Prolonged exposure to stressful conditions in early life imparts changes to physiology and health and may trigger or exacerbate neuropsychiatric disorders. Overt dysfunction in sociability is also a hallmark of disorders such as autism spectrum disorder (ASD) and schizophrenia. Likewise, abnormal social interaction in otherwise healthy individuals is itself a trigger for mental health disorders. In addition, for most social animals, the relative position an individual occupies in its social hierarchy strongly modulates psychosocial stress.
Early life stress (ELS) induced by maternal separation is acknowledged to have long-term effects on animal behavior and is considered one of the most potent, naturally-occurring stressors. In humans, childhood adversity, neglect or mistreatment is known to increase the risk for psychiatric disorders, including depression and anxiety. In rodent models of maternal separation, behavioral deficits are observed in emotional behavior and stress responses. At the same time, neurological dysfunctions have been identified in both humans and mice exposed to ELS. However, the precise neuronal substrates and mechanisms that traduce ELS into altered neuronal activity and subsequent social dysfunction in adulthood are poorly understood. While the role of stress impacting adult animals and promoting changes to social behavior and social hierarchies is well described, the influence of ELS on adult social hierarchical rank and social behaviors remains largely unknown. Our results uncovered that ELS induces a dysfunction in social hierarchy and social interactions in mice. We observed that ELS mice display a lower social rank when compared to control animals and are more easily defeated in dominant-subordinate competitions. ELS also led to long-lasting functional alterations in the medial prefrontal cortex (mPFC), as evidenced by an increased c-fos expression in response to social dominance stimuli.
Additionally, neuronal atrophy and increased inhibitory synaptic strength were observed in mPFC neurons from adult mice that experience ELS. In terms of gene expression in the mPFC, we found that the mRNA of Npy1r was upregulated in ELS mice and also in wild-type subordinate animals, suggesting a role for this gene in behaviors regulating social dominance.
Together, our data suggests that ELS leads to long-lasting alterations in gene expression and to altered mPFC activity, inducing a subordinate behavior within a social hierarchy. Lastly, we proposed Npy1r signaling as a key modulator of social rank and a potential therapeutic target for social dysfunctions.