Sex-dependent effects of chronic stress during adolescence on cognitive bias and functional connectome in young adult rats

Negative cognitive biases in depression are more pronounced in females than in males. This sex difference emerges during adolescence, a sensitive developmental stage when chronic stress exposure increases the risk of depression in adulthood. Neuroimaging studies in adult depression suggest that sex differences in negative bias are associated with aberrant functional connectivity.

However, the neurobiology linking adolescent stress to sex‑specific cognitive bias and resting‑state network reorganization in adults remains poorly understood. The study aimed to investigate the longitudinal effects of chronic restraint stress (CRS) during adolescence on cognitive bias and functional connectome in emerging adulthood. 28 Wistar rats (sex-balanced; aged five weeks on arrival) were trained on a judgment bias task with distinct tactile cues signaling differential rewards. Bias was quantified from responses to ambiguous probe trials.

Following training, animals were randomly and equally assigned to CRS or control groups (sex-balanced). Offline resting-state functional MRI scans were conducted at adolescent baseline (pre‑CRS) and again in adulthood (post‑CRS), followed by probe trials to assess neural and behavioral changes. Behaviors were analyzed using linear mixed-effects models, and network connectivity was assessed using Network-Based R-Statistics.

Both behavioral and network analyses identified sex-dependent differences in change from baseline to post-CRS. Specifically, females showed a greater tendency toward negative bias than males. Network analysis suggested female-specific reorganization within a subnetwork, spanning brainstem, limbic, striatal, insula, parahippocampal, orbitofrontal, and retrosplenial regions.

These results highlight the translational importance of considering sex and distributed network organization when modelling how adolescent stress may shape later vulnerability to depression. The authors thank Lakshini Piyasiti, Neha Nair, Rebecca Goodyear, and Will Copping for assistance with chronic restraint stress, and UWA Animal Care Services for excellent animal care. The authors also acknowledge the facilities and scientific and technical assistance of the National Imaging Facility, a National Collaborative Research Infrastructure Strategy (NCRIS) capability, at the Centre for Microscopy, Characterisation and Analysis, UWA.

TD was supported by the Australian Government International Research Training Program scholarship and the Byron Kakulas Prestige scholarship. JR was supported by a program grant from the Stan Perron Charitable Foundation. The funders had no role in study design; data collection, analysis, or interpretation; manuscript preparation; or the decision to submit for publication.