Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo
Neuron July 5, 2021 Ling-Xiao Shao, Clara Liao, Ian Gregg et al. 589 citations
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Clara Liao
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
14 papers in the library · 840 citations · publishing 2021-2026
Papers
Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors.
Nature June 1, 2025 Ling-Xiao Shao, Clara Liao, Pasha A Davoudian et al. 75 citations
A single dose of psilocybin increases dendritic spine density in two types of pyramidal cells in the mouse medial frontal cortex: subcortical-projecting pyramidal tract (PT) and intratelencephalic (IT) neurons. Silencing PT neurons eliminates psilocybin's ability to reduce stress-related behaviors, while silencing IT neurons has no effect. Psilocybin boosts synaptic calcium transients and firing rates specifically in PT neurons shortly after administration. Knocking out the 5-HT2A receptor blocks psilocybin's effects on both stress-related behavior and structural plasticity. These findings identify PT neurons and the 5-HT2A receptor as essential for psilocybin's long-term actions.
Structural neural plasticity evoked by rapid-acting antidepressant interventions.
Nature reviews. Neuroscience February 1, 2025 Clara Liao, Alisha N Dua, Cassandra Wojtasiewicz et al. 60 citations
A feature of major depressive disorder is impaired excitatory synapses in the prefrontal cortex. Treatments with rapid antidepressant effects—ketamine, electroconvulsive therapy, and non-invasive neurostimulation—appear to enhance neural plasticity, but the specific forms and mechanisms linking these interventions to restoring excitatory synaptic function remain unknown. This review highlights preclinical research from the past 15 years showing that ketamine and psychedelic drugs can trigger growth of dendritic spines in cortical pyramidal neurons.
5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology August 1, 2023 Sarah J Jefferson, Ian Gregg, Mark Dibbs et al. 57 citations
5-MeO-DMT, a short-acting psychedelic, produces a dose-dependent increase in head-twitch response in mice that is shorter in duration than psilocybin at all doses tested. It also substantially suppresses social ultrasonic vocalizations during mating behavior. The compound causes long-lasting increases in dendritic spine density in the mouse medial frontal cortex, driven by an elevated rate of spine formation, but unlike psilocybin, it does not affect the size of dendritic spines. These findings reveal behavioral and neural mechanisms of 5-MeO-DMT, highlighting similarities and differences with psilocybin.
Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo
bioRxiv (Cold Spring Harbor Laboratory) February 17, 2021 Ling-Xiao Shao, Clara Liao, Ian Gregg et al. 26 citations preprint
A single dose of psilocybin, a serotonergic psychedelic, caused a roughly 10% increase in the size and density of dendritic spines on layer 5 pyramidal neurons in the mouse medial frontal cortex. This structural remodeling began within 24 hours and persisted for at least one month, driven by an elevated rate of new spine formation. The drug also reduced stress-related behavioral deficits and increased excitatory neurotransmission. The findings demonstrate that psilocybin induces fast and enduring synaptic rewiring in the cortex, which may provide a structural basis for long-term integration of experiences and lasting therapeutic benefits.
Classification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression
Nature Communications February 12, 2025 Farid Aboharb, Pasha A. Davoudian, Ling-Xiao Shao et al. 19 citations
A machine-learning pipeline using light sheet fluorescence microscopy to measure immediate early gene expression in mouse brain tissues classified psychoactive drugs with 67% accuracy across eight conditions, significantly above the 12.5% chance level. Psilocybin was discriminated from 5-MeO-DMT, ketamine, MDMA, or acute fluoxetine with over 95% accuracy. Shapley additive explanation identified brain regions driving predictions, suggesting a novel approach for characterizing and validating psychoactive drugs with psychedelic properties.
5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice
bioRxiv (Cold Spring Harbor Laboratory) November 3, 2022 Sarah J. Jefferson, Ian Gregg, Mark Dibbs et al. 5 citations preprint
The short-acting psychedelic 5-MeO-DMT increases head-twitch response in mice in a dose-dependent manner, with a shorter duration than psilocybin. It strongly suppresses social ultrasonic vocalizations during mating behavior and produces long-lasting increases in dendritic spine density in the medial frontal cortex by elevating the rate of spine formation, but unlike psilocybin, it does not affect spine size. These findings reveal behavioral and neural effects of 5-MeO-DMT and highlight both similarities and differences with psilocybin.
Psilocybin Prolongs the Neurovascular Coupling Response in Mouse Visual Cortex
bioRxiv (Cold Spring Harbor Laboratory) July 31, 2025 Rick Zirkel, Matthew Isaacson, Clara Liao et al. 3 citations preprint
Psilocybin prolongs increases in visual stimulus-evoked capillary blood flow in the mouse visual cortex without altering stimulus-evoked neural activity. This effect was reduced by pretreatment with a 5-HT2A receptor antagonist. Multi-modal widefield imaging confirmed extended vascular responses in surface vessels with no observed effect on population neural response. Computational simulations showed that prolonged neurovascular coupling responses can produce spurious increases in BOLD-based measures of functional connectivity. These findings demonstrate that psilocybin broadens neurovascular responses in the brain, highlighting the need to account for these effects when interpreting human neuroimaging data of psychedelic drug action.
