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Serotonin-mediated reorganization of the adolescent medial prefrontal cortex

Award Number: R56MH139698
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Serotonin-mediated reorganization of the adolescent medial prefrontal cortex - Summary Adolescence is associated with a high incidence of anxiety-related disorders, which often require lifelong management. Anxiety disorders in adolescents are a leading cause of disabilities, as they negatively impact the development of social, cognitive, emotional, and educational skills. The increased prevalence of anxiety disorders during adolescence coincides with the suppression of fear extinction, an inhibitory learning that attenuates conditioned fear memory. Consistently, cognitive behavioral therapy (CBT), which relies on the principles of fear extinction, is effective in only a subset of affected adolescents. Recent studies show that a combination of CBT and selective serotonin (5-hydroxytryptamine, 5HT) reuptake inhibitors (SSRIs) exhibits superior effectiveness compared to either CBT or SSRIs alone in adolescents, suggesting a potential interaction between 5HT signaling and fear extinction. However, little is known about how 5HT modulates the adolescent ventromedial prefrontal cortex, a brain region that mediates the expression of fear extinction. Based on our recent studies, the goal of this proposal is to determine whether and how enhancing 5HT transmission in the mouse infralimbic medial prefrontal cortex (ILmPFC), a brain region analogous to the primate ventromedial prefrontal cortex, during adolescence suppresses activity in ILmPFC somatostatin (SST) neurons and hence augments ILmPFC-mediated top-down regulation of the amygdala and fear extinction in adolescents and adults. These studies are particularly important as SST neuron-mediated inhibition in the ILmPFC is increased during adolescence, and this development-dependent GABAergic plasticity overlaps with an attenuation of ILmPFC pyramidal neuron plasticity and a suppression of fear extinction in adolescents. Our studies show that 5HT enhances synaptic inhibition in ILmPFC SST neurons by acting on synapses from upstream 5HT3a receptor- expressing neurons. We hypothesize that activating the ILmPFC 5HT transmission during adolescence augments synaptic inhibition in ILmPFC SST neurons, leading to 1) a reduced inhibition of pyramidal neurons, 2) an augmentation of ILmPFC-mediated top-down regulation of the amygdala, and 3) an enhancement of fear extinction in adolescents and adults. We will test this hypothesis by establishing whether activation of ILmPFC 5HT transmission during adolescence suppresses ILmPFC SST neuron activity and ILmPFC SST neuron- mediated GABAergic transmission in adolescents and adults (Aim 1), enhances ILmPFC-mediated glutamatergic transmission in the basomedial amygdala of adolescents and adults (Aim 2), and augments fear extinction in adolescents and adults (Aim 3). The findings of this study are expected to provide critical mechanistic insights into future evidence-based and developmentally tailored therapeutic approaches to managing anxiety disorders in adolescents and adults.


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 = $0 )
2026	2025	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Mental Health Research Grants	000	1	4/9/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $545,759 )
2025	2025	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Mental Health Research Grants	000	1	5/21/2025	NEW	$545,759
														Subtotal = $545,759

Grand Total All Awards = $545,759

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Serotonin-mediated reorganization of the adolescent medial prefrontal cortex

Award Number: R56MH139698

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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