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Synaptic circuit mechanisms underlying psilocybin's therapeutic effects in the stressed brain

Award Number: R01MH136381
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/25/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Synaptic circuit mechanisms underlying psilocybin's therapeutic effects in the stressed brain - PROJECT SUMMARY Psychedelics are chemicals best known for their ability to induce profound changes in the human conscious experience. After a several-decade hiatus, research on psychedelics is undergoing a renaissance, driven by their potential to treat psychiatric disorders with rapid onset and enduring effect. Recent research reveals that psychedelics can rapidly promote the structural and functional plasticity of synapses, leading to the conjecture that neural plasticity underlies their long-term therapeutic values. However, the neurobiological mechanisms remain largely elusive. Our overarching goal is to understand the cellular and circuit mechanisms underlying psychedelics’ long-lasting therapeutic effects. In this proposal, we focus on the classical serotonergic psychedelic psilocybin and investigate how it rescues the deleterious effects of stress, a major risk factor for many neuropsychiatric disorders. Our central hypothesis is that psilocybin affects the brain at multiple levels, from synaptic plasticity to the functional network; although psilocybin only transiently enhances synapse formation, it permanently alters the synaptic circuit in an experience-dependent manner; the incorporation of new synapses into the neural circuit is essential for psilocybin’s long-lasting rescue of stress-induced functional and behavioral deficits. Specifically, in Aim 1, we will determine the acute and enduring effects of psilocybin on the stressed brain, particularly on the structural reorganization of synaptic circuits, on cortical functional networks, and on the representation of behavioral variables by cortical neuronal ensembles. Aim 2 determines how the environmental and behavioral contexts in which psilocybin is administered impact its rescuing effects on the stressed brain. Aim 3 determines the contribution of psilocybin-induced neuroplasticity, particularly the stabilization of newly formed dendritic spines, to its rescuing effects on the stressed brain. Overall, these studies will provide an integrated, mechanistic understanding of psilocybin’s rescuing effects across the organizational hierarchy of the brain, from molecules and synapses to circuits and functional networks, and lay the foundation for its clinical application in treating stress-related psychiatric disorders.


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	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Mental Health Research Grants	000	1	12/16/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Mental Health Research Grants	000	1	8/28/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $679,118 )
2024	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Mental Health Research Grants	000	1	9/24/2024	NEW	$679,118
														Subtotal = $679,118

Grand Total All Awards = $679,118

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Synaptic circuit mechanisms underlying psilocybin's therapeutic effects in the stressed brain

Award Number: R01MH136381

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/25/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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