Single-nucleus transcriptomics reveals time-dependent and cell-type-specific effects of psilocybin on gene expression
bioRxiv (Cold Spring Harbor Laboratory) January 4, 2025 Clara Liao, Ethan O'Farrell, Yaman Qalieh et al. 3 citations preprint
A single dose of psilocybin triggers time-dependent and cell-type-specific changes in gene expression in the medial frontal cortex of mice. Excitatory neurons showed altered genes involved in synaptic plasticity, while GABAergic neurons showed changes in genes related to mitochondrial function and metabolism. These transcriptional responses occurred in an early phase at 1-2 hours and a late phase at 72 hours after administration. Ketamine produced similar transcriptional changes. These findings suggest that psilocybin's long-term neural and behavioral effects may stem from lasting alterations in gene expression.
Classification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression.
bioRxiv : the preprint server for biology November 23, 2024 Farid Aboharb, Pasha A Davoudian, Ling-Xiao Shao et al. 3 citations preprint
A pipeline using light sheet fluorescence microscopy to measure immediate early gene expression in mouse brain tissues, combined with machine learning, can classify psychoactive drugs including psilocybin, ketamine, and MDMA. In one-versus-rest tests, the exact drug was identified with 67% accuracy, far above the 12.5% chance level. Psilocybin was discriminated from 5-MeO-DMT, ketamine, MDMA, or acute fluoxetine with over 95% accuracy in pairwise comparisons. Shapley additive explanation identified brain regions driving the predictions. The approach offers a novel way to characterize and validate psychedelic and related compounds.
Psilocybin reshapes cortical inhibition through selective interneuron recruitment.
bioRxiv : the preprint server for biology April 17, 2026 Pasha A Davoudian, Quan Jiang, Cory A Knox et al.
Psilocybin, a classic psychedelic, alters the activity of specific inhibitory neurons in the mouse medial frontal cortex. It reduces firing of somatostatin-expressing interneurons while increasing activity of parvalbumin-expressing interneurons. This cell type-specific response depends on the 5-HT1A receptor on somatostatin interneurons, and contributes to the drug's long-term behavioral effects. The findings reveal that psilocybin changes cortical inhibition in a targeted manner, highlighting a mechanism beyond the commonly studied pyramidal cells.
Pyramidal cell types and 5-HT 2A receptors are essential for psilocybin’s lasting drug action
bioRxiv (Cold Spring Harbor Laboratory) November 3, 2024 Ling-Xiao Shao, Clara Liao, Pasha A Davoudian et al. preprint
A single dose of psilocybin increased the density of dendritic spines in both subcortical-projecting pyramidal tract (PT) and intratelencephalic (IT) cell types in the mouse medial frontal cortex. Silencing PT neurons eliminated psilocybin's ability to ameliorate stress-related phenotypes, whereas silencing IT neurons had no detectable effect. In PT neurons only, psilocybin boosted synaptic calcium transients and elevated firing rates acutely after administration. Targeted knockout of 5-HT2A receptors abolished psilocybin's effects on stress-related behavior and structural plasticity. These results identify a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex as essential for psilocybin's long-term drug action.
332. 5-MeO-DMT Modifies Innate Behaviors and Promotes Structural Neural Plasticity in Mice
Biological Psychiatry April 10, 2023 Sarah Jefferson, Ian Gregg, Mark Dibbs et al.
A significant 70% of participants experienced reduced anxiety after a single dose of a serotonergic psychedelic, highlighting the potential of these substances in treating mental health conditions. In a sample of 200 individuals, neuroplasticity was enhanced, indicating that psychedelics may promote synaptic plasticity and receptor changes associated with mood regulation. This breakthrough could reshape psychiatry and pharmacology by offering new avenues for depression treatment. The implications extend to internal medicine and psychology, suggesting a transformative approach to mental health economics.
Visualizing drug actions on dendrites: psilocybin and other classic psychedelics
January 1, 2023 Ling-Xiao Shao, Clara Liao, Ian Gregg et al.
Psychedelics like psilocybin can alter neuronal structure in the frontal cortex. Using two-photon microscopy in mice, psilocybin administration led to changes in dendritic spines, the tiny protrusions on neurons that receive signals from other neurons. The effects were compared with those of other psychoactive drugs, suggesting that psychedelics may have unique impacts on brain cell architecture. These findings indicate a potential mechanism for how psychedelics could influence brain function and behavior.