LOW DOSES OF THE PSYCHEDELIC PSILOCYBIN ACTIVATE VENTRAL CA2 OF MOUSE HIPPOCAMPUS AND MODULATE SOCIAL BEHAVIOUR

Recent human and animal studies highlight psilocybin’s efficacy in alleviating depressive- and anxiety-like behaviours, potentially by enhancing synaptic plasticity and reconfiguring neural networks. However, the dose- and state-dependent effects of psilocybin on distributed neural populations remain enigmatic. This study mapped brain-wide neural activation following double dosing of psilocybin in adult Fos2A-CreERxtdTomato (FosTRAP2) mice (12 mice/group, mixed-gender) under different affective states. tdTomato/c-fos immunohistochemistry and hierarchical Bayesian modelling were used to count neurons activated by first and second injections (2 weeks apart), and social preference tests used to quantify behavioural effects. Under neutral states, a first dose of psilocybin (0.3 mg/kg i.p.) robustly activated neurons in ventral CA2 (vCA2) and dorsal CA2 (dCA2) of hippocampus, with moderate activation in epithalamus, median eminence, isocortex, thalamus, and lateral amygdala. A second dose strongly reactivated vCA2 neurons, with weaker activation in dCA2, median eminence, ventral tegmental area and substantia nigra. 1 mg/kg psilocybin generally induced less robust activation. Positive (post-play) and negative (post-restraint) affective states modulated network activation, reflecting the impact of emotional context on network dynamics. vCA2 was consistently activated by psilocybin and is implicated in regulating social valence. Unexpectedly, acute psilocybin significantly reduced sociability in wild-type mice. These findings chart brain-wide psilocybin-associated neuronal ensembles across different affective states and signpost vCA2 as a critical region mediating psilocybin’s diverse effects. Ongoing electrophysiological recordings in vCA2 aim to further elucidate psilocybin’s mechanisms of action.