Early life stress causes sex-specific changes in adult fronto-limbic connectivity that differentially drive learning


The risk of developing medical conditions and multiple psychopathologies over the lifespan is increased by exposure to childhood maltreatment. Despite being a significant risk factor for abnormal brain development in industrialized countries, there is a poor understanding of how childhood maltreatment affects neurodevelopment and psychopathology in males and females. For the effective diagnosis and treatment of the enormous clinical and economic burden associated with childhood maltreatment, there is a need to clarify these issues. Previous studies carried out on rodents have shown that responses to stress and injury are moderated by sex. However, most of these early life stress (ELS) studies specifically translational work that has used human imaging were conducted only in male rodents.

Now a new study by Yale University School of Medicine researchers: Jordon White, Alexa Pugliese and led by Professor Arie Kaffman from the Department of Psychiatry in collaboration with Tanzil M Arefin, Choong Lee and Dr. Jiangyang Zhang at New York University School of Medicine and Dr. Jeff Gassen  at Texas Christian University used advanced high-resolution diffusion magnetic resonance imaging to identify neuroanatomical changes in adult male and female mice exposed to unpredictable postnatal stress (UPS). Their findings showed that UPS induces several neuroanatomical alterations that resemble those seen in human imaging and were seen in both males and females. Interestingly, UPS increased fronto-limbic connectivity in males, but not in females, demonstrating an exquisite specificity by which sex moderates some circuits in response to ELS. The research work is published in the Journal Elife.

Early life stress causes similar behavioral abnormalities in many mammalian species, including nonhuman primates and rodents, suggesting that animal models may help elucidate the molecular and cellular changes that guide these developmental changes in children. Professor Kaffman is recognized leader in the field of ELS and has previously developed several models of ELS in mice to study effect of ELS on neurodevelopment. In this current investigation, the research team has used a mouse model of complex and unpredictable ELS, abbreviated as UPS. UPS exposes mice to multiple distinct stressors early in life, some of which are unpredictable, in order to mimic the complex and chaotic features that are commonly seen in individuals exposed to childhood adversity. Using this model the authors asked whether UPS causes similar neuroanatomical changes to those reported in humans and whether some of these changes differentially affected adult male and female mice. To accomplish this they have used high resolution diffusion MRI to characterize structural and network properties and linked these findings to behavioral and physiological changes detected in mice exposed to UPS.

UPS caused several changes that similarly affected males and females. These include reduced body weight, increased neophobia when exploring a novel object and impaired freezing in the contextual fear conditioning test. UPS mice showed several neuroanatomical changes that resemble those seen in humans exposed to ELS and were seen in both males and females. These include reduced global efficiency, increased small-worldness, reduced volume and fractional anisotropy in the corpus collosum, frontal cortex atrophy, and increased amygdala size.

Important differences between male and female UPS mice were also seen. For example, UPS increased fronto-limbic connectivity in males, but not in females. Interestingly,  the increase in fronto-limbic connectivity predicted reduced contextual freezing in males and not in females. Further, UPS reduced connectivity between the amygdala and the hypothalamus in males and not in females providing a possible explanation for the blunted basal corticosterone levels seen in UPS males and not female mice.

In summary, using sophisticated high resolution dMRI the authors show that exposing mice to complex and unpredictable stress early in life results in long lasting central anatomical and behavioral changes that resemble those seen in humans, some of which are moderated by sex. These findings serve as a foundation for further translational research in both humans and animals aimed at regulating the effect sex has on childhood maltreatment-induced outcomes.


White JD, Arefin TM, Pugliese A, Lee CH, Gassen J, Zhang J, Kaffman A. Early life stress causes sex-specific changes in adult fronto-limbic connectivity that differentially drive learning. Elife. 2020;9:e58301.

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