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Providing New Insight Into Adolescent Dendritic Development

Award Number: R01MH132586
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Providing New Insight Into Adolescent Dendritic Development - Project Summary/Abstract. The extent of a neuron’s dendritic arbor plays a critical role in the processing of sensory information in mammalian neocortex. Dendrites grow rapidly after birth and then exhibit an apparent stability during adolescence and adulthood resulting from a dynamic, homeostatic balance of opposing growth and retraction pathways. Disruption of this balance could induce structural changes in previously formed dendritic arbors, leading to deficits in cortical dendritic architecture which characterize several adolescent-onset neuropsychiatric disorders. Many of the factors controlling dendritic growth and regression in adolescence remain unknown, creating a critical gap in knowledge regarding both normal and abnormal adolescent dendritic development. We recently identified that Oligodendrocyte Myelin Glycoprotein (OMGp) in can induce dendritic regression, via a Kalirin-9 (KAL9) dependent mechanism. OMGp expression increases naturally across adolescence, suggesting it contributes to the apparent dendritic stability in adolescence by counterbalancing growth signals. In support of this interpretation, we observed that a gain of function (GOF) in OMGp signaling (ie KAL9-PT) induces adolescent-onset dendritic regression in Layer 3 pyramidal cells (PCs) in primary auditory cortex in vivo. In addition to the shape of its dendritic arbor, the extent of a PC’s output is determined through tight control of dendritic postsynaptic integration by inhibitory somatostatin (SST) neurons. Inhibitory synapses from SST cells targeting the dendrites of Layer 2/3 PCs in primary sensory cortex are highly dynamic even into adulthood, and therefore may remain susceptible to adolescent-onset changes in dendritic architecture. This proposal seeks to test the overall hypothesis that OMGp is a critical regulator of normal dendritic development in adolescence and increased activity downstream of OMGp leads to dendritic regression with resultant functional impairments in SST-dependent intracortical sensory processing. We will test this hypothesis in a set of integrated Aims. Aim 1 will induce oligodendrocyte- and neuronal-specific OMGp KO at timepoints spanning adolescence to examine the role of cell-type specific OMGp in maintaining cortical dendritic architecture stability. Aim 2 will identify the functional consequences of adolescent-onset dendritic regression on cortical signal processing, using a highly translational auditory stimulation paradigm and chemicogenetic suppression to evaluate the impact on SST- dependent (and as a comparator parvalbumin (PV)-dependent) cortical processing. Completion of these studies will serve to increase basic knowledge of dendrite development and cortical refinement during adolescence, and how OMGp influences these processes.


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: 2026 ( Subtotal = $647,146 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	000	3	12/3/2025	NON-COMPETING CONTINUATION	$647,146
														Subtotal = $647,146

Issue Date FY: 2025 ( Subtotal = $521,734 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	000	2	11/18/2024	NON-COMPETING CONTINUATION	$443,475
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	001	2	9/18/2025	NON-COMPETING CONTINUATION	$78,259
														Subtotal = $521,734

Issue Date FY: 2024 ( Subtotal = $530,760 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	000	1	11/24/2023	NEW	$479,159
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	001	1	5/10/2024	NEW	$51,601
														Subtotal = $530,760

Grand Total All Awards = $1,699,640

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Providing New Insight Into Adolescent Dendritic Development

Award Number: R01MH132586

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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