Psilocybin induces hallucinations through its active metabolite psilocin, which acts as serotonin (5-HT)_2A receptor agonist. Although classified as drugs of abuse, psilocybin and other hallucinogens may be clinically used for several psychiatric disorders, including major depressive disorder. Preliminary clinical studies advocate administering single doses of psilocybin intermittently, based on the observation that a single dose induces long-lasting therapeutic effects. Neuronal plasticity may underlie these long-lasting effects. In humans, psilocybin acutely increases the activity of the prefrontal cortex, likely by facilitating thalamocortical signaling. This coincides with the localization of 5-HT_2A receptors, which are expressed in frontal cortex pyramidal cells postsynaptically and putatively in thalamic afferents on the presynaptic site. In rodent brain slices, 5-HT and various hallucinogens acutely increase synaptic strength of glutamate afferents onto cortical pyramidal neurons. Specific neuronal circuits and synapses that may be persistently changed after psilocybin have not been identified and we lack proof of causality for antidepressant efficacy. We will therefore examine synaptic plasticity in defined neuronal circuits as a mechanism underlying psilocybin’s effect on anhedonia, a key symptom of depression. Further, we will investigate a simple, translational strategy to refine psilocybin pharmacotherapy. Akin to classical conditioning, pairing psilocybin treatment with a cue may allow recalling the therapeutic benefits through cue exposure when the initial drug effect wears off. This strategy could enhance the efficacy of psilocybin treatment sessions.

This project builds on the hypotheses that psilocybin induces long-lasting forms of plasticity at thalamocortical synapses, which underlie its antidepressant-like effects, and that the potential therapeutic effect can be recalled through exposure to a drug-associated cue.

We aim to identify neuronal circuits involved in psilocybin-induced long-term synaptic plasticity, establish psilocybin efficacy for antidepressant-like effects and elucidate the underlying mechanism, and provide evidence for recall of psilocybin effects through drug-cue conditioning that may be clinically translated.

Optogenetics and whole-cell patch-clamp slice recordings will be used for celltype- and circuit-specific observations and manipulations. Behavioral testing of anhedonia in an anxiogenic environment will be applied, as this can report the antidepressant potential of a drug. This research will reveal the clinically relevant mode of action of psilocybin and provide blueprints for improved treatment strategies such as the supportive application of conditioned drug cues.