Negative cognitive biases—where mood colors learning and memory—are a core feature of major depressive disorder, and reversing them may be key to how rapid-acting antidepressants work. In rats, a single dose of ketamine, scopolamine, or psilocybin selectively weakened a negative affective bias induced in an associative learning task. Low doses of ketamine and psilocybin, but not high doses, reversed the valence of the bias 24 hours later. Only psilocybin produced a lasting positive bias that depended on new learning. Ketamine's relearning effects required protein synthesis in the medial prefrontal cortex and could be altered by cue reactivation, pointing to experience-dependent neural plasticity as a shared mechanism for both the rapid and sustained effects of these drugs.
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.