Abstract

Background Circadian rhythms are endogenous manifestations of the external 24-hour light-dark cycle that allow the organism to adapt and to anticipate daily temporal changes in the environment. These ~24-hour rhythms, also called circadian clocks, are driven by clock genes in almost each cell throughout our body and are set to 24 hours each day by the external light and dark cycle. Because circadian clocks regulate virtually all of our physiology and behavior, organisms may be susceptible to various types of disorders when circadian rhythms are disrupted. Thus, there is, for example, a bidirectional relationship between the disturbance of circadian clocks and the development of psychiatric disorders, such as anxiety disorders, and alcohol use disorder (AUD), whereby alcohol consumption can influence the circadian system, but conversely, disturbed circadian rhythms are a risk factor for addiction. Results We show that Cryptochrome 1 and 2 (Cry1/2-/-) double knockout mice, which do not express endogenous circadian rhythms, exhibit a pronounced anxiety-like phenotype and are more sensitive to stressful situations. These behavioral effects are confirmed by increased neuronal activity (c-Fos) in the basolateral amygdala. Furthermore, we show that the Cry1/2-/- mice exhibit distinct traits that predispose humans to an increased risk of problematic alcohol consumption. Cry1/2-/- mice show lower alcohol consumption behavior (liking) concomitant with higher motivation to acquire the substance (wanting), a finding that is consistent with the incentive sensitization theory of addiction. These phenotypes are also supported by molecular analyses: In the absence of the Cry genes, the stress hormone corticosterone is continuously elevated, and the level of the orexin precursor prepro-orexin is persistently low, which together represent explanatory factors for an overall altered alcohol preference. In terms of gene-environment interaction, the phenotype of altered alcohol drinking behavior of Cry1/2-/- mice, was enhanced by additional environmental circadian perturbations (shift work model). Outlook Our results underline the importance of stable endogenous and environmental circadian rhythms as well as their interaction for mental health. From our findings, we assume that patients suffering from anxiety disorders, AUD, or both, regardless of whether underlying circadian rhythm disturbances are genetically or environmentally induced, may benefit from chronotherapies. This is why, based on our results, we developed a new adjunctive chronotherapeutic treatment for AUD patients.