RESUMO
The expression of circadian clock genes, either centrally or in the periphery, has been shown to play an integral role in the control of behavior. Brain region-specific downregulation of clock genes revealed behavioral phenotypes associated with neuropsychiatric disorders and neurodegenerative disease. The specific function of the clock genes as well as the underlying mechanisms that contribute to the observed phenotypes, however, are not yet fully understood. We assessed anxiety- and depressive-like behavior and motor functions in male and female mice with a conditional ablation of Bmal1 or Per2 from medium spiny neurons (MSNs) of the striatum as well as mice lacking one copy of Gpr88. Whereas the conditional knockout of Bmal1 and Per2 had mild effects on affective behaviors, a pronounced effect on motor functions was found in Bmal1 knockout mice. Subsequent investigation revealed an attenuated response of Bmal1 knockout mice to dopamine receptor type 1 agonist treatment, independently of the expression of targets of the dopamine signaling pathway or mitochondrial respiration in MSNs. The study thus suggests a potential interaction of Bmal1 within the direct dopamine signaling pathway, which may provide the link to a shared, MSN-dependent mechanism regulating affective behavior and motor function in mice.
RESUMO
Disruption of circadian rhythmicity distorts physiological and psychological processes and has major consequences on health and well-being. A chronic misalignment within the internal time-keeping system modulates alcohol consumption and contributes to stress-related psychiatric disorders which are known to trigger alcohol misuse and relapse. While there is growing evidence of the deleterious impact of circadian disruption on male physiology and behavior, knowledge about the effect in females remains limited. The present study aims to fill the gap by assessing the relationship between internal desynchronization and alcohol intake behavior in female rats. Female Wistar rats kept under standard 24-h, 22-h light-dark conditions, or chronic 6-h advanced phase shifts, were given intermittent access to 20% alcohol followed by an extended alcohol deprivation period. Alcohol consumption under altered light-dark (LD) conditions was assessed and emotional behavior during alcohol abstinence was evaluated. Internally desynchronization in female rats does not affect alcohol consumption but alters scores of emotionality during alcohol abstinence. Changes in affective-like behaviors were accompanied by reduced body weight gain and estrous irregularities under aberrant LD conditions. Our data suggest that internal desynchronization caused by environmental factors is not a major factor contributing to the onset and progression of alcohol abuse, but highlights the need of maintaining circadian hygiene as a supportive remedy during alcohol rehabilitation.
RESUMO
Alcohol consumption has been strongly associated with circadian clock gene expression in mammals. Analysis of clock genes revealed a potential role of Bmal1 in the control of alcohol drinking behavior. However, a causal role of Bmal1 and neural pathways through which it may influence alcohol intake have not yet been established. Here we show that selective ablation of Bmal1 (Cre/loxP system) from medium spiny neurons of the striatum induces sexual dimorphic alterations in alcohol consumption in mice, resulting in augmentation of voluntary alcohol intake in males and repression of intake in females. Per2mRNA expression, quantified by qPCR, decreases in the striatum after the deletion of Bmal1. To address the possibility that the effect of striatal Bmal1 deletion on alcohol intake and preference involves changes in the local expression of Per2, voluntary alcohol intake (two-bottle, free-choice paradigm) was studied in mice with a selective ablation of Per2 from medium spiny neurons of the striatum. Striatal ablation of Per2 increases voluntary alcohol intake in males but has no effect in females. Striatal Bmal1 and Per2 expression thus may contribute to the propensity to consume alcohol in a sex -specific manner in mice.
