Circadian Rhythm Abnormalities Research Articles

Sleep and circadian rhythm dysfunctions in movement disorders beyond Parkinson's disease and atypical parkinsonisms.

This review aimed to comprehensively outline sleep and circadian rhythm abnormalities in hyperkinetic movement disorders beyond Parkinson's disease and atypical parkinsonisms, including tremor, dystonia, choreiform movements, tics, and ataxia disorders. Insomnia, poor sleep quality, and excessive daytime sleepiness (EDS) are commonly reported in essential tremor, Wilson's disease, tics or Tourette's syndrome, and spinocerebellar ataxia (SCA). REM sleep behavior disorder (RBD) have been observed in Wilson's disease and SCA. A combination of REM and non-REM parasomnias, along with nocturnal stridor with the initiation of sleep and re-entering after awakening, are characterized by undifferentiated Non-REM and poorly structured N2 in anti-IgLON5 disease. Restless legs syndrome (RLS) has been reported commonly in SCAs. Sleep-related dyskinesia has been reported in ADCY5-related disease and GNAO1-related movement disorder. Sleep problems can manifest as a result of movement disorders, either through direct motor disturbances or secondary nonmotor symptoms. Medication effects must be considered, as certain medications for movement disorders can exacerbate or alleviate sleep disturbances. Distinguishing sleep problems in some diseases might involve pathognomonic symptoms and signs, aiding in the diagnosis of movement disorders.

Heart Rate Acceleration and Deceleration Capacities Associated With 24-Hour Circadian Blood Pressure Variation of Hypertension Patients

Abstract OBJECTIVE To observe the relationship between 24-hour ambulatory blood pressure circadian rhythm and heart rate acceleration (AC), deceleration capacities (DC) in patients with hypertension. METHODS A total of 198 patients with essential hypertension were included and were monitored by 24-hour ambulatory blood pressure. Based on the nocturnal decline rate of systolic blood pressure, patients were divided into 2 groups: dippers (decline rate 10%–20%, n = 58) and non-dippers (decline rate <10%, n = 140). DC and AC values were calculated based on dynamic electrocardiogram data and compared between 2 groups. Pearson correlation analysis was used to analyze the correlation between DC, AC, and blood pressure and circadian blood pressure variation. Multivariate logistic regression analysis was used to analyze the influencing factors of non-dippers. RESULTS Compared with dippers, AC increased, while DC, standard deviation of normal R–R intervals (SDNN), percentage of heart beats with difference between adjacent normal RR intervals >50 ms in the total number of NN intervals (PNN50%) decreased in non-dippers (P < 0.05). Pearson analysis showed that AC was positively correlated to nighttime systolic blood pressure (r = 0.297), slowest heart rate (r = 0.221) and negatively correlated to SDNN (r = −0.233) and PNN50 (r = −0.238), while DC was negatively correlated to nighttime systolic blood pressure (r = −0.300), 24-hour average heart rate (r = −0.144), slowest heart rate (r = −0.213), and positively correlated to SDNN (r = 0.230), PNN50 (r = 0.267) (all P < 0.05). Multivariate logistic regression analysis showed that in the model included AC, AC (odds ratio [OR] = 1.320, 95% confidence interval [CI] 1.102–1.580, P = 0.003), age (OR = 1.029, 95% CI 1.001–1.057, P = 0.039), and 24-hour average heart rate (OR = 1.062, 95% CI 1.010–1.116, P = 0.02) were independent risk factors for non-dippers, while in the model included DC, DC (OR = 0.824, 95% CI 0.709–0.956, P = 0.011), age (OR = 1.027, 95% CI 1.001–1.055, P = 0.046), and 24-hour average heart rate (OR = 1.058, 95% CI 1.007–1.113, P = 0.025) were independent risk factors for non-dippers. CONCLUSIONS AC increases and DC decreases in patients with non-dipper hypertension. Nighttime systolic blood pressure positively correlates with AC and negatively correlates with DC. AC and DC are independent risk factors for abnormal circadian rhythm of blood pressure in hypertensives.

