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Mechanisms of Psilocybin-Induced Restoration of Cognitive Flexibility Following Chronic Stress

Award Number: F30MH146024
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Mechanisms of Psilocybin-Induced Restoration of Cognitive Flexibility Following Chronic Stress - Project Summary: Major Depressive Disorder (MDD) is one of the leading causes of disability in the United States and there is tremendous unmet need for improved treatments. Cognitive flexibility deficits are a core feature of MDD and many other stress-related illnesses. Psychedelic-assisted therapy has shown promise in clinical trials for treating MDD and other illnesses and has been shown to promote cognitive flexibility in patients with MDD for up to 4 weeks after a single administration. The promotion of cognitive flexibility may represent a trans-diagnostic therapeutic mechanism through which psychedelic-assisted therapy exerts its therapeutic effects. This project seeks to test this hypothesis using rodent models to assay how psychedelics promote cognitive flexibility following chronic stress. Preliminary data using attentional set-shifting models of cognitive flexibility indicate that the effects of chronic stress and psilocybin may be selective for novel, as opposed to familiar, attentional set-shifts and that psilocybin may provide sustained rescue of chronic stress deficits in attentional set-shifting. This project tests the hypothesis that 5-HT2A agonism directly on layer V neurons in the prelimbic cortex is both necessary and sufficient for psychedelic-mediated rescue of dendritic spine density following chronic stress. Moreover, it is hypothesized that the rescue of attentional set-shifting is influenced by the context in which the psychedelic is administered. Aim 1 will involve psilocybin dose-response experiments and will utilize a novel behavioral paradigm allowing for introduction of two novel set-shifts to measure whether the context of an initial set-shift under the acute effects of psilocybin will affect outcomes on a set-shift several days later. Aim 2.1 will use a novel selective 5-HT2A agonist (TGF-8027) and a selective 5- HT2A antagonist (M100907) to determine whether systemic 2A agonism is necessary and sufficient for psilocybin rescue of attentional set-shifting and dendritic spine density following chronic stress. Aim 2.2 will use CRISPR interference to selectively knock down Htr2a in the prelimbic cortex to determine whether 5-HT2A in prelimbic neurons is necessary for psilocybin rescue of attentional set-shifting following chronic stress. The fellowship will allow for comprehensive technical training and integrated clinical and professional development; a team of mentors with expertise in behavioral analysis, pharmacology and drug development, neuronal imaging, genetic manipulations, and clinical expertise has been formed to provide guidance on all aspects of the project. Technical training will include coursework in programming, sophisticated behavioral analysis and coding, novel drug development, dendritic spine imaging and analysis, and cutting-edge CRISPR-based genetic manipulations. Additionally, clinical experiences, community-engaged harm reduction initiatives, public policy engagement, conference attendance, teaching, and other activities have been planned to allow the candidate to progress to the next stage of their career in becoming an independent physician-neuroscientist.


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 = $52,114 )
2026	2026	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Mental Health Research Grants	000	1	8/6/2026	NEW	$52,114
2026	2026	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Mental Health Research Grants	001	1	8/6/2026	NEW	$0
														Subtotal = $52,114

Grand Total All Awards = $52,114

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Mechanisms of Psilocybin-Induced Restoration of Cognitive Flexibility Following Chronic Stress

Award Number: F30MH146024

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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