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DIFFERING NEURONAL MECHANISMS MEDIATING LOCOMOTION AND SPASMS AFTER SPINAL CORD INJURY

Award Number: R01NS047567
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: 09/15/2004
PERIOD OF PERFORMANCE END DATE: 01/31/2022

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DIFFERING NEURONAL MECHANISMS MEDIATING LOCOMOTION AND SPASMS AFTER SPINAL CORD INJURY - DESCRIPTION (provided by applicant): A primary goal for recovery following spinal cord injury (SCI) is restoration of locomotor capacity (e.g. walking). This is feasible because the core neuronal circuitry for locomotion resides within the spinal cord, and usually remains intact with spinal cord injury. However, a major problem for restoration of locomotion is that sensory input to the spinal cord often induces muscle spasms that can interfere with locomotion. On the other hand, intense locomotor training has been reported to inhibit spasms. We suggest that these opposing actions of locomotion and spasms arise from separate mutually inhibitory neuronal mechanisms in the spinal cord, including separate networks of interneurons and separate ionic currents in motoneurons. Thus, these differing mechanisms can be selectively targeted to promote locomotion and at the same time reduce spasms. Aim 1: In our previous studies, we showed that L-type calcium channels on motoneurons produce large persistent inward currents (Ca PICs) that are fundamental for generating long-lasting spasms after SCI. We have also demonstrated that NMDA receptors on motoneurons induce equally large persistent inward currents (NMDA PICs), but these are followed by large persistent outward currents (NMDA POCs), which terminate all PICs. These NMDA currents potentially contribute to controlling the amplitude and duration of rhythmic locomotor activity. Thus, in this proposal we examine the hypothesis that after SCI activation of NMDA receptors on motoneurons during rhythmic locomotor activity amplifies motor output (via NMDA PICs) and at the same time terminates Ca PIC driven spasms (via NMDA POCs). Aim 2: Our preliminary studies suggest that after SCI interneurons in the deep dorsal horn generate a burst of firing following sensory stimulation, which could trigger PICs in motoneurons and spasms. We hypothesize that: bursting interneurons in the deep dorsal horn are strongly involved in triggering of spasms, but at the same time inhibit locomotor activity. Aim 3: If the interneurons involved in locomotion and spasm are mutually inhibitory, then increasing the activation of locomotor interneurons should decrease spasms. To test this idea we examine the V3 interneurons known to be involved in locomotion in normal mice, and hypothesize that after SCI the V3 interneurons promote locomotion and inhibit spasms, transforming tonic spastic activity to coordinated locomotor drive. We employ optogenetic activation of V3 neurons after SCI. The novel concept that the interneurons that generate locomotion are different and mutually inhibitory to the interneurons that generate spasms opens up promising new avenues to treating spasms and promoting locomotion after SCI, especially when combined with potential therapeutic viral/genetic manipulation of these interneurons. From a general point of view, the tonic spasm generating interneurons and ionic currents (Ca PICs) are likely related to normal postural activity, and thus our studies shed light on the general interplay of neuronal circuits that differentially control posture and locomotion.


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: 2022 ( Subtotal = $0 )
2022	2020	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB			CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	3/21/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB			CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	5/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $284,269 )
2020	2020	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB	T6G 2R3		CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	15	2/11/2020	NON-COMPETING CONTINUATION	$28,426
2020	2020	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB	T6G 2R3		CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	1/15/2020	NON-COMPETING CONTINUATION	$255,843
														Subtotal = $284,269

Issue Date FY: 2019 ( Subtotal = $284,269 )
2019	2019	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB	T6G 2R3		CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	1/15/2019	NON-COMPETING CONTINUATION	$284,269
														Subtotal = $284,269

Issue Date FY: 2018 ( Subtotal = $284,269 )
2018	2018	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB	T6G 2R3		CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	4/25/2018	NON-COMPETING CONTINUATION	$28,426
2018	2018	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	8625 112 ST NW SUITE 222	EDMONTON	AB	T6G 1K8		CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	1/16/2018	NON-COMPETING CONTINUATION	$255,843
														Subtotal = $284,269

