Sex-dependent prosocial effects of psilocybin in mice exposed to early-life stress

Background. Early-life stress can cause sex-dependent changes in mood and social behavior and is recognized as a main risk for neurodevelopmental and psychiatric disorders. Interestingly, psychedelic drugs, due to their rapid neuroplastic and prosocial effects, are gaining attention for treating neuropsychiatric conditions. Here, we studied sex differences in the long-term behavioral, social, and neurobiological consequences of Maternal Separation (MS) in mice, as well as the modulatory effects of a single administration of the psychedelic drug psilocybin. Methods. C57BL/6 male and female pups were exposed to maternal separation (3 h/day; PND2-14). Behavior was assessed at PND 25, 37 and 50 using the home-cage monitoring system Phenotyper2 with the video-tracking software Ethovision XT (Noldus), allowing in-depth and automatized behavioral phenotyping. 1 week before the last recording and sacrifice, some mice received a single dose of psilocybin (1 mg/kg i.p.). Results. At PND50, we found sex-dependent effects of stress, particularly regarding social behavior. When housed in pairs, MS male mice spent more time in the shelter and tend to reduce the time spent in proximity to the other animal, while MS females engaged less in social interactions (reduced movements towards peers). Importantly, acute psilocybin induced no obvious behavioral changes in unstressed animals but reversed social alterations in both sexes. Conclusions. Our data show that psilocybin has a therapeutic potential in reversing social dysfunctions induced by stress in early life. Ongoing spatial transcriptomic analyses will provide insights into the putative molecular determinants of early-life stress and psilocybin behavioral readouts.