Background:Abnormalities in circadian rhythms may be causal factors in development of major depressive disorder. The biology underlying a causal relationship between circadian rhythm disturbances and depression is slowly being unraveled. Although there is no direct evidence of dysregulation of clock gene expression in depressive patients, many studies have reported single-nucleotide polymorphisms in clock genes in these patients.Methods:In the present study we investigated whether a depression-like state in rats is associated with alternations of the diurnal expression of clock genes. The validated chronic mild stress (CMS) animal model of depression was used to investigate rhythmic expression of three clock genes: period genes 1 and 2 (Per1 and Per2) and Bmal1. Brain and liver tissue was collected from 96 animals after 3.5 weeks of CMS (48 control and 48 depression-like rats) at a 4h sampling interval within 24h. We quantified expression of clock genes on brain sections in the prefrontal cortex, nucleus accumbens, pineal gland, suprachiasmatic nucleus, substantia nigra, amygdala, ventral tegmental area, subfields of the hippocampus, and the lateral habenula using in situ hybridization histochemistry. Expression of clock genes in the liver was monitored by real-time quantitative polymerase chain reaction (PCR).Results:We found that the effect of CMS on clock gene expression was selective and region specific. Per1 exhibits a robust diurnal rhythm in most regions of interest, whereas Bmal1 and in particular Per2 were susceptible to CMS.Conclusion:The present results suggest that altered expression of investigated clock genes is likely associated with the induction of a depression-like state in the CMS model.

The altered activity of the hypothalamic-pituitary-adrenal (HPA) axis is often observed in stress-related disorders. According to the literature, about 60% of patients with major depressive disorder elicit high levels of cortisol. It is still unclear why high cortisol levels are not observed in all patients. In this study, we used the chronic mild stress (CMS) rat model of depression, which is based on continuous exposure to unpredictable stressors, to track longitudinal changes in HPA function using fecal corticosterone metabolites (FCM) as a read out. The dexamethasone suppression test was used to assess negative feedback inhibition of the HPA axis. Our results show (1) a disturbance in diurnal corticosterone rhythm measured as fluctuations of the diurnal FCM peak, (2) differences in corticosterone levels between stress-susceptible and stress-resilient animals, (3) recovery of diurnal corticosterone rhythm after 8 weeks of CMS, and (4) alterations in sensitivity to dexamethasone in negative feedback regulation of corticosterone secretion during the time course of CMS. Thus, a disruption of HPA axis circadian rhythmicity coincides with the initial state in the development of depression-like behavior. This chronobiological abnormality, as well as the hypersecretion of corticosterone, is state, rather than trait, dependent.

There is limited knowledge pertaining to the history of the Greenland Ice Sheet (GIS) during the last glacial‐interglacial transition as it retreated from the continental margins to an inland position. Here we use multiproxy data, including ice‐rafted debris (IRD); planktonic isotopes; alkenone temperatures; and tephra geochemistry from the northern Labrador Sea, off southwest Greenland, to investigate the deglacial response of the GIS and evaluate its implications for the North Atlantic deglacial development. The results imply that the southern GIS retreated in three successive stages: (1) early deglaciation of the East Greenland margins, by tephra‐rich IRD that embrace Heinrich Event 1; (2) progressive retreat during Allerød culminating in major meltwater releases (δ18O depletion of 1.2‰) at the Allerød–Younger Dryas transition (12.8–13.0 kyr B.P.); and (3) a final stage of glacial recession during the early Holocene (∼9–11 kyr B.P.). Rather than indicating local temperatures of ambient surface water, the alkenones likely were transported to the core site by the Irminger Current. We attribute the timing of GIS retreat to the incursion of warm intermediate waters along the base of grounded glaciers and below floating ice shelves on the continental margin. The results lend support to the view that GIS meltwater presented a forcing factor for the Younger Dryas cooling.