Casein kinase 1 epsilon and circadian misalignment impact affective behaviours in mice.

Affective behaviours and mental health are profoundly affected by disturbances in circadian rhythms. Casein kinase 1 epsilon (CSNK1E) is a core component of the circadian clock. Mice with tau or null mutation of this gene have shortened and lengthened circadian period respectively. Here, we examined anxiety-like, fear, and despair behaviours in both male and female mice of these two different mutants. Compared with wild-type mice, we found reductions in fear and anxiety-like behaviours in both mutant lines and in both sexes, with the tau mutants exhibiting the greatest phenotypic changes. However, the behavioural despair had distinct phenotypic patterns, with markedly less behavioural despair in female null mutants, but not in tau mutants of either sex. To determine whether abnormal light entrainment of tau mutants to 24-h light-dark cycles contributes to these phenotypic differences, we also examined these behaviours in tau mutants on a 20-h light-dark cycle close to their endogenous circadian period. The normalized entrainment restored more wild-type-like behaviours for fear and anxiety, but it induced behavioural despair in tau mutant females. These data show that both mutations of Csnk1e broadly affect fear and anxiety-like behaviours, while the effects on behavioural despair vary with genetics, photoperiod, and sex, suggesting that the mechanisms by which Csnk1e affects fear and anxiety-like behaviours may be similar, but distinct from those affecting behavioural despair. Our study also provides experimental evidence in support of the hypothesis of beneficial outcomes from properly entrained circadian rhythms in terms of the anxiety-like and fear behaviours.

The impacts of sex and the 5xFAD model of Alzheimer's disease on the sleep and spatial learning responses to feeding time.

Introduction: The relationships between the feeding rhythm, sleep and cognition in Alzheimer's disease (AD) are incompletely understood, but meal time could provide an easy-to-implement method of curtailing disease-associated disruptions in sleep and cognition. Furthermore, known sex differences in AD incidence could relate to sex differences in circadian rhythm/sleep/cognition interactions. Methods: The 5xFAD transgenic mouse model of AD and non-transgenic wild-type controls were studied. Both female and male mice were used. Food access was restricted each day to either the 12-h light phase (light-fed groups) or the 12-h dark phase (dark-fed groups). Sleep (electroencephalographic/electromyographic) recording and cognitive behavior measures were collected. Results: The 5xFAD genotype reduces NREM and REM as well as the number of sleep spindles. In wild-type mice, light-fed groups had disrupted vigilance state amounts, characteristics, and rhythms relative to dark-fed groups. These feeding time differences were reduced in 5xFAD mice. Sex modulates these effects. 5xFAD mice display poorer spatial memory that, in female mice, is curtailed by dark phase feeding. Similarly, female 5xFAD mice have decreased anxiety-associated behavior. These emotional and cognitive measures are correlated with REM amount. Discussion: Our study demonstrates that the timing of feeding can alter many aspects of wake, NREM and REM. Unexpectedly, 5xFAD mice are less sensitive to these feeding time effects. 5xFAD mice demonstrate deficits in cognition which are correlated with REM, suggesting that this circadian-timed aspect of sleep may link feeding time and cognition. Sex plays an important role in regulating the impact of feeding time on sleep and cognition in both wild-type and 5xFAD mice, with females showing a greater cognitive response to feeding time than males.

A Prebiotic Diet Alters the Fecal Microbiome and Improves Sleep in Response to Sleep Disruption in Rats.

Sleep disruption is a challenging and exceedingly common physiological state that contributes to a wide range of biochemical and molecular perturbations and has been linked to numerous adverse health outcomes. Modern society exerts significant pressure on the sleep/wake cycle via myriad factors, including exposure to electric light, psychological stressors, technological interconnection, jet travel, shift work, and widespread use of sleep-affecting compounds. Interestingly, recent research has identified a link between the microbiome and the regulation of sleep, suggesting that interventions targeting the microbiome may offer unique therapeutic approaches to challenges posed by sleep disruption. In this study, we test the hypothesis that administration of a prebiotic diet containing galactooligosaccharides (GOS) and polydextrose (PDX) in adult male rats improves sleep in response to repeated sleep disruption and during recovery sleep. We found that animals fed the GOS/PDX prebiotic diet for 4 weeks exhibit increased non-rapid eye movement (NREM) and rapid eye movement (REM) sleep during 5 days of sleep disruption and increased total sleep time during 24 h of recovery from sleep disruption compared to animals fed a control diet, despite similar baseline sleep characteristics. Further, the GOS/PDX prebiotic diet led to significant changes in the fecal microbiome. Consistent with previous reports, the prebiotic diet increased the relative abundance of the species Parabacteroides distasonis, which positively correlated with sleep parameters during recovery sleep. Taken together, these findings suggest that the GOS/PDX prebiotic diet may offer an approach to improve resilience to the physiologic challenge of sleep disruption, in part through impacts on the microbiome.

NMDAR activation regulates the daily rhythms of sleep and mood.

