Circadian Clocks as Modulators of Metabolic Cormorbidity in Major Depressive Disorder

• Applicant: Dr. Dominic Landgraf
• Subject Area: Biological Psychiatry
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 356460907

The scientific work of my research group is focused on the question to what extent a disturbance of circadian rhythms contributes to the comorbid development of various mental and metabolic disorders. Here, the focus is on identifying physiological and molecular targets and – based on these – the development of novel treatments for metabolic and mental disorders. The research work of our laboratory is thus highly translational and includes molecular biology, metabolism, and behavioral experiments in various animal models, and the development and clinical testing of novel treatments.Our results to date, obtained under the current Emmy-Noether grant, strongly demonstrate that circadian disturbances are causally involved in the development of comorbidities of psychiatric and metabolic disorders in both mice and humans. Importantly, we also show that restoration or stabilization of circadian rhythms in mice and humans can simultaneously prevent or significantly improve comorbid conditions. For example, our studies show that cryptochrome-deficient mice lacking endogenous circadian clocks have diabetes-like and anxiety-like phenotypes and that restoration of their endogenous rhythms by viral expression of rhythmic cryptochromes in the suprachiasmatic nucleus reverses these phenotypes. Likewise, stabilization of circadian rhythms by adherence to strict daily schedules in humans improves body weight and concomitant depressive symptomatology and sleep quality. Furthermore, our results from another human study show that stabilizing circadian rhythms in patients suffering from Alcohol Use Disorder who are in withdrawal at our clinic significantly prevents relapse and improves depressive symptoms and sleep quality.Our other studies, which are currently ongoing and for which personnel and additional investment and consumption funds are requested in the present application, aim to identify physiological and molecular interfaces between circadian clocks and the regulation of mental functions and metabolism. On the one hand, this will be done using mice whose circadian rhythmicity is specifically disrupted in the orexin system. On the other hand, we use cutting-edge telemetric EEG equipment to measure the influence of circadian rhythms of neuronal activity and time-of-day-dependent communication of mood-regulating brain regions and a novel screening method to identify signal transduction pathways in these brain regions that are under the influence of circadian control (cisProfiler). These projects will make it possible to develop new and specific targets for personalized therapies that go beyond current, rather non-specific chronotherapies.

• DFG Programme: Independent Junior Research Groups