Amygdala circadian rhythms in mouse models of mood disorders

Depression is among the most debilitating mental illnesses and is associated with high morbidity and mortality. Etiologies of depression and other mood disorders are still not well understood. The determination of the neurobiological determinants is important to enable the precise diagnosis of the biologically distinct sub-types of depressive disorders and the development of specific, etiology-based treatment strategies. Based on the rational of centuries-old observations of biological rhythm alterations in mood disorders, updated by current descriptions of sleep-wake and circadian rhythm disturbances in psychiatric disorders and recent very detailed delineation of the molecular and functional circuitry of the endogenous clock system we propose here to investigate alterations of the molecular clock in animal models of mood disorders. We intend to specifically focus on the amygdala, a key structure for processing of emotional information and determination of emotional states that is proposed to be importantly involved in depressive disorders and response to antidepressant treatment in humans. First we will describe the potential existence of elements of the molecular clock and their circadian oscillations in the amygdala. Next, we aim to induce depressive symptoms in the mouse using administration of lipopolysacharides (LPS) that is known to provoke "sickness behavior" including depression-like states. By contrasting alterations in the circadian oscillations of clock genes and functional activity in the amygdala in this model of depression with those induced by a different, non-immunological model (unpredictable chronic mild stress, UCMS) we additionally set out to test the influence of the immune system on circadian regulation in the context of mood disorders. Finally we plan to investigate the signaling pathway involved in mediating the effect of the depressive phenotype on the alterations in circadian rhythmicity in the amygdala and to determine if the immunological and the non- immunological treatment leading to depressive symptoms share commonalities in their molecular signaling mechanisms.

Disturbances in circadian rhythm-related physiological and behavioral processes are frequently observed in depressed patients and several clock genes have been identified as genetic risk factors for the development of mood disorders. However, a direct involvement of the circadian system in the pathophysiology of depression and its molecular regulatory interface has not been described. This project used three complementing approaches to shed light on the possible role of clock gene dysregulation in depressive-like states in the mouse, focusing on brain regions forming part of the neural circuitry involved in depression. First, it was demonstrated that environmentally induced anhedonic behavior also observed as central symptom in depressed patients - is associated with disturbed circadian oscillation of the expression of several core clock genes in the mouse amygdala (Savalli et al. 2014). Second, in a mouse strain generated by selected breeding, experimental evidence for a dysregulation of behavioral circadian rhythms in a genetic model of depression and comorbid anxiety was firstly provided and suggested a relevance for the clock gene cry2 in the associated neurobiological mechanisms (Griesauer et al. 2014). Moreover, the reversal of both, the behavioral and the molecular phenotype, by antidepressant drug treatment was revealed (Schaufler et al. 2016). Third, the particular role of cry2 in depression was assessed by the behavioral characterization of cry2-deficient mice which were found to present with alterations in anhedonic behavior and depression-related anxiety (Savalli et al. 2015). Jointly, these data support the hypothesis that aberrant control of circadian rhythmicity related to depression may indeed directly result from the disease state itself and provide substantial evidence for a direct involvement of clock gene dysregulation in the underlying neuropathological mechanisms. These results further lay the ground for future investigations aiming at the identification of alternative drug targets and novel biomarkers for depression and invites consideration of the relevance of disrupted circadian rhythmicity in therapeutic interventions for the disease.