Early life stress induced sex-specific changes in behavior is paralleled by altered locus coeruleus physiology in BALB/cJ mice

Abstract

Adverse childhood experiences have been associated with many neurodevelopmental and affective disorders including attention deficit hyperactivity disorder and generalized anxiety disorder, with more exposures increasing negative risks. Sex and genetic background are biological variables involved in adverse psychiatric outcomes due to early life trauma. Females in general have an increased prevalence of stress-related psychopathologies beginning after adolescence, indicative of the adolescent time period being a female-specific sensitive period. To understand the underlying neuronal components responsible for this relationship between genetic background, sex, stress/trauma, and cognitive/affective behaviors, we assessed behavioral and neuronal changes in a novel animal model of early life stress exposure. Male and female BALB/cJ mice that express elevated basal anxiety-like behaviors and differences in monoamine associated genes, were exposed to an early life variable stress protocol that combined deprivation in early life with unpredictability in adolescence. Stress exposure produced hyperlocomotion and attention (5 choice serial reaction time task) in male and female mice along with female-specific increased anxiety-like behavior. These behavioral changes were paralleled by reduced excitability of locus coeruleus (LC) neurons, due to resting membrane potential hyperpolarization in males and a female specific increase in action potential delay time. These data describe a novel interaction between sex, genetic background, and early life stress that results in behavioral changes in clinically-relevant domains and potential underlying mechanistic lasting changes in physiological properties of neurons in the LC. HIGHLIGHTSO_LIBALB/cJ mice exposed to early life stress are hyperactive in adolescence and displayed attention deficits in adulthood. C_LIO_LIOnly female BALB/cJ mice develop increased anxiety in adolescence after early life stress. C_LIO_LIEarly life stress causes reduced excitability of locus coeruleus neurons in BALB/cJ mice. C_LIO_LIOnly locus coeruleus neurons from female BALB/cJ mice exposed to early life stress displayed an increase in action potential delay time upon depolarization. C_LI