Associations of sleep-related variables with reverse dipping patterns of blood pressure in α-synucleinopathies

IntroductionThe reverse dipping blood pressure (BP) pattern is very common in α-synucleinopathies. We aimed to explore the associations of sleep-related variables with abnormal BP circadian rhythms in Parkinson's disease (PD) and multiple system atrophy (MSA). MethodsA total of 126 patients, 76 with PD and 50 with MSA, were included. All participants underwent ambulatory BP monitoring and full-night polysomnography (PSG). We analyzed abnormal dipping patterns and sleep-related parameters, including moderate to severe obstructive sleep apnea (OSA), rapid eye movement behavior disorder (RBD), average oxygen saturation (SaO2%), lowest SaO2%, duration of SaO2% <90%, and apnea-hypopnea index (AHI). Binary logistic regression was performed to explore the associations between paraclinical variables, sleep-related variables, and reverse dipping patterns. ResultsReverse dipping patterns were predominant in patients with PD (58.5 %) and MSA (68.0 %). Patients with MSA had higher AHI, RBD, and lower average SaO2% than those with PD. Taking both diseases together as a whole group of α-synucleinopathies, logistic regression analysis indicates the Hoehn-Yahr stage (odds ratio [OR] = 2.00 for reverse systolic and 2.34 for reverse diastolic dipping patterns), moderate to severe OSA (OR = 2.71 for reverse systolic and 2.53 for reverse diastolic dipping patterns), average SaO2% (OR = 1.35 for reverse systolic dipping patterns), and male sex (OR = 2.70 for reverse diastolic dipping patterns) were independently associated with reverse dipping patterns. ConclusionsReverse dipping patterns were common in patients with PD and MSA. Hoehn-Yahr stage, moderate to severe OSA, average SaO2%, and male sex were associated with reverse dipping patterns in α-synucleinopathy.

Abnormalities of Rest-Activity and Light Exposure Rhythms Associated with Cognitive Function in Patients with Mild Cognitive Impairment (MCI).

We aimed to examine the difference in rest-activity rhythm (RAR) and light exposure rhythm (LER) between patients with mild cognitive impairment (MCI) and normal controls (NC), and to verify their relationships with cognitive functions. The neuropsychological battery was administered to participants above 50 years old. The MCI diagnosis was made according to Petersen's criteria. Ten patients with MCI (77.90 ± 6.95 years) and eight NC (74.75 ± 5.06 years) were studied. Actigraphy (Actiwatch 2; Philips Respironics) was recorded at home for 5 days. RAR and LER variables, including interdaily stability (IS), intradaily variability (IV) and relative amplitude, were calculated using nonparametric analyses. The associations between cognitive performance and RAR and LER variables were explored using generalized linear models. There were no significant differences in RAR or LER variables between MCI and NC. There was a significant main effect of RAR-IS on the Stroop Color and Word Test (SCWT), indicating a positive relationship between RAR stability and SCWT performance. There was a significant group by RAR-IS interaction on Trail Making Test-A, indicating a negative relationship in MCI compared to NC. There was a significant group by LER-IV interaction on the Boston Naming Test, indicating a positive relationship in MCI compared to NC. There was no disruption in RAR and LER in patients with MCI. Our study showed that circadian rhythm abnormality was associated with a decline in executive function. However, circadian rhythm abnormality was not associated with declines in processing speed and language function in patients with MCI, implying an altered pathophysiology compared to NC.

Molecular mechanisms of artificial light at night affecting circadian rhythm disturbance.

Artificial light at night (ALAN) pollution has been regarded as a global environmental concern. More than 80% of the global population is exposed to light pollution. Exacerbating this issue, artificially lit outdoor areas are growing by 2.2% per year, while continuously lit areas have brightened by 2.2% each year due to rapid population growth and expanding urbanization. Furthermore, the increasing prevalence of night shift work and smart device usage contributes to the inescapable influence of ALAN. Studies have shown that ALAN can disrupt endogenous biological clocks, resulting in a disturbance of the circadian rhythm, which ultimately affects various physiological functions. Up until now, scholars have studied various disease mechanisms caused by ALAN that may be related to the response of the circadian system to light. This review outlines the molecular mechanisms by which ALAN causes circadian rhythm abnormalities in sleep disorders, endocrine diseases, cardiovascular disease, cancer, immune impairment, depression, anxiety and cognitive impairments.

