Elucidating the mechanisms underlying sex biases in the prevalence and severity of diseases can advance our understanding of their pathophysiological basis and serve as a guide for developing treatments. A well-established sex difference in psychiatry is the higher incidence of mood and anxiety disorders in females. These disorders share stress as a potential etiological contributor and hyperarousal as a core symptom, suggesting that the distinction between sexes lies at the intersection of stress and arousal systems. This review focuses on the link between the stress axis and the brain norepinephrine arousal system as a key point at which sex differences occur and are translated to differences in the expression of mood disorders. Evidence for a circuit designed to relay emotion-related information via the limbic corticotropin-releasing factor (CRF) system to the locus coeruleus (LC)-norepinephrine arousal system is reviewed. This is followed by recent novel findings of sex differences in CRF receptor signaling and trafficking that would result in an enhanced arousal response and a compromised ability to adapt to chronic stress in females. Finally, we discuss the evidence for sex differences in LC dendritic structure that allow for an increased receipt and processing of limbic information in females compared to males. Together these complementary sets of data suggest that in females, the LC arousal system is poised to process more limbic information and to respond to some of this information in an enhanced manner compared to males. The clinical and therapeutic considerations arising from this perspective are discussed. This article is part of a Special Issue entitled 'Anxiety and Depression'.
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