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Causal Interactions between genetic risk, precise cortical connectivity, and autism-associated behaviors

Award Number: R01NS110307
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: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Causal Interactions between genetic risk, precise cortical connectivity, and autism-associated behaviors - PROJECT SUMMARY The overarching goal of this project is to better understand the links between ASD genetic risk, resulting distributed brain connectivity impairments, and the impact of this on ASD-relevant behaviors. We will do this by performing state-of-the art in vivo electrophysiology studies in awake-behaving animals that model a monogenic form of ASD. This research project is significant because altered brain connectivity is routinely observed in ASD patients, though it remains unknown how brain connectivity alterations cause abnormal behaviors relevant to ASD. In the animal model, we will focus on behaviors that optimize active touch. This is approach is valid because altered sensory function, including touch, is a core manifestation of ASD and somatomotor brain areas display altered activation in ASD patients. An emerging idea is that altered functioning of sensory systems directly impairs the functions of other major neural domains, such as cognitive and social systems. Active touch arises through rapid adaptions in the dynamics of touch organs in response to physical contact with objects. This behavioral transformation optimizes touch-related input into the brain and is an emergent behavior resulting from sensorimotor integration at various levels in the nervous system. Therefore, we generally hypothesize that genetic variants that cause ASD disrupt key points of functional connectivity within the somatomotor system, which in turn causes altered active touch behaviors, leading to altered acquisition of tactile information. This hypothesis is significant because it could define a neural process (i.e. altered distributed functional connectivity) that explains how sensory-guided adaptive behaviors are impaired by genetic variants that cause ASD. Our modeling studies also have the potential to define how altered brain connectivity can disrupt relevant behaviors. We will test this hypothesis in the first aim by recording the flow of information throughout the major areas of the somato-motor system in a mouse model for a monogenic form of ASD. The proposed in vivo recordings in awake-behaving animals will utilize state-of-art silicon neural probes that will enable us to measure local and long-range functional connectivity of neurons during distinct behaviors, including during active touches of objects. These sophisticated measurements will identify circuits that are functionally impaired during ASD-relevant behaviors. The second aim takes a distinct, but complementary approach by regionally and temporally disrupting expression of the causal ASD gene and then observing the impact of these perturbations on behaviors that define etiologically-relevant active touch. We expect to find that proper expression of the ASD gene is required in developing somatomotor cortical areas to promote normal active touch behaviors. The combined impact of these complementary approaches is that they are expected to define the circuits that cause abnormal active touch-related behaviors in the mouse model. Thus, the proposed research is expected to advance our understanding of how major ASD risk genes disrupt the connectivity of neural circuits that underlie relevant behaviors.


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 = $0 )
2025	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	4/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $509,411 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	4/16/2024	NON-COMPETING CONTINUATION	$36,761
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	11/9/2023	NON-COMPETING CONTINUATION	$472,650
														Subtotal = $509,411

Issue Date FY: 2023 ( Subtotal = $525,167 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	2/2/2023	NON-COMPETING CONTINUATION	$52,517
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	11/30/2022	NON-COMPETING CONTINUATION	$472,650
2023	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/14/2022	NON-COMPETING CONTINUATION	-$97,553
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	11/14/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$97,553
														Subtotal = $525,167

Issue Date FY: 2022 ( Subtotal = $525,167 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/15/2021	NON-COMPETING CONTINUATION	$472,650
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/28/2022	NON-COMPETING CONTINUATION	$52,517
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	6/7/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$197,423
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	6/6/2022	NON-COMPETING CONTINUATION	-$197,423
														Subtotal = $525,167

Issue Date FY: 2021 ( Subtotal = $525,167 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/23/2020	NON-COMPETING CONTINUATION	$472,650
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/26/2021	NON-COMPETING CONTINUATION	$52,517
														Subtotal = $525,167

Issue Date FY: 2020 ( Subtotal = $553,017 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/29/2019	NEW	$553,017
														Subtotal = $553,017

Grand Total All Awards = $2,637,929

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Causal Interactions between genetic risk, precise cortical connectivity, and autism-associated behaviors

Award Number: R01NS110307

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: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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