Sex differences in the development of anxiodepressive-like behavior of mice subjected to sciatic nerve cuffing.

We investigated the contribution of nucleus locus ceruleus (LC) to the development of pain-associated affective behavior. Mice of both sexes were subjected to sciatic nerve cuffing, a model of peripheral nerve injury, and monitored for 45 days. Although the thermal and mechanical thresholds were equally decreased in both males and females, only the male mice developed anxiodepressive-like behavior, which was complemented by suppressed hippocampal neurogenesis. Furthermore, the LC activity was lower in males when compared with females subjected to sciatic cuffing. Next, we used a chemogenetic approach to modulate the activity of LC projections to the dentate gyrus of the hippocampus in females without cuffs and in males with sciatic cuffs. Sustained inhibition of the LC projections to the dentate gyrus for 15 days induced anxiodepressive-like behavior and reduced the hippocampal neurogenesis in females. Activation of the LC projections to the dentate gyrus for 15 days prevented the development of anxiodepressive-like behavior and increased the hippocampal neurogenesis in males with cuffs. In sum, we demonstrated that the LC projections to the hippocampus link the sensory to the affective component of neuropathic injury and that the female mice are able to dissociate the nociception from affect by maintaining robust LC activity. The work provides evidence that sex differences in LC response to pain determine the sex differences in the development of pain phenotype.