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Perineuronal nets, hippocampal plasticity and autism spectrum disorder

Award Number: R01MH118631
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/19/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Perineuronal nets, hippocampal plasticity and autism spectrum disorder - Project Abstract Autism spectrum disorder (ASD) is a heterogeneous condition affecting approximately 1 in 59 children in the US. ASD is characterized by deficits in social interactions, repetitive behaviors and/or restricted interests, and is often associated with intellectual disability. Although ASD is clearly developmental, with diagnoses typically occurring by 2-3 years of age, most people do not outgrow the diagnosis and continue to suffer with dysfunction in adulthood. Adults with ASD experience greater unemployment and social isolation than their peers with other developmental disorders, strongly supporting the need for therapies targeted to adults. A few studies have reported improvements in symptoms of ASD patients with interventions in adulthood, raising the possibility that plastic processes in the adult ASD brain may be enhanced to optimize function. Many brain regions have been implicated in ASD but among them the hippocampus is notable in that it is involved in both social and cognitive behavior and displays ongoing plasticity throughout life. Perineuronal nets (PNNs) are extracellular matrix structures that dampen plasticity and have been linked to neuropsychiatric disease. Studies have found evidence for mutations in genes associated with the extracellular matrix in ASD but previous work has not investigated whether PNNs contribute to social and cognitive dysfunction. Research indicates that PNNs and orthodenticle homeobox 2 (OTX2), a transcription factor important for PNN maintenance, are excessive in ASD mice in the hippocampal CA2 and CA3 regions, areas important for social and contextual/spatial processing. No studies have investigated whether interventions that normalize PNNs and OTX2 in the hippocampus mitigate problematic behaviors associated with ASD. Previous work suggests that ASD mice have reduced postnatal neurogenesis in the hippocampus and since adult-generated neurons contribute to social behavior as well as learning and memory, diminished adult neurogenesis may exacerbate ASD symptoms. Many target sites of new neurons in the hippocampus are surrounded by PNNs and since PNNs are known to inhibit plasticity, their over production in ASD may prevent optimal connections from forming. This proposal will address gaps in our understanding about how aberrant PNNs and their connections with adult-generated neurons contribute to behavioral dysfunction in ASD mice. The experiments will use transgenic and inbred ASD mouse models, manipulations of PNNs and OTX2, retroviral labeling of new neurons, immunolabeling with confocal and electron microscopy, drug and experiential stimulation of neurogenesis and behavioral analyses to explore the efficacy of interventions to mitigate ASD symptoms by normalizing PNNs, reducing OTX2 and optimizing connections between new neurons and PNN+ targets. The proposed work will advance our understanding of how structural plasticity in the hippocampus may be enhanced in the service of improving social and cognitive dysfunction in adults with ASD.


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: 2023 ( Subtotal = $401,146 )
2023	2023	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Mental Health Research Grants	000	5	4/17/2023	NON-COMPETING CONTINUATION	$401,146
														Subtotal = $401,146

Issue Date FY: 2022 ( Subtotal = $401,146 )
2022	2022	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Mental Health Research Grants	000	4	4/15/2022	NON-COMPETING CONTINUATION	$401,146
														Subtotal = $401,146

Issue Date FY: 2021 ( Subtotal = $401,146 )
2021	2021	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Mental Health Research Grants	000	3	4/9/2021	NON-COMPETING CONTINUATION	$401,146
														Subtotal = $401,146

Issue Date FY: 2020 ( Subtotal = $401,146 )
2020	2020	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Mental Health Research Grants	000	2	4/16/2020	NON-COMPETING CONTINUATION	$401,146
														Subtotal = $401,146

Issue Date FY: 2019 ( Subtotal = $401,146 )
2019	2019	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Mental Health Research Grants	000	1	7/19/2019	NEW	$401,146
														Subtotal = $401,146

Grand Total All Awards = $2,005,730

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Perineuronal nets, hippocampal plasticity and autism spectrum disorder

Award Number: R01MH118631

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/19/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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