Early life stress induces sex-specific changes in behavior and parallel locus coeruleus neuron excitability

Many psychiatric disorders are associated with specific risk factors, including biological sex, chronic stress, and adversity in childhood, but mechanisms underlying these relationships are unknown. The locus coeruleus (LC) is a brain area that contains adrenergic norepinephrine (NE)-releasing neurons with established sex differences in excitability and stress sensitivity. To understand how adversity in early life affects cognitive/affective behavior and LC physiology, we exposed C57BL/6J mice to a dual-phase (early development and adolescence) early life variable stress (ELVS) paradigm and assessed behavior and LC physiology in early adulthood. ELVS caused females, but not males, to display increased novel environment exploration and reduced preference for sucrose. In addition, ELVS caused elevated activity in a familiar environment, modest deficits in Y-maze performance, and altered attention in an operant task, regardless of sex. A reduction in LC neuron excitability, partly due to an increase in action potential delay time, was also found only in female mice exposed to ELVS, paralleling robust behavioral changes. Pharmacological compensation of these changes in LC activity with reboxetine corrected some ELVS-induced behavioral changes. CRF-induced changes in LC neuron activity were also mediated by different preferential signaling pathways in male and female mice, a potential mechanism for lasting sex-specific changes in LC physiology in response to ELVS. Through this animal model of early life stress, we identified sex differences in behavior and parallel changes in LC neuron excitability and CRF sensitivity, identifying mechanisms involved in determining how stress and sex interact to cause LC activity dysregulation and related behavioral changes.