Targeting Cartilage miR-195/497 Cluster for Osteoarthritis Treatment Regulates the Circadian Clock

Introduction: Osteoarthritis (OA) is the most prevalent and debilitating joint disease without an effective therapeutic option. Multiple risk factors for OA have been identified, including abnormal chondrocyte miRNA secretion and circadian rhythms disruption, both of which have been found to cause progressive damage and loss of articular cartilage. Environmental disruption of circadian rhythms in mice predisposes animals to cartilage injury and OA. Methods: The role of miR-195/497 cluster during OA progression was verified by mouse OA model with intra-articular injection of Agomir and Antagomir. We performed micro-CT analysis, Osteoarthritis Research Society International scores, and histological analysis in mouse knee joints. RNA sequencing was performed on the mouse cartilage cell line to explore the molecular mechanism of the miR-195/497 cluster and proteins in signaling pathway were evaluated using Western blot. Senescence-associated phenotypes were detected by Western blot, senescence β-galactosidase staining, and immunofluorescence. Results: This study demonstrated that miR-195/497-5p expression is disrupted in OA with senescent chondrocytes. In addition, miR-195/497-5p influenced the circadian rhythm of mice chondrocytes by modulating the expression of the Per2 protein, resulting in the gradual degradation of articular cartilage. We found that the miR-195/497 cluster targets DUSP3 expression. The deletion of the miR-195/497 cluster increased the level of DUSP3 expression and decreased the levels of phosphorylated ERK 1/2 and CREB. Per2 transcription is upregulated by stimulating CREB and ERK 1/2 phosphorylation. Conclusion: Our findings identify a regulatory mechanism connecting chondrocyte miR-195/497-5p to cartilage maintenance and repair and imply that circadian rhythm disturbances affected by miR-195/497-5p are risk factors for age-related joint diseases such as OA.

THU303 The Associations Between Rest-Activity Parameters, Sleep-Disordered Breathing Severity And Glucose Metabolism In Patients With Prediabetes

Abstract Disclosure: J. Paewponsong: None. B.S. Gerber: None. N. Chirakalwasan: None. S. Saetung: None. T. Anothaisintawee: None. S. Reutrakul: None. Background: Circadian rhythm abnormalities and sleep-disordered breathing (SDB) can have an adverse effect on glucose metabolism. In addition, studies have suggested that SDB itself could be associated with circadian disruption. This study aimed to determine if circadian characteristics, as measured by rest-activity rhythm parameters, were connected with SDB severity in individuals with prediabetes, and whether rest-activity rhythm parameters were related with glycemia. Methods: A total of 79 patients with prediabetes were enrolled. Actigraphy recordings (Actiwatch 2, Phillips Respironics) spanning 7 days yielded non-parametric rest-activity rhythm parameters and sleep duration. The parameters included M10 (mean activity of the most active 10-h period), L5 (mean activity of the least active 5-h period), intradaily variability (reflecting rhythm fragmentation), interdaily stability (reflecting sleep regularity across days), and relative amplitude (reflecting the activity between M10 and L5 activity). SDB was assessed using an overnight sleep monitor (WatchPAT200). Fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) were obtained via phlebotomy. Independent predictors of rest-activity rhythm parameters, FBG, and HbA1c were determined using multiple stepwise regression analyses. Model covariates included age, sex, body mass index (BMI), and SDB severity. Results: Increasing SDB severity was associated with lower M10 and greater intradaily variability, but not with FBG, HbA1c or other rest-activity rhythm parameters. After adjusting for age, sex and BMI, increasing SDB severity was independently related with lower M10 (B= -0.102, p=0.001). Further, bivariate analyses showed that a higher HbA1c was associated with a shorter sleep duration, lower relative amplitude, and higher L5. FBG was not related to any rest-activity rhythm parameters. After adjusting for age, sex, BMI and sleep duration, lower relative amplitude, but not L5, was independently related with higher HbA1c (B= −0.027, p=0.031). Conclusion: In prediabetes, a lower relative amplitude, indicating a less robust 24 hour rest-activity rhythm, was associated with a higher HbA1c. These findings suggest that circadian rhythmicity contributes to glycemic control. Greater SDB severity was correlated with decreased activity, but relationships with other rest-activity rhythm parameters were not observed. Presentation: Thursday, June 15, 2023

Cognitive impairment in heart failure patients: association with abnormal circadian blood pressure rhythm: a review from the HOPE Asia Network.

