Diurnal Oscillation of Amygdala Clock Gene Expression and Loss of Synchrony in a Mouse Model of Depression

Background: Disturbances in circadian rhythm-related physiological and behavioral processes are frequently observed in depressed patients and several clock genes have been identified as risk factors for the development of mood disorders. However, the particular involvement of the circadian system in the pathophysiology of depression and its molecular regulatory interface is incompletely understood. Methods: A naturalistic animal model of depression based upon exposure to chronic mild stress was used to induce anhedonic behavior in mice. Micro-punch dissection was used to isolate basolateral amygdala tissue from anhedonic mice followed by quantitative real-time PCRbased analysis of gene expression. Results: Here we demonstrate that chronic mild stress-induced anhedonic behavior is associated with disturbed diurnal oscillation of the expression of Clock, Cry2, Per1, Per3, Id2, Rev-erb, Ror- and Ror- in the mouse basolateral amygdala. Clock gene desynchronization was accompanied by disruption of the diurnal expressional pattern of vascular endothelial growth factor A expression in the basolateral amygdala of anhedonic mice, also reflected in alterations of circulating vascular endothelial growth factor A levels. Conclusion: We propose that aberrant control of diurnal rhythmicity related to depression may indeed directly result from the illness itself and establish an animal model for the further exploration of the molecular mechanisms mediating the involvement of the circadian system in the pathophysiology of mood disorders.(VLID)458050