Inhibition of cortico-amygdala projections underlies affective bias modification by psilocybin

Psilocybin, the active compound in magic mushrooms, produces rapid and lasting antidepressant effects in people with major depressive disorder, but the underlying brain mechanisms are not fully understood. In rats, psilocin (the active metabolite of psilocybin) alters negative affective biases—a key feature of depression—by acting on a specific circuit in the medial prefrontal cortex. It suppresses excitatory signals to cortico-amygdala projection neurons while enhancing excitatory transmission to other targets, effects dependent on 5HT1A and 5HT2A receptors. These changes persist for at least 24 hours and shift from suppressed excitation to enhanced inhibition in those same cells. Chemogenetically inhibiting these neurons reproduced psilocybin's effects on affective biases and reward memories, identifying this circuit as a key substrate for its antidepressant actions.

Study at a glance

Abstract

Abstract Psilocybin, a serotonergic psychedelic, can produce rapid and enduring antidepressant effects in patients with major depressive disorder (MDD)[1, 2], yet the neural mechanisms underlying these effects remain unclear. Negative affective biases are an important neuropsychological mechanism central to the development and perpetuation of MDD[3]. Using a translational rodent model, we previously demonstrated that psilocybin modulates negative affective biases which, we hypothesize, contribute to its antidepressant effects[4]. Here, we identify the prelimbic subregion (PrL) of the rat medial prefrontal cortex (mPFC) as a key locus for the modulation of affective biases by psilocin, the active metabolite of psilocybin, and reveal a cell-type-specific bidirectional regulation of synaptic transmission. Psilocin selectively suppressed excitatory synaptic input to cortico-amygdala (CA) projection neurons, but enhanced excitatory transmission to other, putatively cortico-cortical, targets. Interestingly, suppression of the excitatory input to CA cells by psilocin, and modulation of affective biases by psilocybin, were both dependent on 5HT 1A and 5HT 2A receptor signaling. Consistent with the long-term therapeutic effects of rapidly acting antidepressants[1, 2, 4, 5], psilocin produced sustained changes to affective biases evident 24 hours after PrL infusion. In parallel, the suppressed excitatory transmission shifted to enhanced inhibitory synaptic input selectively in CA cells. Finally, chemogenetic inhibition of CA neurons in PrL recapitulated both the acute and sustained modulation of negative affective biases by psilocybin, as well as positively biasing new reward memories. Together, these findings identify modulation of the PrL cortico-amygdala circuit as a key substrate for affective bias modification by psilocybin, an effect which could explain its rapid and sustained antidepressant actions.