Cognitive impairment (CI) is frequently a comorbid condition in heart failure (HF) patients, and is associated with increased cardiovascular events and death. Numerous factors contribute to CI in HF patients. Decreased cerebral blood flow, inflammation, and activation of neurohumoral factors are all thought to be factors that exacerbate CI. Hypoperfusion of the brain due to decreased systemic blood flow, cerebral venous congestion, and atherosclerosis are the main mechanism of CI in HF patients. Abnormal circadian BP rhythm is one of the other conditions associated with CI. The conditions in which BP does not decrease sufficiently or increases during the night are called non-dipper or riser BP patterns. Abnormal circadian BP rhythm worsens CI in HF patients through cerebral congestion during sleep and atherosclerosis due to pressure overload. Interventions for CI in HF patients include treatment for HF itself using cardiovascular drugs, and treatment for fluid retention, one of the causes of abnormal circadian rhythms. Proposed pathways of cognitive impairment in heart failure through abnormal circadian blood pressure rhythm.

Effects of Different Hay Feeders, Availability of Roughage on Abnormal Behaviors and Cortisol Circadian Rhythm in Horses Kept in Dry Lots

Free choice forage could be the best option regarding horses’ welfare but can lead to increased body weight (BW), and waste of hay. Automatic box feeders (BF) and slow feeders (SF) decrease food waste, but it is unknown how these affect the horses' time-budget (TB). This study compared the effects of feeding free choice hay (FC), to a SF and an automated BF on the horses’ cortisol circadian rhythm (CCR) and behavior by 24-hours continuous behavioral sampling (CBS). The study was designed as a 3 × 3 Latin square design with 15 polo horses divided into 3 groups, for 15 days on each treatment. Every 15 days, BW was assessed, blood collected for CCR analysis, the behavior recorded during the last 24 hours of the last day of each treatment and the video analyzed with CBS. Time spent on all behaviors was evaluated and used for the determination of the animals’ TB. The effects of the different feeders were analyzed with ANOVA. FC horses consumed and wasted more hay daily (16.6 ± 0.5kg) (P < .001), compared with BF (10.4 ± 0.5 kg), and SF (9.30 ± 0.45 kg). FC horses had higher weight gain (P < .001, 23.5 ± 4.6kg), compared to BF (1.2 ± 5.7 kg) and SF (0.37 ± 4.6) kg. FC and SF horses spent more than 50% of the TB foraging, generating a TB similar to grazing horses. BF horses spent less time eating (P < .001), increasing time spent standing, sniffing the ground, and practicing coprophagy (P < .050). BF horses showed the highest aggression (P < .043). CCR was not different among treatments.

Changes in Blood Pressure Variability in Children with Postural Tachycardia Syndrome.

(1) Objective: In this research, we explored the difference in blood pressure variability (BPV) between children with postural tachycardia syndrome (POTS) and healthy children. Furthermore, we tried to investigate the effect of BPV on POTS and its relationship with prognosis of POTS. (2) Methods: 47 children with POTS (11.2 ± 1.8 years, 23 males) were enrolled in the POTS group and 30 healthy children (10.9 ± 1.9 years, 15 males) were matched for the control group. All participants completed 24 h ambulatory blood pressure monitoring (24hABPM). Thirty-three children with POTS were followed up for 52.0 (30.5, 90.5) days and were divided into a response group and a non-response group after evaluation. (3) Results: The 24 h diastolic blood pressure standard deviation (24hDSD), daytime diastolic blood pressure standard deviation (DDSD), nighttime systolic blood pressure standard deviation (NSSD), daytime diastolic blood pressure variation coefficient (DDCV) and nighttime systolic blood pressure variation coefficient (NSCV) in the control group were lower than those in the POTS group (p < 0.05). Percentage of females, age and height were lower in the response group than in the non-response group in children with POTS (p < 0.05). Univariate analysis showed that 24hDSD, DDSD, NSSD, DDCV and NSCV were potential risk factors for POTS, and sex and height were potential risk factors for poor prognosis of POTS. After adjusting for covariates, the risk of POTS increased by 48%, 53% and 49% when DDSD, NSSD and NSCV increased by 1 mmHg, 1 mmHg and 1%, respectively. The risk of poor prognosis in females was 12.99 times higher than that in males. (4) Conclusions: The results suggest that children with POTS may have an abnormal circadian rhythm in blood pressure and increased BPV. DDSD, NSSD and NSCV are independent risk factors for POTS, and being female is an independent risk factor for poor prognosis of POTS.

