ADOLESCENT SOCIAL ISOLATION INDUCED TRANSCRIPTOMIC CHANGES IN THE HYPOTHALAMUS DRIVES ALTERED NEUROENDOCRINE AND BEHAVIOURAL OUTCOMES

Adolescence is a critical period of brain maturation during which individuals are particularly vulnerable to environmental stressors. Social isolation during this developmental window is a significant risk factor for mental health disorders, as highlighted during the COVID-19 pandemic, yet underlying mechanisms remain unclear.
Here, we aimed to determine whether chronic social isolation (CSI) during adolescence can induce hypothalamic-pituitary-adrenal (HPA) axis dysfunction, leading to maladaptive behavioural and endocrine outcomes.
Juvenile male and female mice were subjected to CSI from weaning through adolescence into adulthood and assessed for their neuroendocrine and behavioural outcomes. Bulk RNA sequencing was performed on hypothalamic and pituitary tissues to characterise transcriptomic changes at baseline and following acute stress.
Adolescent CSI induced sex-dependent metabolic, endocrine, and behavioural alterations compared to group-housed controls. Transcriptomic analyses revealed that acute stress amplified molecular differences between isolated and group-housed animals, revealing dynamic, stimulus-dependent adaptations within the hypothalamus and pituitary. Notably, males exhibited more pronounced endocrine and behavioural alterations following isolation, accompanied by a greater number of differentially expressed genes relative to females. In males, social isolation was associated with changes in hypothalamic genes encoding for transcription factors and epigenetic modifiers, alongside pituitary gene expression changes related to hormonal regulation.
These findings provide novel insights into the long-term impact of adolescent social isolation on HPA axis function. They support the concept that social stress during adolescence may prime specific neuroendocrine pathways in a sex-dependent manner, with implications for understanding vulnerability to psychiatric disorders and developing targeted interventions.