Prior trauma shapes the effects of psilocybin on stress sensitization in mice.

Exposure to traumatic events induces persistent alterations in defensive behavior that extend beyond associative fear memories, including heightened responses to novel stimuli (stress sensitivity) and sustained defensive states in neutral contexts (stress sensitization). While serotonergic psychedelics such as psilocybin have been shown to facilitate fear extinction in associative paradigms, their effects on trauma-induced non-associative stress adaptations remain poorly understood. Here, we developed a behavioral paradigm in mice that dissociates contextual fear recall from stress sensitivity and stress sensitization within the same subjects. Male C57BL/6J mice were exposed to an acute foot-shock stressor, followed by assessment of trauma recall, administration of psilocybin (1 mg/kg) or vehicle, and subsequent evaluation of responses to a novel auditory stimulus and context. Trauma-exposed mice displayed robust associative fear and increased freezing in response to a novel auditory stimulus, consistent with enhanced stress sensitivity. However, psilocybin did not significantly alter this stimulus-evoked response. In contrast, psilocybin produced bidirectional, experience-dependent effects on stress sensitization - it reduced baseline freezing in non-traumatized mice but increased freezing in trauma-exposed animals when re-exposed to a novel context in the absence of a stimulus. Together, these findings demonstrate that psilocybin does not uniformly attenuate trauma-related behaviors, but instead modulates non-associative defensive responses in a manner dependent on prior experience. This work highlights the importance of distinguishing between associative and non-associative components of fear and suggests that psychedelic-induced plasticity may amplify latent trauma-related states under certain conditions.