Circadian gene × environment perturbations influence alcohol drinking in Cryptochrome-deficient mice.

Alcohol use disorder (AUD) is a widespread addiction disorder with severe consequences for health. AUD patients often suffer from sleep disturbances and irregular daily patterns. Conversely, disruptions of circadian rhythms are considered a risk factor for AUD and alcohol relapses. In this study, we investigated the extent to which circadian genetic and environmental disruptions and their interaction alter alcohol drinking behaviour in mice. As a model of genetic circadian disruption, we used Cryptochrome1/2-deficient (Cry1/2-/- ) mice with strongly suppressed circadian rhythms and found that they exhibit significantly reduced preference for alcohol but increased incentive motivation to obtain it. Similarly, we found that low circadian SCN amplitude correlates with reduced alcohol preference in WT mice. Moreover, we show that the low alcohol preference of Cry1/2-/- mice concurs with high corticosterone and low levels of the orexin precursor prepro-orexin and that WT and Cry1/2-/- mice respond differently to alcohol withdrawal. As a model of environmentally induced disruption of circadian rhythms, we exposed mice to a "shift work" light/dark regimen, which also leads to a reduction in their alcohol preference. Interestingly, this effect is even more pronounced when genetic and environmental circadian perturbations interact in Cry1/2-/- mice under "shift work" conditions. In conclusion, our study demonstrates that in mice, disturbances in circadian rhythms have pronounced effects on alcohol consumption as well as on physiological factors and other behaviours associated with AUD and that the interaction between circadian genetic and environmental disturbances further alters alcohol consumption behaviour.

An in-depth neurobehavioral characterization shows anxiety-like traits, impaired habituation behavior, and restlessness in male Cryptochrome-deficient mice.

Many psychiatric disorders, for example, anxiety, are accompanied by disturbances of circadian rhythms, including disturbed sleep/wake cycles, changes in locomotor activity, and abnormal endocrine function. Conversely, alternations of circadian rhythms are a risk factor for the development of psychiatric disorders. This assumption is supported by animals with clock gene mutations which often display behaviors that resemble human psychiatric disorders. In this study, we performed an in-depth behavioral analysis with male mice lacking the central clock genes Cryptochrome 1 and 2 (Cry1/2-/- ), which are thus unable to express endogenous circadian rhythms. With wild-type and Cry1/2-/- mice, we performed an extensive behavioral analysis to study their cognitive abilities, social behavior, and their expression of depression-like and anxiety-like behavior. While Cry1/2-/- mice showed only mild abnormalities at cognitive and social behavioral levels, they were consistently more anxious than wildtype mice. Anxiety-like behavior was particularly evident in reduced mobility in new environments, altered ability to habituate, compensatory behavior, and consistent restless behavior across many behavioral tests. In line with their anxiety-like behavioral phenotype, Cry1/2-/- mice have higher c-Fos activity in the amygdala after exposure to an anxiogenic stressor than wild-type mice. In our study, we identified Cry1/2-/- mice as animals that qualify as a translational mouse model for anxiety disorder in humans because of its consistent behavior of restlessness, increased immobility, and dysfunctional habituation in new environments.

DAILY-A Personalized Circadian Zeitgeber Therapy as an Adjunctive Treatment for Alcohol Use Disorder Patients: Study Protocol for a Randomized Controlled Trial.

Background: Hallmarks of alcohol use disorder (AUD) are disturbances of circadian rhythms and everyday structures. While circadian rhythms dictate the timing of daily recurring activities such as sleep, activity, and meals, conversely, these activities represent time cues, so called Zeitgebers, that the circadian system uses to synchronize with the environment. Here we present a study protocol for our newly developed therapy approach for AUD patients, in which we take advantage of this mutual influence and stabilize and strengthen their circadian system by creating strict daily schedules for daily Zeitgeber activities. Since every person has a circadian system with its own characteristics and is subject to social obligations, the daily plans are personalized for each test person. Our hypothesis is that a regular exposure to Zeitgebers stabilizes behavioral and physiological circadian rhythms and thereby reduces the risk of alcohol relapses and depressive symptoms and facilitates physical recovery in AUD patients during the 1st weeks of their addiction therapy. Methods/design: The study is a 6-weeks single site trial with a controlled, randomized, single-blinded, parallel-group design including patients with a diagnosis of AUD. The study runs parallel to the standard addiction therapy of the clinic. Patients are randomly assigned to either an intervention group (DAILY) or a sham control group (placebo treatment). Questionnaires and physiological assessments of both groups are conducted before and immediately after the intervention or control treatment. According to our hypothesis, the primary outcomes of this study are improvements of regularity, alcohol consumption, and relapse rate in AUD patients compared to AUD patients receiving control treatment. Secondary outcomes are reduced depressive symptoms and increased physical recovery. Discussion: This study is a randomized controlled trial to investigate the efficacy of a personalized circadian Zeitgeber therapy as an adjunctive treatment for alcohol use disorder patients. The overall goal of this and more extended future studies is the development of an adjunctive therapy for AUD patients that is uncomplicated in its use and easy to implement in the clinical and everyday routine. Trial registration: This study is registered at the German Clinical Trial Register with the trial number DRKS00019093 on November 28, 2019.

Prospects for circadian treatment of mood disorders.

Disruption of circadian clocks is strongly associated with mood disorders. Chronotherapies targeting circadian rhythms have been shown to be very effective treatments of mood disorders, but still are not widely used in clinical practice. The mechanisms by which circadian disruption leads to mood disorders are poorly characterized and, therefore, may not convince clinicians to apply chronotherapies. Hence, in this review, we describe specific potential mechanisms, in order to make this connection more credible to clinicians. We believe that four major features of disrupted clocks may contribute to the development of mood disorders: (1) loss of synchronization to environmental 24-h rhythms, (2) internal desynchronization among body clocks, (3) low rhythm amplitude, and (4) changes in sleep architecture. Discussing these attributes and giving plausible examples, we will discuss prospects for relatively simple chronotherapies addressing these features that are easy to implement in clinical practice. Key messages In this review, we describe specific potential mechanisms by which disrupted clocks may contribute to the development of mood disorders: (1) loss of synchronization to environmental 24-h rhythms, (2) internal desynchronization among body clocks, (3) low rhythm amplitude, and (4) changes in sleep architecture. We provide prospects for relatively simple chronotherapies addressing these features that are easy to implement in clinical practice.