Does a Red House Affect Rhythms in Mice with a Corrupted Circadian System?

locomotor activity, body temperature, and many biological functions are regulated by the circadian timing system in mammals. This system efficiently orchestrates physiology so that living organisms adapt to environmental cycles through partly elucidated complex and interacting dynamic mechanisms ([

the timing of physiological events is carefully controlled so that incompatible processes do not compete and complementary functions coincide. Given the pivotal role of the hypothalamus in homeostatic regulation, the discovery that a master circadian pacemaker resides in this region was not

The influence of circadian rhythms on memory has long been studied; however, the molecular prerequisites for their interaction remain elusive. The hippocampus, which is a region of the brain important for long-term memory formation and temporary maintenance, shows circadian rhythmicity in pathways central to the memory-consolidation process. As neuronal plasticity is the translation of numerous inputs, illuminating the direct molecular links between circadian rhythms and memory consolidation remains a daunting task. However, the elucidation of how clock genes contribute to synaptic plasticity could provide such a link. Furthermore, the idea that memory training could actually function as a zeitgeber for hippocampal neurons is worth consideration, based on our knowledge of the entrainment of the circadian clock system. The integration of many inputs in the hippocampus affects memory consolidation at both the cellular and the systems level, leaving the molecular connections between circadian rhythmicity and memory relatively obscure but ripe for investigation.

After completing this article, readers should be able to: 1. Describe how circadian rhythms are generated. 2. Describe how lighting influences the circadian system. 3. Delineate the period during which the origin of circadian rhythms develops. 4. Describe the relationship between maternal circadian rhythms and the development of circadian rhythms in infants. 5. Characterize the potential sequelae of impaired fetal and early neonatal circadian rhythms related to sleep patterns. 6. Describe beneficial lighting patterns for preterm infants in the neonatal intensive care nursery. Circadian rhythms are endogenously generated rhythms that have a period length of about 24 hours. Evidence gathered over the past decade indicates that the circadian timing system develops prenatally, with the suprachiasmatic nuclei (SCN) in the anterior hypothalamus, the site of a circadian clock, present by mid-gestation in primates. Recent evidence also shows that the circadian system of primate infants is responsive to light at very early stages (as early as 25 to 28 weeks’ gestation in humans) and that low-intensity lighting can regulate the developing clock. After birth, circadian system outputs mature progressively, with rhythms in sleep-wake cycles, body temperature, and hormone production generally developing between 1 and 3 months of age. The importance of light in regulation of circadian rhythm in infants is highlighted by the early establishment of rest-activity patterns that are in phase with the 24-hour light-dark cycle in preterm infants exposed to low-intensity cycled lighting. With the continued elucidation of circadian system development and influences on human physiology and illness, it is anticipated that consideration of circadian biology will become an increasingly important component of neonatal care. ### The Circadian Timing System Notable examples of circadian rhythms include the sleep-wake cycle and daily rhythms in body temperature and hormone production. Circadian rhythms are also involved in the pathogenesis of illnesses, such as reactive airway disease (eg, asthma) and myocardial infarction. The system responsible …

Neural regulation of circadian rhythms.

Clock genes Cryptochrome (Cry1) and Cry2 are essential for expression of circadian rhythms in mice under constant darkness (DD). However, circadian rhythms in clock gene Per1 expression or clock protein PER2 are detected in the cultured suprachiasmatic nucleus (SCN) of neonatal Cry1 and Cry2 double deficient (Cry1 -/-/Cry2 -/-) mice. A lack of circadian rhythms in adult Cry1 -/-/Cry2 -/- mice is most likely due to developmentally disorganized cellular coupling of oscillating neurons in the SCN. On the other hand, neonatal rats exposed to constant light (LL) developed a tenable circadian system under prolonged LL which was known to fragment circadian behavioral rhythms. In the present study, Cry1 -/-/Cry2 -/- mice were raised under LL from postnatal day 1 for 7 weeks and subsequently exposed to DD for 3 weeks. Spontaneous movement was monitored continuously after weaning and PER2::LUC was measured in the cultured SCN obtained from mice under prolonged DD. Surprisingly, Chi square periodogram analysis revealed significant circadian rhythms of spontaneous movement in the LL-raised Cry1 -/-/Cry2 -/- mice, but failed to detect the rhythms in Cry1 -/-/Cry2 -/- mice raised under light-dark cycles (LD). By contrast, prolonged LL in adulthood did not rescue the circadian behavioral rhythms in the LD raised Cry1 -/-/Cry2 -/- mice. Visual inspection disclosed two distinct activity components with different periods in behavioral rhythms of the LL-raised Cry1-/-/Cry2-/- mice under DD: one was shorter and the other was longer than 24 hours. The two components repeatedly merged and separated. The patterns resembled the split behavioral rhythms of wild type mice under prolonged LL. In addition, circadian rhythms in PER2::LUC were detected in some of the LL-raised Cry1-/-/Cry2-/- mice under DD. These results indicate that neonatal exposure to LL compensates the CRY double deficiency for the disruption of circadian behavioral rhythms under DD in adulthood.

Manipulating the Cellular Circadian Period of Arginine Vasopressin Neurons Alters the Behavioral Circadian Period

A light-induced small G-protein gem limits the circadian clock phase-shift magnitude by inhibiting voltage-dependent calcium channels.