STUDY OBJECTIVES: The present studies examine the effects of NMDAR activation by NYX-2925 diurnal rhythmicity of both sleep and wake as well as emotion. METHODS: Twenty-four-hour sleep EEG recordings were obtained in sleep-deprived and non-sleep-deprived rats. In addition, the day-night cycle of both activity and mood was measured using home cage ultrasonic-vocalization recordings. RESULTS: NYX-2925 significantly facilitated non-REM (NREM) sleep during the lights-on (sleep) period, and this effect persisted for 3 days following a single dose in sleep-deprived rats. Sleep-bout duration and REM latencies were increased without affecting total REM sleep, suggesting better sleep quality. In addition, delta power during wake was decreased, suggesting less drowsiness. NYX-2925 also rescued learning and memory deficits induced by sleep deprivation, measured using an NMDAR-dependent learning task. Additionally, NYX-2925 increased positive affect and decreased negative affect, primarily by facilitating the transitions from sleep to rough-and-tumble play and back to sleep. In contrast to NYX-2925, the NMDAR antagonist ketamine acutely (1-4 hours post-dosing) suppressed REM and non-REM sleep, increased delta power during wake, and blunted the amplitude of the sleep-wake activity rhythm. DISCUSSION: These data suggest that NYX-2925 could enhance behavioral plasticity via improved sleep quality as well as vigilance during wake. As such, the facilitation of sleep by NYX-2925 has the potential to both reduce symptom burden on neurological and psychiatric disorders as well as serve as a biomarker for drug effects through restoration of sleep architecture.

Cross-species systems analysis identifies gene networks differentially altered by sleep loss and depression.

To understand the transcriptomic organization underlying sleep and affective function, we studied a population of (C57BL/6J × 129S1/SvImJ) F2 mice by measuring 283 affective and sleep phenotypes and profiling gene expression across four brain regions. We identified converging molecular bases for sleep and affective phenotypes at both the single-gene and gene-network levels. Using publicly available transcriptomic datasets collected from sleep-deprived mice and patients with major depressive disorder (MDD), we identified three cortical gene networks altered by the sleep/wake state and depression. The network-level actions of sleep loss and depression were opposite to each other, providing a mechanistic basis for the sleep disruptions commonly observed in depression, as well as the reported acute antidepressant effects of sleep deprivation. We highlight one particular network composed of circadian rhythm regulators and neuronal activity-dependent immediate-early genes. The key upstream driver of this network, Arc, may act as a nexus linking sleep and depression. Our data provide mechanistic insights into the role of sleep in affective function and MDD.

Altered Body Weight Regulation in CK1ε Null and tau Mutant Mice on Regular Chow and High Fat Diets.

Disruption of circadian rhythms results in metabolic dysfunction. Casein kinase 1 epsilon (CK1ε) is a canonical circadian clock gene. Null and tau mutations in CK1ε show distinct effects on circadian period. To investigate the role of CK1ε in body weight regulation under both regular chow (RC) and high fat (HF) diet conditions, we examined body weight on both RC and HF diets in CK1ε (-/-) and CK1ε (tau/tau) mice on a standard 24 hr light-dark (LD) cycle. Given the abnormal entrainment of CK1ε (tau/tau) mice on a 24 hr LD cycle, a separate set of CK1ε (tau/tau) mice were tested under both diet conditions on a 20 hr LD cycle, which more closely matches their endogenous period length. On the RC diet, both CK1ε (-/-) and CK1ε (tau/tau) mutants on a 24 hr LD cycle and CK1ε (tau/tau) mice on a 20 hr LD cycle exhibited significantly lower body weights, despite similar overall food intake and activity levels. On the HF diet, CK1ε (tau/tau) mice on a 20 hr LD cycle were protected against the development of HF diet-induced excess weight gain. These results provide additional evidence supporting a link between circadian rhythms and energy regulation at the genetic level, particularly highlighting CK1ε involved in the integration of circadian biology and metabolic physiology.

Csnk1e is a genetic regulator of sensitivity to psychostimulants and opioids.

Csnk1e, the gene encoding casein kinase 1-epsilon, has been implicated in sensitivity to amphetamines. Additionally, a polymorphism in CSNK1E was associated with heroin addiction, suggesting that this gene may also affect opioid sensitivity. In this study, we first conducted genome-wide quantitative trait locus (QTL) mapping of methamphetamine (MA)-induced locomotor activity in C57BL/6J (B6) × DBA/2J (D2)-F(2) mice and a more highly recombinant F(8) advanced intercross line. We identified a QTL on chromosome 15 that contained Csnk1e (63-86 Mb; Csnk1e=79.25 Mb). We replicated this result and further narrowed the locus using B6.D2(Csnk1e) and D2.B6(Csnk1e) reciprocal congenic lines (78-86.8 and 78.7-81.6 Mb, respectively). This locus also affected sensitivity to the µ-opioid receptor agonist fentanyl. Next, we directly tested the hypothesis that Csnk1e is a genetic regulator of sensitivity to psychostimulants and opioids. Mice harboring a null allele of Csnk1e showed an increase in locomotor activity following MA administration. Consistent with this result, coadministration of a selective pharmacological inhibitor of Csnk1e (PF-4800567) increased the locomotor stimulant response to both MA and fentanyl. These results show that a narrow genetic locus that contains Csnk1e is associated with differences in sensitivity to MA and fentanyl. Furthermore, gene knockout and selective pharmacological inhibition of Csnk1e define its role as a negative regulator of sensitivity to psychostimulants and opioids.