Bipolar Disorder, Circadian Rhythm and Clock Genes.

Sleep disturbance and abnormal circadian rhythm might be closely related to bipolar disorder. Several studies involving disturbed sleep/wake cycle, changes in rhythms such as melatonin and cortisol, clock genes, and circadian preference have shown the relationship between bipolar disorder and circadian rhythm. The results differed across different studies. In some studies, a delay in the circadian rhythm was observed in the depressive episode and advanced circadian rhythm was observed during the manic episode. In other studies, a delay in circadian rhythm was observed independent of mood episodes. Accordingly, circadian rhythm disorder was proposed as a trait marker for bipolar disorder. The altered circadian rhythm may represent a pathological mechanism that contributes to the mood episodes. However, a prospective cohort study is needed for further clarification.

Cuticle sclerotization precursor N-β-alanyldopamine also plays a role in the regulation of larval phototactic behaviour in Drosophila melanogaster (Diptera: Drosophilidae)

Phototaxis is a well-studied insect behaviour described as rigid and stereotyped. Larval response to light can be assessed by a fast and highly repetitive assay like a half-dark/half-illuminated plate. Drosophila melanogaster Meigen (Diptera: Drosophilidae) mutants can be used to study the response of larvae to sensory stimuli. Adults of the ebony mutant show behavioural deficits such as abnormal circadian rhythms and severe defects in vision, whereas the tan mutants show a slight deficiency in vision. We analysed the response of D. melanogaster mutant larvae for N-β-alanyl derivatives metabolism (ebony and tan) to determine whether they also show abnormal phototactic behaviour. Our results showed that ebony larvae exhibited a random response to light, whereas tan larvae showed a similar response to wild-type larvae. To assess if N-β-alanyl derivatives metabolism might be involved in the response of larvae to light, we fed them with N-β-alanyldopamine (NBAD), N-β-alanylhistamine (carcinine) or dopamine. NBAD restored the wt response in ebony larvae, whereas carcinine and DA produced no effect. These results suggest, for the first time, that NBAD might act as a neuroactive compound involved in the phototactic response of the D. melanogaster larvae.

The relationship between circadian rhythm of blood pressure and vascular dysfunction in essential hypertension

ABSTRACT Objective This study aimed to explore whether circadian rhythm of blood pressure is associated with brachial-ankle pulse wave velocity (baPWV) and brachial artery flow-mediated dilation (FMD) in patients with essential hypertension. Method This cross-sectional study included 4,217 patients with essential hypertension who completed 24-hour ambulatory blood pressure monitoring, baPWV, and FMD. BaPWV and FMD were measured to evaluate arterial stiffness and endothelial dysfunction. Participants were divided into dipper, non-dipper, and reverse dipping groups according to the nocturnal systolic blood pressure dipping percentage. Results In this study, baPWV was highest in the reverse dipping groups, followed by non-dipper and dipper groups (1667.11 ± 327.90 vs. 1613.88 ± 325.11 vs. 1577.45 ± 306.15 cm/s, P < .001) and FMD gradually increased (4.41 ± 2.87 vs. 4.70 ± 2.84 vs. 4.92 ± 2.79%, P = .001). baPWV and FMD were significantly associated with declining nocturnal systolic blood pressure (SBP). Interestingly, FMD (β = 0.042, P = .014) was only positively associated with a drop in nocturnal SBP decline in patients <65 years of age. Whereas baPWV was consistently negatively associated with nocturnal SBP decline regardless of age (β = -0.065, P < .001, age <65 years; β = -0.149, P = .002, age ≥ 65). Receiver operating characteristics (ROC) curves analysis showed areas under the curve (AUC) of baPWV/FMD for predicting circadian rhythm of blood pressure are 0.562/0.554 with a sensitivity of 51.7%/53.9% and specificity of 56.4%/53.4. Conclusion Impairment of baPWV and FMD were correlated with abnormal circadian rhythm of blood pressure in essential hypertension, suggesting a decrease in nighttime SBP may associate with endothelial function and arterial stiffness.