Chapter 6 - When does it start ticking? Ontogenetic development of the mammalian circadian system

The circadian timing system controlled by the suprachiasmatic nuclei (SCN) of the hypothalamus regulates daily rhythms of motor activity and adrenocortical secretion. An alteration in these rhythms is associated with poor survival of patients with metastatic colorectal or breast cancer. We developed a mouse model to investigate the consequences of severe circadian dysfunction upon tumor growth. The SCN of mice were destroyed by bilateral electrolytic lesions, and body activity and body temperature were recorded with a radio transmitter implanted into the peritoneal cavity. Plasma corticosterone levels and circulating lymphocyte counts were measured (n = 75 with SCN lesions, n = 64 sham-operated). Complete SCN destruction was ascertained postmortem. Mice were inoculated with implants of Glasgow osteosarcoma (n = 16 with SCN lesions, n = 12 sham-operated) or pancreatic adenocarcinoma (n = 13 with SCN lesions, n = 13 sham-operated) tumors to determine the effects of altered circadian rhythms on tumor progression. Time series for body temperature and rest-activity patterns were analyzed by spectral analysis and cosinor analysis. Parametric data were compared by the use of analysis of variance (ANOVA) and survival curves with the log-rank test. All statistical tests were two-sided. The 24-hour rest-activity cycle was ablated and the daily rhythms of serum corticosterone level and lymphocyte count were markedly altered in 75 mice with complete SCN destruction as compared with 64 sham-operated mice (two-way ANOVA for corticosterone: sampling time effect P<.001, lesion effect P =.001, and time x lesion interaction P<.001; for lymphocytes P =.001,.002, and.002 respectively). Body temperature rhythm was suppressed in 60 of the 75 mice with SCN lesions (P<.001). Both types of tumors grew two to three times faster in mice with SCN lesions than in sham-operated mice (two-way ANOVA: P<.001 for lesion and for tumor effects; P =.21 for lesion x tumor effect interaction). Survival of mice with SCN lesions was statistically significantly shorter compared with that of sham-operated mice (log-rank P =.0062). Disruption of circadian rhythms in mice was associated with accelerated growth of malignant tumors of two types, suggesting that the host circadian clock may play an important role in endogenous control of tumor progression.

In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which coordinates the circadian rhythm and controls locomotor activity rhythms. In addition to SCN cells, the peripheral tissues and embryonic fibroblasts also have clock genes, such as Per1/2 and Bmal1, which generate the transcriptional-translational feedback loop to produce an approximately 24-h cycle. Aging adversely affects the circadian clock system and locomotor functions. Oak extract has been reported to improve age-related physiological changes. However, no study has examined the effect of oak extract on the circadian clock system. We examined the effects of oak extract and its metabolites (urolithin A [ULT] and ellagic acid [EA]) on clock gene expression rhythms in mouse embryonic fibroblasts (MEFs) and SCN. Furthermore, locomotor activity rhythm was assessed in young and aged mice. Chronic treatment with EA and ULT delayed the phase of PER2::LUC rhythms in SCN explants, and ULT prolonged the period of PER2::LUC rhythms in MEFs in a dose-dependent manner and increased the amplitude of PER2::LUC rhythms in MEFs, though only at low concentrations. Acute treatment with ULT affected the phase of PER2::LUC rhythms in MEFs depending on the concentration and timing of the treatment. In addition, oak extract prolonged the activity time of behavioral rhythms in old mice and tended to increase daily wheel-running revolutions in both young and old mice. These results suggest that oak extract is a novel modulator of the circadian clock in vitro and in vivo. The online version contains supplementary material available at 10.1007/s41105-021-00365-2.

Response to Honma and Honma: Do circadian rhythms in cytosolic Ca 2+ modulate autonomous gene transcription cycles in the SCN?

Double-stranded RNA-mediated suppression of Period2 expression in the suprachiasmatic nucleus disrupts circadian locomotor activity in rats

Mammalian circadian rhythms are driven by the transcriptional-translational feedback loop of clock genes in the hypothalamic suprachiasmatic nucleus. However, chronic methamphetamine treatment induces circadian activity rhythms in arrhythmic animals with suprachiasmatic nucleus lesions or clock gene deletions. Activation of dopaminergic neurotransmission by methamphetamine is considered to induce activity rhythms. Adenosine antagonizes the actions of dopamine at heteromers of dopamine and adenosine receptors (dopamine D1 and adenosine A1 receptors, dopamine D2 and adenosine A2A receptors). In this study, we considered that adenosine inhibition acts similarly to methamphetamine and administered an antagonist of adenosine A1 and A2A receptors, caffeine, in drinking water. Chronic caffeine treatment extended the circadian activity period of wild-type mice under constant darkness. The circadian period extension continued for 3 weeks after the replacement of caffeine with water. Chronic caffeine treatment induced circasemidian (~12 h), circadian, and longer-period activity rhythms in clock gene deficient, cryptochrome (Cry) 1 and Cry 2 double knockout mice under constant darkness. These activity rhythms changed periods spontaneously over time and became arrhythmic upon caffeine withdrawal. In humans, rhythms with periods shorter or longer than 24 h are hypothesized to cause internal desynchronization of the sleep-wake rhythm from the ~24 h body temperature rhythm under temporal isolation. Circasemidian rhythms are hypothesized to cause afternoon sleepiness and naps. Caffeine-induced rhythms may help understand rhythms with periods shorter or longer than 24 h in humans.

Drosophila Ebony Activity Is Required in Glia for the Circadian Regulation of Locomotor Activity