Rescue of Comorbid Behavioral and Metabolic Phenotypes of Arrhythmic Mice by Restoring Circadian Cry1/2 Expression in the Suprachiasmatic Nucleus

Anisja Hühne-Landgraf; Katharina Laurent; Muriel K Frisch; Michael C Wehr; Moritz J Rossner; Dominic Landgraf

doi:10.1016/j.bpsgos.2023.06.002

Rescue of Comorbid Behavioral and Metabolic Phenotypes of Arrhythmic Mice by Restoring Circadian Cry1/2 Expression in the Suprachiasmatic Nucleus

Biol Psychiatry Glob Open Sci. 2023 Jul 1;3(4):632-641. doi: 10.1016/j.bpsgos.2023.06.002. eCollection 2023 Oct.

Authors

Anisja Hühne-Landgraf¹, Katharina Laurent¹, Muriel K Frisch^{1

2}, Michael C Wehr^{3

4}, Moritz J Rossner^{4

5}, Dominic Landgraf¹

Affiliations

¹ Circadian Biology Group, Section of Molecular Neurobiology, Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich, Munich, Germany.
² International Max Planck Research School for Translational Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
³ Cell Signaling Group, Section of Molecular Neurobiology, Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich, Munich, Germany.
⁴ Systasy Bioscience GmbH, Munich, Germany.
⁵ Section of Molecular Neurobiology, Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich, Munich, Germany.

Abstract

Background: Psychiatric and metabolic disorders occur disproportionately often comorbidly, which poses particular hurdles for patients and therapists. However, the mechanisms that promote such comorbidities are largely unknown and therefore cannot yet be therapeutically targeted for the simultaneous treatment of both conditions. Because circadian clocks regulate most physiological processes and their disruption is a risk factor for both psychiatric and metabolic disorders, they may be considered as a potential mechanism for the development of comorbidities and a therapeutic target. In the current study, we investigated the latter assumption in Cry1/2^-/- mice, which exhibit substantially disrupted endogenous circadian rhythms and marked metabolic and behavioral deficits.

Methods: By targeted virus-induced restoration of circadian rhythms in their suprachiasmatic nucleus, we can restore behavioral as well as several metabolic processes of these animals to near-normal circadian rhythmicity.

Results: Importantly, by rescuing suprachiasmatic nucleus rhythms, several of their anxiety-like behavioral as well as diabetes- and energy homeostasis-related deficits were significantly improved. Interestingly, however, this did not affect all deficits typical of Cry1/2^-/- mice; for example, restlessness and body weight remained unaffected.

Conclusions: Taken together, the results of this study demonstrate, on the one hand, that restoration of disturbed circadian rhythms can be used to simultaneously treat psychiatric and metabolic deficits. On the other hand, the results also allow us to distinguish processes that depend more on local canonical clocks from those that depend more on suprachiasmatic nucleus rhythms.

Keywords: Behavior; Circadian; Comorbidity; Cryptochromes; Metabolism; Suprachiasmatic nucleus.