies will determine if this cellular dysfunction underlies the abnormal network function and altered cognition after mTBI.


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 = $495,360 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	12	4/16/2025	NON-COMPETING CONTINUATION	$495,360
2025	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	2/21/2025	COMPETING CONTINUATION	$387
2025	2021	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	2/21/2025	NON-COMPETING CONTINUATION	-$387
														Subtotal = $495,360

Issue Date FY: 2024 ( Subtotal = $514,440 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	4/11/2024	COMPETING CONTINUATION	$514,440
														Subtotal = $514,440

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	5/10/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $588,177 )
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	5/19/2021	NON-COMPETING CONTINUATION	$588,177
														Subtotal = $588,177

Issue Date FY: 2020 ( Subtotal = $588,177 )
2020	2020	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	1/22/2020	NON-COMPETING CONTINUATION	$529,358
2020	2020	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	2/11/2020	NON-COMPETING CONTINUATION	$58,819
														Subtotal = $588,177

Issue Date FY: 2019 ( Subtotal = $588,177 )
2019	2019	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	1/22/2019	NON-COMPETING CONTINUATION	$588,177
														Subtotal = $588,177

Issue Date FY: 2018 ( Subtotal = $588,177 )
2018	2018	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	1/18/2018	NON-COMPETING CONTINUATION	$529,358
2018	2018	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	4/25/2018	NON-COMPETING CONTINUATION	$58,819
														Subtotal = $588,177

Issue Date FY: 2017 ( Subtotal = $588,177 )
2017	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	2/3/2017	COMPETING CONTINUATION	$5,198
2017	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	6	7/20/2017	COMPETING CONTINUATION	$232
2017	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	1/13/2017	COMPETING CONTINUATION	$582,979
2017	2015	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/11/2017	NON-COMPETING CONTINUATION	$0
2017	2015	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	7/20/2017	NON-COMPETING CONTINUATION	-$232
														Subtotal = $588,177

Issue Date FY: 2015 ( Subtotal = $442,813 )
2015	2015	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/14/2015	NON-COMPETING CONTINUATION	$442,813
														Subtotal = $442,813

Issue Date FY: 2014 ( Subtotal = $438,385 )
2014	2014	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/5/2014	NON-COMPETING CONTINUATION	$438,385
														Subtotal = $438,385

Issue Date FY: 2013 ( Subtotal = $427,316 )
2013	2013	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/15/2013	NON-COMPETING CONTINUATION	$427,316
														Subtotal = $427,316

Issue Date FY: 2012 ( Subtotal = $442,812 )
2012	2012	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/9/2012	NON-COMPETING CONTINUATION	$442,812
														Subtotal = $442,812

Issue Date FY: 2011 ( Subtotal = $512,940 )
2011	2011	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/22/2011	NEW	$500,666
2011	2011	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	8/26/2011	NEW	$12,274
														Subtotal = $512,940

Grand Total All Awards = $6,214,951

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Mild traumatic brain injury alters interneuron structure and function

Award Number: R01NS077675

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: 09/01/2011

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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