Sex-dependent cross-resilience to social defeat and learned helplessness: The role of BDNF-ERK signaling and norepinephrine.
- 1Douglas Mental Health Institute, McGill University, Montreal, QC, H4H 1R3, Canada.
- 2Integrated Program in Neuroscience, McGill University, Montreal, QC, H3A 2B4, Canada.
- 3Université Paris Cité, INCC UMR 8002, CNRS, Paris, F-75006, France.
Abstract
Major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are two of the most prevalent and disabling psychiatric conditions, both closely tied to stress exposure. While they have distinct diagnostic criteria, MDD and PTSD share considerable comorbidity, overlapping behavioral symptoms, and common neurobiological pathways. However, not all individuals exposed to chronic or traumatic stress develop these disorders, highlighting the importance of resilience, the capacity to maintain psychological and physiological stability under stress. An emerging yet incompletely understood aspect of stress adaptation is cross-resilience, defined as the extent to which resilience or susceptibility to one form of stress generalizes to subsequent stressors across contexts. While animal models have effectively captured individual differences in stress responses, few have explored whether resilience generalizes across distinct stress modalities or differs by sex. We examined cross-resilience using two validated rodent models: chronic social defeat stress (CSDS) and learned helplessness (LH). These paradigms model complementary aspects of stress vulnerability. We assessed how prior CSDS experience influenced subsequent responses to LH. We also evaluated the role of the noradrenergic system using wild-type and norepinephrine (NE)-deficient (VMAT2loxDBHcre KO) mice. Behavioral phenotyping was combined with molecular analyses in key brain regions involved in emotion, motivation, and fear processing: the ventral tegmental area (VTA), nucleus accumbens (NAc), and amygdala (AMY). We focused on BDNF and ERK/MAPK signaling pathways, known to mediate neuroplasticity and stress resilience. Our findings reveal sex-specific patterns of cross-resilience, with prior CSDS resilience predicting LH resilience in males but not females. Molecular results indicate distinct adaptations across brain regions and sexes, underscoring the biological complexity of resilience. These insights may inform personalized strategies for preventing and treating stress-related disorders.
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BibTeX
@article{bairachnaya2026sexdependent,
title = {{Sex-dependent cross-resilience to social defeat and learned helplessness: The role of BDNF-ERK signaling and norepinephrine.}},
author = {Maryia Bairachnaya and Lucy Penney and Gohar Fakhfouri and Elsa Isingrini and Bruno Giros},
journal = {Neurobiology of stress},
year = {2026},
month = oct,
doi = {10.1016/j.ynstr.2026.100858},
url = {https://europepmc.org/article/MED/42927174},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Sex-dependent cross-resilience to social defeat and learned helplessness: The role of BDNF-ERK signaling and norepinephrine.
AU - Maryia Bairachnaya
AU - Lucy Penney
AU - Gohar Fakhfouri
AU - Elsa Isingrini
AU - Bruno Giros
PY - 2026
DA - 2026/10/14
JO - Neurobiology of stress
DO - 10.1016/j.ynstr.2026.100858
UR - https://europepmc.org/article/MED/42927174
AB - Major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are two of the most prevalent and disabling psychiatric conditions, both closely tied to stress exposure. While they have distinct diagnostic criteria, MDD and PTSD share considerable comorbidity, overlapping behavioral symptoms, and common neurobiological pathways. However, not all individuals exposed to chronic or traumatic stress develop these disorders, highlighting the importance of resilience, the capacity to maintain psychological and physiological stability under stress. An emerging yet incompletely understood aspect of stress adaptation is cross-resilience, defined as the extent to which resilience or susceptibility to one form of stress generalizes to subsequent stressors across contexts. While animal models have effectively captured individual differences in stress responses, few have explored whether resilience generalizes across distinct stress modalities or differs by sex. We examined cross-resilience using two validated rodent models: chronic social defeat stress (CSDS) and learned helplessness (LH). These paradigms model complementary aspects of stress vulnerability. We assessed how prior CSDS experience influenced subsequent responses to LH. We also evaluated the role of the noradrenergic system using wild-type and norepinephrine (NE)-deficient (VMAT2loxDBHcre KO) mice. Behavioral phenotyping was combined with molecular analyses in key brain regions involved in emotion, motivation, and fear processing: the ventral tegmental area (VTA), nucleus accumbens (NAc), and amygdala (AMY). We focused on BDNF and ERK/MAPK signaling pathways, known to mediate neuroplasticity and stress resilience. Our findings reveal sex-specific patterns of cross-resilience, with prior CSDS resilience predicting LH resilience in males but not females. Molecular results indicate distinct adaptations across brain regions and sexes, underscoring the biological complexity of resilience. These insights may inform personalized strategies for preventing and treating stress-related disorders.
SN - 2352-2895
ER -