MIDBRAIN NEURAL CORRELATES OF PSILOCYBIN'S IMPACT ON FEAR LEARNING IN A NATURALISTIC FEAR CONDITIONING PARADIGM

Our previous research suggests that psilocybin can modulate fear learning. However, the circuit-level mechanisms responsible for these changes remain unresolved. Here, we tested whether psilocybin (1mg/kg, i.p.) alters defensive behaviour and concurrent midbrain dynamics. Mice (c57 males; n=4 per group) were implanted with Neuropixels 2.0 recording probes spanning the superior colliculus and lateral periaqueductal grey. They were subjected to 3 sessions of Pavlovian behavioural testing: (1) fear memory acquisition (3x visual looming stimulus (CS)-shock (US) pairings); (2) extinction (24hr later, treatment: psilocybin or saline followed by 20x unpaired CS); and (3) retention (6d later, 20x unpaired CS). Multi-camera video footage was processed using DeepLabCut and behavioural freezing extracted as a function of velocity. Darting, rearing and grooming behaviours were classified using supervised models. Preliminary analysis showed similar baseline behavioural expression during habituation (5 mins pre-extinction, no stimulation); however, CS-evoked freezing in the psilocybin group was lower across both extinction and retention, although this did not reach significance with current the sample size. CS-evoked darting was comparable between groups for both extinction and retention. Ongoing neural analyses will be presented to determine drug-related changes in functional response profiles of neurons. Poisson generalised linear models will allow tuning and response-magnitude comparisons of functional neuronal populations within defined brain regions between treatment groups. Our current findings suggest that psilocybin reduces the passive fear response to realistic conditioned threats without causing a compensatory increase in active avoidance, providing further motivation for our electrophysiological investigations to determine functional neural signatures of this behavioural effect.