Hippocampal Cdk5 is regulated by distinct stress paradigms in male and female mice.

Anxiety and mood disorders have been rising since the COVID-19 pandemic, marked by social isolation and stress. Women are disproportionately affected by stress-related disorders, yet the interaction between social isolation and stress remains understudied in females. Cyclin-dependent kinase 5 (Cdk5) is an atypical kinase that exhibits sex-specific regulation following various stressors but is studied almost exclusively in males. To complement these findings, we examined sex differences in mouse hippocampal Cdk5 mRNA and protein following short and long restraint stress with or without concomitant social isolation stress. While short restraint stress was sufficient to promote anxiety-like in both male and female mice, it did not alter Cdk5. Rather, hippocampal Cdk5 mRNA increased only after a longer restraint stress duration followed by social isolation, and only in male mice. Hippocampal Cdk5 protein also shifted from the cytosolic to the nuclear compartment only in male hippocampus. Surprisingly, repeated restraint stress promoted exploratory behavior in both group-housed and socially isolated male and female mice. Social isolation alone increased Cdk5 protein in females only. Finally, under all conditions, female mice were less immobile and more exploratory than male mice. Together, these results provide new insight into the sex-specific regulation of hippocampal Cdk5 by the combination of psychological and environmental stressors.