Early Life Stress Impairs Contextual Threat Expression in Female, but Not Male, Mice

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Abstract

Early life stress (ELS) is associated with altered processing of threat signals, and increased lifetime risk of anxiety and affective pathology, disorders that disproportionately affect females. We tested the impact of a limited bedding paradigm of ELS (from P4-11) on contextual threat learning, context memory, footshock sensitivity, and anxietylike behavior, in adult male and female mice. To examine contextual threat learning, mice conditioned by context/footshock association were tested 24 hr later for the context memory. To determine the effect of ELS on footshock sensitivity, a separate cohort of mice were exposed to footshocks of increasing intensity (0.06 to 0.40 mA) and behavioral responses (jump and audible vocalization) were assessed by observers blind to treatment condition, sex, and cycle stage. ELS impaired context memory in female, but not male, mice. ELS increased footshock-induced threshold to vocalize, but not to jump, in both sexes. In female mice, this effect was most apparent during estrus. Decreased body weight, indicative of higher stress incurred by an individual mouse, correlated with increased threshold to jump in both sexes reared in ELS, and to audibly vocalize in ELS females. As ELS effects on shock sensitivity were present in both sexes, the contextual recall deficit in females was not likely driven by changes in the salience of aversive footshocks. No effects on anxietylike behavior, as measured in the elevated plus maze (EPM), were observed. More work is needed to better understand the impact of ELS on both somatic and gonadal development, and their potential contribution to threat learning.

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