Pregnancy complicated with adrenal adenoma causing ACTH-independent Cushing's syndrome, accompanied by obstetric antiphospholipid syndrome and severe pre-eclampsia: case report and literature review.

This case report shares the management experience of a patient with pregnancy combined with adrenal adenoma causing ACTH-independent Cushing's syndrome (CS), accompanied by obstetric antiphospholipid syndrome (OAPS) and severe pre-eclampsia. The case was a 26-year-old that presented with typical clinical symptoms and signs of CS. The patient had a history of 4 spontaneous abortions in the last 4 years. The 24-hour urinary free cortisol was significantly increased, an abnormal cortisol circadian rhythm was demonstrated by a high late-night salivary cortisol, blood ACTH was suppressed (< 1ng/dL), anticardiolipin antibody was positive, and imaging examination showed an adrenal tumor. The patient underwent laparoscopic adrenal tumor resection under general anesthesia at 23 weeks of gestation. The tumor was pathologically confirmed to be an adrenocortical adenoma. The patient underwent a cesarean section at 39 weeks of gestation to give birth to a healthy baby girl with an Apgar score of 10. Pregnancy complicated by CS is clinically rare, easily masked by normal physiological changes of pregnancy, and is difficult to diagnose. The determination of 24-hour urinary free cortisol, the circadian rhythm of serum cortisol, ultrasound, and MRI can be helpful in the diagnosis of CS during pregnancy. Surgery is the first choice for the treatment of CS during pregnancy. As a subtype of antiphospholipid syndrome, patients with OAPS are prone to thrombotic events and recurrent miscarriages if not treated accordingly. To our knowledge no cases of CS with OAPS and severe pre-eclampsia have been reported. We summarize the experience of the treatment of this patient and review the literature to improve clinicians' awareness of this disease.

Disturbed circadian rhythm and retinal degeneration in a mouse model of Alzheimer’s disease

The circadian clock is synchronized to the 24 h day by environmental light which is transmitted from the retina to the suprachiasmatic nucleus (SCN) primarily via the retinohypothalamic tract (RHT). Circadian rhythm abnormalities have been reported in neurodegenerative disorders such as Alzheimer's disease (AD). Whether these AD-related changes are a result of the altered clock gene expression, retina degeneration, including the dysfunction in RHT transmission, loss of retinal ganglion cells and its electrophysiological capabilities, or a combination of all of these pathological mechanisms, is not known. Here, we evaluated transgenic APP/PS1 mouse model of AD and wild-type mice at 6- and 12-month-old, as early and late pathological stage, respectively. We noticed the alteration of circadian clock gene expression not only in the hypothalamus but also in two extra-hypothalamic brain regions, cerebral cortex and hippocampus, in APP/PS1 mice. These alterations were observed in 6-month-old transgenic mice and were exacerbated at 12 months of age. This could be explained by the reduced RHT projections in the SCN of APP/PS1 mice, correlating with downregulation of hypothalamic GABAergic response in APP/PS1 mice in advanced stage of pathology. Importantly, we also report retinal degeneration in APP/PS1 mice, including Aβ deposits and reduced choline acetyltransferase levels, loss of melanopsin retinal ganglion cells and functional integrity mainly of inner retina layers. Our findings support the theory that retinal degeneration constitutes an early pathological event that directly affects the control of circadian rhythm in AD.

Cerebellum and neurodevelopmental disorders: RORα is a unifying force.