Issue Date FY: 2017 ( Subtotal = $284,269 )
2017	2017	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	8625 112 ST NW SUITE 222	EDMONTON	AB	T6G 1K8		CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	12	5/25/2017	NON-COMPETING CONTINUATION	$28,426
2017	2017	THE GOVERNORS OF THE UNIVERSITY OF ALBERTA	8625 112 ST NW SUITE 222	EDMONTON	AB	T6G 1K8		CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	1/11/2017	NON-COMPETING CONTINUATION	$255,843
														Subtotal = $284,269

Issue Date FY: 2016 ( Subtotal = $286,269 )
2016	2016	UNIVERSITY OF ALBERTA	Administration Building	CALGARY, ALBERTA				CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	2/18/2016	COMPETING CONTINUATION	$286,269
2016	2014	UNIVERSITY OF ALBERTA	**	CALGARY, ALBERTA		00000		CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	2/16/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $286,269

Issue Date FY: 2014 ( Subtotal = $273,528 )
2014	2014	UNIVERSITY OF ALBERTA	Administration Building	CALGARY, ALBERTA				CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	5/5/2014	NON-COMPETING CONTINUATION	$273,528
														Subtotal = $273,528

Issue Date FY: 2013 ( Subtotal = $266,620 )
2013	2013	UNIVERSITY OF ALBERTA	Administration Building	CALGARY, ALBERTA				CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	6/3/2013	EXTENSION WITH OR WITHOUT FUNDS	$266,620
														Subtotal = $266,620

Issue Date FY: 2012 ( Subtotal = $276,290 )
2012	2012	UNIVERSITY OF ALBERTA	Administration Building	CALGARY, ALBERTA				CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	5/2/2012	NON-COMPETING CONTINUATION	$276,290
														Subtotal = $276,290

Issue Date FY: 2011 ( Subtotal = $276,290 )
2011	2011	UNIVERSITY OF ALBERTA	Administration Building	CALGARY, ALBERTA				CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	5/30/2011	NON-COMPETING CONTINUATION	$276,290
														Subtotal = $276,290

Issue Date FY: 2010 ( Subtotal = $279,081 )
2010	2010	UNIVERSITY OF ALBERTA	Administration Building	CALGARY, ALBERTA				CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	6/8/2010	COMPETING CONTINUATION	$279,081
														Subtotal = $279,081

Issue Date FY: 2007 ( Subtotal = $230,292 )
2007	2007	UNIVERSITY OF ALBERTA	**	CALGARY, ALBERTA		00000		CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/26/2007	NON-COMPETING CONTINUATION	$230,292
														Subtotal = $230,292

Issue Date FY: 2006 ( Subtotal = $237,170 )
2006	2006	UNIVERSITY OF ALBERTA	**	CALGARY, ALBERTA		00000		CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/19/2006	NON-COMPETING CONTINUATION	$237,170
														Subtotal = $237,170

Issue Date FY: 2005 ( Subtotal = $242,877 )
2005	2005	UNIVERSITY OF ALBERTA	**	CALGARY, ALBERTA		00000		CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/19/2005	NON-COMPETING CONTINUATION	$242,877
														Subtotal = $242,877

Issue Date FY: 2004 ( Subtotal = $244,877 )
2004	2004	UNIVERSITY OF ALBERTA	**	CALGARY, ALBERTA		00000		CAN	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/8/2004	NEW	$244,877
														Subtotal = $244,877

Grand Total All Awards = $3,750,370

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DIFFERING NEURONAL MECHANISMS MEDIATING LOCOMOTION AND SPASMS AFTER SPINAL CORD INJURY

Award Number: R01NS047567

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: 09/15/2004

PERIOD OF PERFORMANCE END DATE: 01/31/2022

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