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Molecular Analysis of Neural Circuit Excitation and Inhibition

Award Number: R01NS064263
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: 09/15/2009
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Molecular Analysis of Neural Circuit Excitation and Inhibition - Developmental remodeling of circuit connectivity is a key process in shaping the mature organization of neural circuits in the brain, optimizing their connectivity in order to perform specific functions. Remodeling is triggered by both environmental stimuli and intrinsic genetic mechanisms, and deficits in remodeling processes are thought to be a primary factor underlying altered patterns of connectivity observed in a variety of neurodevelopmental and neuropsychiatric disorders. Despite the clear importance of these developmental processes for normal brain physiology and health, there are major gaps in our understanding of the cellular and molecular mechanisms that regulate neural circuit remodeling. Studies of genetic models have proven to be extremely fruitful for identifying fundamental mechanisms underlying neural circuit development and function. Our previous studies have pioneered new approaches for elucidating mechanisms for the specification of synaptic connectivity in a genetically tractable model, the nematode Caenorhabditis elegans. During the previous funding period, we demonstrated the remodeling of postsynaptic specializations located on GABAergic neurons in the C. elegans motor circuit, and showed that the formation of new synapses during remodeling is associated with the outgrowth of previously uncharacterized spines on GABAergic dendrites. Moreover, we uncovered a novel mechanism required for spine outgrowth and synapse assembly that depends on the synaptic organizer neurexin. These findings demonstrate the strength of this system for identifying key genes with conserved roles in shaping neural circuit connectivity and place us in a strong position for a deep investigation of in vivo molecular mechanisms. Indeed, in preliminary studies supporting this application we have identified the homeodomain transcription factor DVE-1, a homolog of mammalian chromatin organizers SATB1/2, as a key hub for regulation of synapse elimination during remodeling of the motor circuit. In Aim 1 of this proposal we investigate a novel transcriptional network controlling synapse disassembly and elimination. In Aim 2, we explore cellular and molecular mechanisms underlying the assembly of new synapses during circuit remodeling, focusing on the role of the conserved synaptic organizer neurexin. We expect that our studies of this experimentally tractable circuit in the worm will have a major impact on our understanding of the molecular processes involved in circuit remodeling. Additionally, we anticipate that the novel molecules and signaling mechanism we identify will be excellent candidates for therapeutic intervention to treat neurodevelopmental disorders involving disruptions in circuit connectivity.


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 = $399,690 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	11/15/2024	NON-COMPETING CONTINUATION	$399,690
														Subtotal = $399,690

Issue Date FY: 2024 ( Subtotal = $435,798 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	11/14/2023	NON-COMPETING CONTINUATION	$404,351
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	4/22/2024	NON-COMPETING CONTINUATION	$31,447
														Subtotal = $435,798

Issue Date FY: 2023 ( Subtotal = $522,879 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	12	1/30/2023	NON-COMPETING CONTINUATION	$44,926
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	12	2/8/2023	SUPPLEMENT FOR EXPANSION	$73,602
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	12/2/2022	NON-COMPETING CONTINUATION	$404,351
														Subtotal = $522,879

Issue Date FY: 2022 ( Subtotal = $449,277 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	3/24/2022	NON-COMPETING CONTINUATION	$44,925
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	11/3/2021	NON-COMPETING CONTINUATION	$404,352
														Subtotal = $449,277

Issue Date FY: 2021 ( Subtotal = $449,277 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	12/28/2020	COMPETING CONTINUATION	$449,277
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	1/7/2021	COMPETING CONTINUATION	$0
2021	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	9	8/21/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $449,277

Issue Date FY: 2019 ( Subtotal = $366,406 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	12/13/2018	NON-COMPETING CONTINUATION	$366,406
														Subtotal = $366,406

Issue Date FY: 2018 ( Subtotal = $366,406 )
2018	2018	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	5/7/2018	NON-COMPETING CONTINUATION	$36,641
2018	2018	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	12/13/2017	NON-COMPETING CONTINUATION	$329,765
														Subtotal = $366,406

Issue Date FY: 2017 ( Subtotal = $366,406 )
2017	2017	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	6/2/2017	NON-COMPETING CONTINUATION	$36,641
2017	2017	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	12/6/2016	NON-COMPETING CONTINUATION	$329,765
														Subtotal = $366,406

Issue Date FY: 2016 ( Subtotal = $366,406 )
2016	2016	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	12/24/2015	COMPETING CONTINUATION	$366,406
														Subtotal = $366,406

Issue Date FY: 2013 ( Subtotal = $340,304 )
2013	2013	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/13/2013	NON-COMPETING CONTINUATION	$317,383
2013	2013	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/24/2013	NON-COMPETING CONTINUATION	$22,921
														Subtotal = $340,304

Issue Date FY: 2012 ( Subtotal = $352,647 )
2012	2012	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/29/2012	NON-COMPETING CONTINUATION	$352,647
														Subtotal = $352,647

Issue Date FY: 2011 ( Subtotal = $352,647 )
2011	2011	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/14/2011	NON-COMPETING CONTINUATION	$323,859
2011	2011	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	6/3/2011	NON-COMPETING CONTINUATION	$28,788
														Subtotal = $352,647

Issue Date FY: 2010 ( Subtotal = $356,246 )
2010	2010	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/4/2010	NON-COMPETING CONTINUATION	$356,246
														Subtotal = $356,246

Issue Date FY: 2009 ( Subtotal = $359,480 )
2009	2009	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/11/2009	NEW	$359,480
														Subtotal = $359,480

Grand Total All Awards = $5,483,869

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Molecular Analysis of Neural Circuit Excitation and Inhibition

Award Number: R01NS064263

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: 09/15/2009

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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