Summary: Researchers have identified two central brain mechanisms that appear to underlie psilocybin’s durable antidepressant effects: a specific pyramidal cell type in the medial frontal cortex and the serotonin 5-HT2A receptor. The new study points to pyramidal tract neurons as crucial mediators of psilocybin’s therapeutic action, while implicating the 5-HT2A receptor in both the therapeutic and perceptual responses to the drug.
The work distinguishes the neural circuitry that supports mood improvement from the circuits that produce subjective perceptual experiences. While the medial frontal cortex—particularly pyramidal tract neurons—seems necessary for sustained antidepressant effects, the hallucinatory “trip” likely arises from other regions, such as visual pathways. These findings may guide future strategies to deliver psychedelic-based therapies more selectively, maximizing clinical benefit while reducing unwanted hallucinatory effects.
Key Facts:
- Cell Target Identified: Pyramidal tract (PT) neurons in the medial frontal cortex are required for psilocybin’s antidepressant-like actions.
- Receptor Involved: The serotonin 5-HT2A receptor is essential for both the drug’s long-lasting behavioural effects and its perceptual effects.
- Implication for Drug Design: Region-specific targeting of drugs may allow therapeutic benefits to be retained while minimizing hallucinatory side effects.
Source: Cornell University
Psilocybin, the active compound in “magic mushrooms,” has shown promise for treating depression in clinical and preclinical studies. Cornell University researchers set out to map how psilocybin’s cellular effects translate into sustained changes in behaviour and mood by identifying which cell types and receptors are necessary for those effects.
Led by Alex Kwan, associate professor of biomedical engineering, the team combined in vivo optical imaging, chemogenetic perturbation and cell-type-specific electrophysiology to observe how psilocybin affects the two primary pyramidal cell types in the mouse medial frontal cortex: the subcortical-projecting pyramidal tract (PT) neurons and intratelencephalic (IT) neurons.
A single dose of psilocybin increased dendritic spine density in both PT and IT cell types, indicating drug-evoked structural plasticity. However, functional and behavioural experiments revealed a cell-type-specific role: selective silencing of PT neurons removed psilocybin’s ability to improve stress-related behaviours, while silencing IT neurons produced no detectable change in those behavioural outcomes. In addition, psilocybin acutely increased synaptic calcium transients and firing rates specifically in PT neurons.
The researchers also showed that targeted removal of 5-HT2A receptors prevents both the structural plasticity and the behavioural benefits normally produced by psilocybin. Together, these results indicate that PT neurons and the 5-HT2A receptor in the medial frontal cortex are essential to the drug’s lasting antidepressant-like effects.
These findings have practical implications for the development of psychedelic-derived therapies. Many pharmaceutical efforts aim to preserve the therapeutic mood benefits of compounds like psilocybin while eliminating perceptual side effects such as hallucinations. Because both therapeutic and perceptual responses appear to engage the same receptor, one promising alternative may be to deliver drugs more selectively to the brain regions responsible for mood regulation—targeting the medial frontal cortex circuitry that mediates antidepressant effects—rather than attempting to block the receptor system-wide.
“We asked which cell types are important for psilocybin’s behavioural effects,” said Kwan. “If we silence some of these neurons, will psilocybin still be able to do its thing and be therapeutic? The results highlight that region- and cell-type-specific actions matter for separating therapeutic benefits from subjective effects.”
Funding: The research was supported by the National Institutes of Health; a One Mind–COMPASS Rising Star Award; Source Research Foundation; and the Connecticut Department of Mental Health and Addiction Services.
About this neuropharmacology and psychedelics research news
Author: Becka Bowyer
Source: Cornell University
Contact: Becka Bowyer – Cornell University
Image: The image is credited to Neuroscience News
Original Research: Closed access. “Psilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors” by Alex Kwan et al., published in Nature.
Abstract
Psilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors
Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses. At the cellular level, psychedelics induce structural neural plasticity, exemplified by drug-evoked growth and remodeling of dendritic spines in cortical pyramidal cells. A key question is how these cellular modifications map onto cell-type-specific circuits to produce the behavioural actions of psychedelics.
Using in vivo optical imaging, chemogenetic perturbation and cell-type-specific electrophysiology, the study examined the two main pyramidal cell types in the mouse medial frontal cortex. A single dose of psilocybin increased dendritic spine density in both subcortical-projecting PT cells and intratelencephalic IT cells. Behaviourally, silencing PT neurons eliminated psilocybin’s ability to ameliorate stress-related phenotypes, while 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 behaviour and structural plasticity.
Collectively, these results identify a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex as essential players in psilocybin’s long-term drug action, clarifying the cellular and circuit mechanisms that support its antidepressant-like effects.