<p>Many psychiatric disorders are associated with specific risk factors, including biological sex and adversity in childhood, but the mechanisms underlying these relationships are unknown. Multiple cognitive and affective processes that are often disrupted in various psychiatric disorders are shaped by norepinephrine (NE) release throughout the brain, which is principally coordinated by noradrenergic locus coeruleus (LC) neurons with established sex differences in multiple properties, including stress sensitivity. Through application of a two-phase early life variable stress (ELVS) exposure to C57BL/6J mice to understand how early life adversity affects cognitive/affective behavior and LC physiology, we found that females displayed pronounced increases in 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 in both sexes. A reduction in LC neuron sensitivity to corticotropin-releasing factor (CRF) and decreased excitability, partly due to an increase in action potential delay, was observed only in female mice exposed to ELVS, paralleling behavioral changes. CRF-induced changes in LC neuron activity were mediated by different preferential signaling pathways in naïve male and female mice - a potential mechanism for ELVS-induced sex-specific changes in LC physiology. Administration of the norepinephrine reuptake blocker reboxetine corrected ELVS-induced behavioral changes. Through this animal model of early life stress, we identified mechanisms involved in determining how stress and sex interact to cause LC activity dysregulation and related behavioral changes.</p>