Biology subjects

Gilbert, A. D.

Publications and source records attributed to Gilbert, A. D..

3 recordsLinked to original sources

bioRxiv2026

Psychedelic drug action at dendrites is gated by behavioral state and serotonin receptors

How psychedelics act on cortical dendrites to produce long-lasting structural plasticity remains poorly understood. Here, we characterize the effects of psilocybin on dendritic calcium dynamics in pyramidal tract neurons of the mouse medial frontal cortex. Psilocybin transiently increases calcium event rates in apical dendritic tufts over a time course that parallels the drugs pharmacokinetics in the brain. This acute effect is brain state-dependent, occurring selectively during quiet wakefulness, and was abolished by cell type-specific deletion of the 5-HT2A receptor. Under control conditions, dendritic calcium signaling predicts subsequent spine formation, but this relationship is not preserved following psilocybin administration. Together, these findings reveal that psilocybin engages brain state- and 5-HT2A receptor-dependent dendritic signaling, while altering the relationship between acute dendritic activity and long-term structural plasticity. The results suggest that the mechanisms linking acute dendritic signaling to structural remodeling differ between physiological and psychedelic-induced plasticity.

neuroscience↗

bioRxiv2026

Structural plasticity and enhanced fear extinction following psilocybin in chronically stressed mice

The classic psychedelic psilocybin elicits long-lasting neural plasticity and behavioral effects, but prior studies largely examined stress-naive animals. Using longitudinal imaging, we show that psilocybin increases dendritic spine density in frontal cortical neurons and facilitates fear extinction after chronic restraint stress, demonstrating psilocybins effects in a translationally relevant mouse model.

neuroscience↗

bioRxiv2025

Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks

Psilocybin holds promise as a treatment for mental illnesses. One dose of psilocybin induces structural remodeling of dendritic spines in the medial frontal cortex in mice. The dendritic spines would be innervated by presynaptic neurons, but the sources of these inputs have not been identified. Here, using monosynaptic rabies tracing, we map the brain-wide distribution of inputs to frontal cortical pyramidal neurons. We discover that psilocybins effect on connectivity is network-specific: strengthening the routing of inputs from perceptual and medial regions (homolog of default mode network) to subcortical targets, while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on the drug-evoked spiking activity, because silencing a presynaptic region during psilocybin administration disrupts the rewiring. Collectively, the results reveal the impact of psilocybin on the connectivity of large-scale cortical networks and demonstrate neural activity modulation as an approach to sculpt the psychedelic-evoked neural plasticity.

neuroscience↗