DISSECTING INTER-INDIVIDUAL VARIABILITY IN ASTROCYTIC METABOLISM IN A MOUSE MODEL OF DEPRESSION

Chronic stress is a major risk factor for several psychiatric disorders, including depression, which affects approximately 5.7% of the adult population worldwide. Despite available pharmacological treatments, therapeutic efficacy remains limited, with a substantial proportion of patients failing to respond adequately. Recent studies highlight the key role of astrocytes in stress-related disorders not only for their metabolic support to neurons, but also for their active regulation of neuronal function (e.g. glutamate uptake, lactate signalling). However, the contribution of astrocytic metabolic impairment to stress-induced behavioural phenotypes of depression remains incompletely understood. The aim of this study is to evaluate the effects of chronic mild stress on astrocytic metabolic pathways using a 10-week Unpredictable Chronic Mild Stress (UCMS) paradigm in male C57BL/6J mice. Control (n=8) and UCMS-exposed (n=12) animals were longitudinally phenotyped using body weight monitoring, nest building, sucrose preference, and elevated plus maze tests. UCMS exposure resulted in a significant reduction in nest-building behaviour (-23%) and body weight gain (-24%) compared to controls. Rather than focusing on group-level behaviour, physiological and behavioural measures were integrated into a global z-score, enabling identification of extreme phenotypes. Four mice per group displaying representative control or UCMS profiles were selected for molecular analyses. Blood and limbic brain regions were collected 24 hours after completion of the UCMS protocol for corticosterone measurement and bulk RNA sequencing, followed by identification of astrocyte-enriched transcripts. This phenotype-stratified approach combines behavioural profiling with transcriptomics to uncover stress-related alterations in astrocytic metabolic pathways, providing insight into glial contributions to stress-related neuropsychiatric disorders.