Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo
This cell study shows that brain cells, specifically the layer five pyramidal neurons in mice, grew by 10% after the introduction of psilocybin. The effects were still present 30 days later, providing more evidence for brain plasticity as an underlying mechanism of psychedelic-assisted therapies' long-lasting effects.
Abstract
Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. There are hints that the use of psychedelics can produce neural adaptations, although the extent and timescale of the impact in a mammalian brain are unknown. In this study, we used chronic two-photon microscopy to image longitudinally the apical dendritic spines of layer 5 pyramidal neurons in the mouse medial frontal cortex. We found that a single dose of psilocybin led to ∼10% increases in spine size and density, driven by an elevated spine formation rate. The structural remodeling occurred quickly within 24 h and was persistent 1 month later. Psilocybin also ameliorated stress-related behavioral deficit and elevated excitatory neurotransmission. Overall, the results demonstrate that psilocybin-evoked synaptic rewiring in the cortex is fast and enduring, potentially providing a structural trace for long-term integration of experiences and lasting beneficial actions.
Research Summary of 'Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo'
Introduction
Serotonergic psychedelics produce atypical conscious states with altered perception, cognition and mood, and have long been investigated for therapeutic potential in disorders such as depression, obsessive-compulsive disorder and addiction. Psilocybin in particular has shown rapid and sustained antidepressant effects in humans and received FDA "Breakthrough Therapy" designation, while structural neuroplasticity in the frontal cortex has been implicated in antidepressant action. Prior work has linked psychedelics to markers of synaptic plasticity in gene expression, to transient spine enlargement and branch proliferation in neuronal cultures, and to presynaptic changes in large animals, but no study had directly demonstrated psilocybin-induced structural remodelling of dendritic spines at cellular resolution in a mammalian brain nor established the time course of such changes in vivo. Shao and colleagues set out to test whether a single dose of psilocybin produces rapid and persistent changes in dendritic spines of medial frontal cortex pyramidal neurons in mice, and whether any structural changes are associated with altered excitatory synaptic transmission and behavioural outcomes. The investigators combined longitudinal in vivo two-photon imaging in Thy1 GFP mice, confocal imaging in a separate cohort, whole-cell electrophysiology, behavioural assays (head-twitch response and learned helplessness), and pharmacological manipulation with the 5-HT2A antagonist ketanserin to probe receptor involvement and persistence of new spines over up to 34 days.
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Shao, L., Liao, C., Gregg, I., Davoudian, P. A., Savalia, N. K., Delagarza, K., & Kwan, A. C. (2021). Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. https://doi.org/10.1101/2021.02.17.431629
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