Providing new insight into adolescent dendritic development

Active Project Grant Awarded Last action

Award ID
R01MH132586
Recipient
Awarding agency
Obligated
$3,231,293

Award facts

Assistance listing
93.242 Mental Health Research Grants
Completion date 59% complete
Place of performance
Pittsburgh, PA 15213, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Transactions

Action Obligated Date
Amendment $647,146
Amendment $78,259
Amendment $78,259
Amendment $443,475
Amendment $443,475
Amendment $51,601
Amendment $51,601
Amendment $479,159
Amendment $479,159
Original award $479,159

Subawards

Subrecipient Amount Awarded
Research Foundation For Mental Hygiene Inc. Providing New Insight Into Adolescent Dendritic Development $101,367
Research Foundation For Mental Hygiene, Inc. $86,162
Georgia State University Research Foundation Inc. $101,369

Quick answers

Who received award R01MH132586?

R01MH132586 was awarded to University Of Pittsburgh - Of The Commonwealth System Of Higher Education by National Institute of Mental Health (National Institutes of Health) on December 1, 2023.

How much is award R01MH132586 worth?

$3,231,293 has been obligated on R01MH132586.

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