Adolescent Stress Sculpts the Brain Differently in Female and Male Rats

Why do women carry roughly twice the lifetime risk of depression compared with men? One of the most robust clues lies in the way negative cognitive bias—the tendency to interpret ambiguous situations pessimistically—emerges more strongly in females, and does so during adolescence. A new study in Translational Psychiatry from researchers at The University of Western Australia and the Perron Institute for Neurological and Translational Sciences now offers a rare longitudinal window into this phenomenon, tracking how chronic stress during the adolescent years reshapes both emotional judgment and whole-brain functional connectivity in young adult rats, with markedly different outcomes for each sex.

The research team, led by Twain Dai and Jennifer Rodger, set out to address a persistent gap in translational neuroscience. Human neuroimaging studies have linked sex differences in negative bias to aberrant functional connectivity in depression, but the causal chain connecting adolescent stress exposure to sex-specific cognitive distortion and resting-state network reorganization in adulthood has remained poorly understood. Animal models allow investigators to control the timing and duration of stress with a precision impossible in clinical populations, making rats an ideal system for disentangling cause from correlation.

Twenty-eight Wistar rats, balanced across sex and arriving at the laboratory at five weeks of age—a developmental window corresponding to adolescence—were first trained on a judgment bias task, a behavioral paradigm widely regarded as one of the best available measures of emotional valence in animals. In this task, distinct tactile cues signaled different reward outcomes, teaching the animals that one texture predicted a large reward while another predicted a smaller one. Once the rats had learned the distinction, the experimenters introduced ambiguous probe cues falling between the trained extremes. How optimistically or pessimistically an animal responded to those ambiguous signals provided a quantifiable index of its cognitive bias.

After training was complete, the animals were randomly and equally assigned to either a chronic restraint stress group or a control group, again balanced by sex. Chronic restraint stress is a standard and well-characterized rodent model of prolonged psychological stress, in which animals are repeatedly placed in restraining tubes for defined periods. Importantly, the study employed a longitudinal design: each animal served as its own baseline, undergoing resting-state functional magnetic resonance imaging before the stress protocol began, and again in young adulthood after it ended. Probe trials followed the second scan, allowing the researchers to relate neural changes to behavioral changes within the same individuals.

Resting-state fMRI measures spontaneous, low-frequency fluctuations in blood-oxygenation signals while an animal lies still, revealing which brain regions tend to activate together and therefore how distributed networks are functionally organized. Because the scans were collected offline and at two time points, the team could compute connectivity change scores for every animal, isolating the effects of the stress exposure from individual differences present from the start. Behavioral data were analyzed with linear mixed-effects models, a statistical framework well suited to repeated-measures designs, while network-level connectivity changes were assessed using Network-Based R-Statistics, a method designed to detect coordinated alterations across interconnected sets of brain regions rather than isolated pairwise links.

The behavioral results were strikingly sex-dependent. When the researchers compared change from adolescent baseline to post-stress testing, females showed a significantly greater tendency than males toward negative cognitive bias. In practical terms, stressed females were more likely to interpret ambiguous cues as signaling the unfavorable outcome, a pattern that echoes the pessimistic interpretation of uncertain situations seen in human depression and that has long been noted to be more pronounced in females than in males. Because the same animals had established optimistic baselines before stress exposure, this shift cannot be attributed to pre-existing differences in temperament between the sexes.

Equally important, the brain imaging data revealed that this behavioral divergence was mirrored by divergent network reorganization. Network-based statistics identified a female-specific reorganization within a distributed subnetwork spanning some of the brain’s most emotion-relevant territory: the brainstem, limbic structures, the striatum, the insula, parahippocampal regions, the orbitofrontal cortex, and the retrosplenial cortex. This collection of regions is far from arbitrary. The limbic system and brainstem together govern threat detection and arousal; the insula integrates bodily and emotional states; the striatum drives reward processing and motivated behavior; and the orbitofrontal cortex evaluates outcomes and updates expectations. Parahippocampal and retrosplenial areas contribute contextual memory and spatial framing, helping an organism situate emotionally salient events in the world.

That chronic adolescent stress preferentially rewired connectivity among precisely these regions in females—but not in males—provides a candidate mechanistic bridge between two well-established clinical observations: that negative cognitive bias in depression is stronger in women, and that adolescent stress is a potent risk factor for adult depression, particularly in females. The alignment between the behavioral measure and the network measure in the same longitudinal cohort strengthens the case that the connectome changes are not incidental but functionally meaningful, potentially representing the neural substrate on which pessimistic interpretation of ambiguity is built during a sensitive developmental period.

The authors emphasize that these results highlight the translational importance of considering both sex and distributed network organization when modeling how adolescent stress shapes later vulnerability to depression. That message carries weight for the broader field. Many preclinical studies still analyze only male animals or pool the sexes, and many neuroimaging analyses focus on single regions rather than networks. This study demonstrates that both choices can obscure exactly the effects that matter most: a stress-induced, female-specific reorganization of a multi-region circuit that would have been invisible without sex-balanced design, longitudinal baseline scanning, and network-aware statistics.

For human health, the implications are cautiously encouraging. If a defined adolescent stressor produces measurable, sex-specific reorganization of emotion-processing circuits that persists into young adulthood, then adolescence represents not merely a period of heightened risk but a concrete window of opportunity for intervention. Biomarkers derived from resting-state connectivity, combined with behavioral measures of cognitive bias, could in principle identify young people whose brains have been reorganized by early stress before full-blown depression develops. The rat model established here—linking a quantifiable judgment bias to longitudinal connectome change—offers a rigorous platform for testing precisely such preventive strategies, and for understanding why females and males may need different ones.

Subject of Research: Sex-dependent effects of chronic adolescent stress on cognitive bias and functional brain networks

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

Article References: Dai, T., Jaeschke-Angi, L., Penrose-Menz, M., Rosenow, T., & Rodger, J. (2026). Sex-dependent effects of chronic stress during adolescence on cognitive bias and functional connectome in young adult rats. Translational Psychiatry. https://doi.org/10.1038/s41398-026-04511-7

Image Credits: AI Generated

DOI: 10.1038/s41398-026-04511-7

Keywords: adolescent stress, cognitive bias, depression, sex differences, resting-state fMRI, functional connectivity, chronic restraint stress, rats, Translational Psychiatry, neuroimaging, limbic system, network-based statistics