Errors of cerebellar development are increasingly acknowledged as risk factors for neuro-developmental disorders (NDDs), such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia. Evidence has been assembled from cerebellar abnormalities in autistic patients, as well as a range of genetic mutations identified in human patients that affect the cerebellar circuit, particularly Purkinje cells, and are associated with deficits of motor function, learning and social behavior; traits that are commonly associated with autism and schizophrenia. However, NDDs, such as ASD and schizophrenia, also include systemic abnormalities, e.g., chronic inflammation, abnormal circadian rhythms etc., which cannot be explained by lesions that only affect the cerebellum. Here we bring together phenotypic, circuit and structural evidence supporting the contribution of cerebellar dysfunction in NDDs and propose that the transcription factor Retinoid-related Orphan Receptor alpha (RORα) provides the missing link underlying both cerebellar and systemic abnormalities observed in NDDs. We present the role of RORα in cerebellar development and how the abnormalities that occur due to RORα deficiency could explain NDD symptoms. We then focus on how RORα is linked to NDDs, particularly ASD and schizophrenia, and how its diverse extra-cerebral actions can explain the systemic components of these diseases. Finally, we discuss how RORα-deficiency is likely a driving force for NDDs through its induction of cerebellar developmental defects, which in turn affect downstream targets, and its regulation of extracerebral systems, such as inflammation, circadian rhythms, and sexual dimorphism.

Is obstructive sleep apnea a circadian rhythm disorder?

Obstructive sleep apnea is the most common sleep-related breathing disorder worldwide and remains underdiagnosed. Its multiple associated comorbidities contribute to a decreased quality of life and work performance as well as an increased risk of death. Standard treatment seems to have limited effects on cardiovascular and metabolic aspects of the disease, emphasising the need for early diagnosis and additional therapeutic approaches. Recent evidence suggests that the dysregulation of circadian rhythms, processes with endogenous rhythmicity that are adjusted to the environment through various cues, is involved in the pathogenesis of comorbidities. In patients with obstructive sleep apnea, altered circadian gene expression patterns have been demonstrated. Obstructive respiratory events may promote circadian dysregulation through the effects of sleep disturbance and intermittent hypoxia, with subsequent inflammation and disruption of neural and hormonal homeostasis. In this review, current knowledge on obstructive sleep apnea, circadian rhythm regulation, and circadian rhythm sleep disorders is summarised. Studies that connect obstructive sleep apnea to circadian rhythm abnormalities are critically evaluated. Furthermore, pathogenetic mechanisms that may underlie this association, most notably hypoxia signalling, are presented. A bidirectional relationship between obstructive sleep apnea and circadian rhythm dysregulation is proposed. Approaching obstructive sleep apnea as a circadian rhythm disorder may prove beneficial for the development of new, personalised diagnostic, therapeutic and prognostic tools. However, further studies are needed before the clinical approach to obstructive sleep apnea includes targeting the circadian system.

Effects of low dose radiation on behavior rhythm of zebrafish (Danio rerio)

Biological rhythm refers to the internal regulation of various life activities of an organism, which are determined by the specific time structure sequences of each individual. Behavior rhythm is the most intuitive embodiment of biological rhythm. To study the effect of low dose radiation on behavioral rhythm, zebrafish (Danio rerio) was used as a model organism in this study. The early embryos of zebrafish were irradiated at doses of 0.01, 0.1, and 1 Gy to observe the changes in zebrafish development, circadian rhythm, key clock genes, related RNA and protein expression, and melatonin. The results revealed that 0.1 and 1 Gy radiation could lead to different degrees of telencephalic nerve cell apoptosis and the formation of vacuolar structures. 0.1 and 1 Gy radiation could reduce the hatching rate of zebrafish embryos at 72 hpf and delay embryo hatching. The analysis of circadian behavior at 120 hpf demonstrated that 1 Gy dose of radiation altered the circadian rhythm of zebrafish, as well as decreased the distance, amplitude, and phase of movement. RT-PCR analysis of the key clock genes (bmal1b, clock1a, per1b, per2, cry2, and nr1d1) involved in regulating circadian rhythm was performed. The results showed that 1 Gy radiation could interfere with the expression of clock genes in zebrafish embryos and upregulate bmal1b, clock1a, and per1b. Western blot experiments further verified the protein expression of key clock genes, bmal1b and clock. Detection of melatonin secretion at different time points over 24 h showed that radiation doses of 0.1 and 1 Gy could increase melatonin secretion. Based on these findings, it is speculated that a certain dose of radiation may affect melatonin secretion, which impacts the telencephalon structure and ontogeny of zebrafish, delays hatching, and changes the circadian rhythm. This effect is thought to be achieved through upregulating the expression of circadian rhythm genes, clock1a and per1b and related proteins, which may be responsible for the abnormal circadian rhythm caused by radiation.

