Circadian phase and sex effects on depressive/anxiety-like behaviors and HPA axis responses to acute stress

Abstract

Circadian dysregulation in sleep pattern, mood, and hypothalamic-pituitary-adrenal (HPA) axis activity, often occurring in a sexually dimorphic manner, are characteristics of depression. However, the inter-relationships among circadian phase, HPA function, and depressive-like behaviors are not well understood. We investigated behavioral and neuroendocrine correlates of depressive/anxiety-like responses during diurnal ('light') and nocturnal ('dark') phases of the circadian rhythm in the open field (OF), elevated plus maze (EPM), forced swim (FST), and sucrose contrast (SC) tests. Plasma corticosterone (CORT) was measured after a) acute restraint and OF testing and b) FST. Both phase and sex significantly influenced behavioral responses to stress. Males were more anxious than females on the EPM in the light but not the dark phase. Further, the open:closed arm ratio was lower in the dark for females, but not males. By contrast, in the FST, females showed more "despair" (immobility) when tested in the dark, while phase did not affect males. Acute restraint stress increased OF activity in the light, but not the dark, phase. CORT levels were increased in both sexes following the FST, and in males and light phase females post-OF. As expected, females had higher CORT levels than males, even at rest, and this effect was more pronounced in the dark phase. Together, our data highlight the sexually dimorphic influences of circadian phase and stress on behavioral and hormonal responsiveness.