¹University of Milan, Department of Medical Biotechnology and Translational Medicine, Segrate, Italy, ²University of Milano-Bicocca, School of Medicine and Surgery, Monza, Italy, ³CNR, Neuroscience Institute, Vedano al Lambro, Italy, ⁴Fondazione, IRCCS San Gerardo dei Tintori, Monza, Italy

Background: Stress is a recognized risk factor for developmental and adult psychiatric disorders. Indeed, stressful events, particularly during the first phases of life, such as trauma, neglect or abuse, have been associated with increased psychiatric risk over the course of a lifetime, although with some sex-differences. Indeed, the biological sex shapes the stress response impacting on specific behavioral phenotypes. Early-life stress can significantly alter how individuals engage in social relationships during their life, often resulting in dysfunctional social behavior. Recently, the psychedelic drug psilocybin has gained increasing interest for the treatment of psychiatric disorders given its rapid neuroplastic and prosocial effect.

Aims & Objectives: Here, we performed an in-depth behavioral phenotyping of male and female mice exposed to maternal separation (MS) during the first weeks of life to investigate how sex and age influenced the onset of social, cognitive, and psychiatric symptoms during adolescence. We have also collected data on Shank3 heterozygous mice, a genetic model predisposing to autism spectrum disorder. Moreover, the putative therapeutic effect of acute psilocybin has been tested.

Method: Wild type and Shank3 heterozygous male and female mice were exposed to two weeks of MS (3 hours/day) from PND2 to PND14. Spontaneous and social behaviors were longitudinally assessed at PND25, 37 and at PND50 during late adolescence using the home-cage monitoring system Phenotyper2 associated with the automatic video-tracking software Ethovision XT (Noldus IT). Moreover, ultrasonic vocalizations have been recorded with the software UltraVox. 1 week before the last behavioral recording and sacrifice, some mice were treated with a single dose of psilocybin i.p. (1 mg/kg).

Results: At PND50, we found sex-dependent effects of stress, particularly regarding social behavior. When housed in pairs, wild-type 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 reversed social alterations in both sexes. Interestingly, preliminary results suggest that genotype could play a role in both the behavioral response to stress and in the effect of psilocybin.

Discussion & Conclusions: Our data show that psilocybin may have 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.