Cognitive dysfunction, elevated anxiety, and reduced cocaine response in circadian clock-deficient cryptochrome knockout mice

Abstract

The circadian clock comprises a set of genes involved in cell-autonomous transcriptional feedback loops that orchestrate the expression of a range of downstream genes, driving circadian patterns of behavior. Cognitive dysfunction, mood disorders, anxiety disorders, and substance abuse disorders have been associated with disruptions in circadian rhythm and circadian clock genes, but the causal relationship of these associations is still poorly understood. In the present study, we investigate the effect of genetic disruption of the circadian clock, through deletion of both paralogs of the core gene cryptochrome (Cry1 and Cry2). Mice lacking Cry1 and Cry2 (Cry1−/−Cry2−/−) displayed attenuated dark phase and novelty-induced locomotor activity. Moreover, they showed impaired recognition memory but intact fear memory. Depression-related behaviors in the forced swim test or sucrose preference tests were unaffected but Cry1−/−Cry2−/− mice displayed increased anxiety in the open field and elevated plus maze tests. Finally, hyperlocomotion and striatal phosphorylation of extracellular signal-regulated kinase (ERK) induced by a single cocaine administration are strongly reduced in Cry1−/−Cry2−/− mice. Interestingly, only some behavioral measures were affected in mice lacking either Cry1 or Cry2. Notably, recognition memory was impaired in both Cry1−/−Cry2+/+ and Cry1+/+Cry2−/− mice. Moreover, we further observed elevated anxiety in Cry1−/−Cry2+/+ and Cry1+/+Cry2−/− mice. Our data indicate that beyond their role in the control of circadian rhythm, cryptochrome genes have a direct influence in cognitive function, anxiety-related behaviors and sensitivity to psychostimulant drugs.

NLRP3 inflammasome activation contributes to long-term behavioral alterations in mice injected with lipopolysaccharide

“…The tubes were weighed again on day 28, and the amount of water and sucrose solution drunk during the 3-day period was calculated as follows: sucrose preference = sucrose consumption (g)/[(water consumption (g) + sucrose consumption (g)]. A reduction in sucrose intake was considered an index of anhedonia (Wang et al, 2008; De Bundel et al, 2013). …”

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith–Magenis and fragile X syndromes

“…Interestingly, loss of CRY2 has been linked to high anxiety, and NR1D2 was recently shown to protect normal metabolic function. 35,36 Anxiety levels and abnormal metabolic function resulting in weight problems are two phenotypes present in these three disorders. The findings of dysregulation of circadian mRNA expression in connection with other phenotypes suggest that circadian rhythm defects not only contribute to sleep disturbances but also to other phenotypes as well.…”

Neuronal correlates of depression

“…Furthermore Clock mutant mice exhibited robust increases in both daytime tyrosine hydroxylase expression and VTA DA neuron activity [294]. Moreover, further evidence that the molecular components of the circadian timing system have a critical role in mood regulation comes from numerous findings that mutations of clock genes Bmal1 and Per2 induce mania-like behaviours in mice while knockout of Cryptochrome 1 and 2 genes induces altered anxiety-like behaviours [295–297]. The circadian nuclear receptor REV-ERBα, an important constituent of molecular circadian signaling that serves as transcriptional repressors of the Bmal RNA, has recently been shown to negatively regulate midbrain DA neuronal function via circadian modulation of tyrosine hydroxylase mRNA transcription [298].…”