UPLC-MS/MS simultaneous quantification of urinary circadian rhythm hormones and related metabolites: Application to air traffic controllers

Civil aviation flight crew and civil aviation air traffic controllers are prone to circadian rhythm abnormalities, which can lead to a slew of other maladies. It could endanger people's health and provide a serious threat to the safety of civil aviation flights if it is not appropriately evaluated and addressed. Early detection of rhythm irregularities and prompt treatment for particular populations that are vulnerable to rhythm disorders are crucial for enhancing civil aviation safety.In general, monitoring of the classical circadian rhythm biomarkers (melatonin or cortisol) in plasma or saliva is an effective way to evaluate the rhythm status. Due to the challenging sample procedure and the trauma of plasma, urine sample testing has received an increasing amount of attention. While, urine circadian rhythm biomarkers have seldom been examined, and the relationship between urinary steroid hormones and melatonin is still poorly understood. In most cases, hormones are determined by immunoassays respectively, mainly enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA). There are also reports describing the liquid chromatography with tandem mass spectrometry (LC-MS/MS) technique as a method of melatonin or few steroid hormones quantification, however, the simultaneous detection of multiple rhythmic hormones in human urine is rarely reported.For the quantification of the rhythmic hormones in human urine, an accurate approach using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was devised in this work. Nine endogenous hormones (melatonin, 6-hydroxymelatonin, 6-sulfatoxymelatonin, cortisol, corticosterone, cortisone, testosterone, epitestosterone and androsterone), in human overnight urine, were quantified after solid phase extraction (SPE). A reverse phase HSS C18 column was used for chromatographic separation with a 9-minute gradient elution and deuterated analogues of each analyte were applied as internal standards. This method was successfully applied to the analysis of 596 overnight urine samples (23:00–9:00) collected from 84 air traffic controllers in the Beijing area during shift work. This study's findings showed a clear correlation not only between melatonin and its metabolites; cortisol-related metabolites, but also between melatonin metabolites and endogenous metabolites upstream and downstream of cortisol, implying that these two categories of hormones can be used as potential biological rhythm indicators to provide circadian rhythm data support for future studies on circadian rhythm disorders.

GWAS-identified bipolar disorder risk allele in the FADS1/2 gene region links mood episodes and unsaturated fatty acid metabolism in mutant mice

Large-scale genome-wide association studies (GWASs) on bipolar disorder (BD) have implicated the involvement of the fatty acid desaturase (FADS) locus. These enzymes (FADS1 and FADS2) are involved in the metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are thought to potentially benefit patients with mood disorders. To model reductions in the activity of FADS1/2 affected by the susceptibility alleles, we generated mutant mice heterozygously lacking both Fads1/2 genes. We measured wheel-running activity over six months and observed bipolar swings in activity, including hyperactivity and hypoactivity. The hyperactivity episodes, in which activity was far above the norm, usually lasted half a day; mice manifested significantly shorter immobility times on the behavioral despair test performed during these episodes. The hypoactivity episodes, which lasted for several weeks, were accompanied by abnormal circadian rhythms and a marked decrease in wheel running, a spontaneous behavior associated with motivation and reward systems. We comprehensively examined lipid composition in the brain and found that levels of certain lipids were significantly altered between wild-type and the heterozygous mutant mice, but no changes were consistent with both sexes and either DHA or EPA was not altered. However, supplementation with DHA or a mixture of DHA and EPA prevented these episodic behavioral changes. Here we propose that heterozygous Fads1/2 knockout mice are a model of BD with robust constitutive, face, and predictive validity, as administration of the mood stabilizer lithium was also effective. This GWAS-based model helps to clarify how lipids and their metabolisms are involved in the pathogenesis and treatment of BD.