Sex-specific outcomes of developmental stress and psilocybin intervention on the brain and behavior

Exposure to stress during brain development is a known risk factor for adult mental illness, which often differs by sex and responds poorly to current treatments. Using a mouse model, this work examined how early-life stress alters the adult brain across multiple levels—transcriptomics, network connectivity, resting-state activity, and behavior—and tested whether the psychedelic psilocybin could reverse these effects. Many adulthood differences caused by developmental stress were distinct and even opposing between sexes, driven by changes in processes active during neurodevelopment. Psilocybin broadly shifted behavior in a direction opposite to the effects of developmental stress, but through different behavioral domains in males and females. The findings highlight the need to consider sex as a biological variable and to improve translational validity in preclinical research.

Study at a glance

Abstract

Stress exposure during periods of neurodevelopment is an established risk factor for the onset of stress-related mental illnesses in adulthood, which have differences in presentation and treatment response depending on an individual’s sex, and are difficult to treat due to a lack of complete biological understanding. A more holistic biological perspective of the adult brain after stress exposure during development is needed to provide new avenues of intervention options. Despite an explosion of neuroscience knowledge in the past few decades, psychiatric treatments remain largely ineffective for many patients, indicating a need for preclinical neuroscience research to better reflect the clinical setting. More recently, here has been renewed interest in using psychedelic drugs like psilocybin as treatments for mental illnesses, due to their long-lasting effects after acute dosage. Sex-specific effects of psilocybin on different behavioral domains and its potential to rescue effects of developmental stress have yet to be characterized. To this end, this work uses a mouse model to characterize alterations in the adult brain and behavior due to prior exposure to stress early in life on different levels of brain organization. We investigate transcriptomics, network connectivity, overall resting state activity, and associations of physiology to behavior. To improve translational validity, we highlight differences due to biological sex, use robust phenotyping to efficiently capture a wide variety of behaviors associated with stress-related disorders, and draw comparisons between data from our mouse model and published data from human cohorts. We show that many adulthood behavioral and physiological differences due to developmental stress can be distinct and even opposing between sexes, driven in the brain by alterations in processes highly active during neurodevelopment. Psilocybin broadly altered the behavioral profile in a direction opposing effects of developmental stress, but via different behavioral domains in males and females, opening questions about interpretation of phenotypes. Through this work, we display the necessity of considering sex as a biological variable, encourage enhanced translational validity of pre-clinical work, and characterize a vast range of lasting effects of developmental stress on the brain, which can be used to aid the progress of finding targeted treatments for stress-related disorders.