Explore the vast range of titles available.

The present studies examine the effects of NMDAR activation by NYX-2925 diurnal rhythmicity of both sleep and wake as well as emotion. 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. 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. 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.

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 CK1εtau/tau mice on a standard 24 hr light-dark (LD) cycle. Given the abnormal entrainment of CK1εtau/tau mice on a 24 hr LD cycle, a separate set of CK1εtau/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 CK1εtau/tau mutants on a 24 hr LD cycle and CK1εtau/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, CK1εtau/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.

Background BACE inhibitors, while effective in lowering amyloid‐beta production, have been associated with mild cognitive worsening in clinical trials. Additional treatment‐related adverse events reported in multiple clinical trials were sleep disturbances and insomnia. The purpose of this study is to determine if sleep disturbances occur in mice receiving BACE inhibitor, if sleep disturbances correlate with cognitive impairment, and the mechanism by which this may occur. Method Adult C57BL/6 mice were treated with high dose BACE inhibitor (Merck) or control chow for 12 weeks. At 12 weeks, mice were implanted with a head mount containing electrodes for EEG and EMG monitoring. Sleep was monitored for 48 hours continuously. Cognitive assessments including object location memory, Y‐maze, and Barnes maze were performed. 10 second sleep epochs were manually scored as “wake”, “REM”, and “non‐REM”, based on EEG and EMG, to then train an algorithm to detect and define all remaining epochs. Fast Fourier transforms were performed on all epochs to identify the relative delta, theta, alpha, sigma, beta, and gamma power. Result Mice receiving BACE inhibitor chow had altered sleep patterns. This was marked by fewer, longer REM bouts than control mice. Additionally, mice receiving BACE inhibitor had less slow wave non‐REM sleep, marked by a reduction in delta power. Conversely, mice had an increase in the higher frequency beta and gamma waves during non‐REM sleep, suggestive of cortical hyperarousal. Conclusion Mice receiving BACE inhibitors for three months had impaired sleep. Longer REM bouts could point to the vivid dreams and disturbed sleep noted in humans. A reduction in the slow wave sleep indicates reduced restorative sleep, which could impair performance on cognitive tests by leading to lethargy and impaired memory consolidation. Furthermore, cortical hyperarousal during non‐REM sleep is prevalent in a number of disorders in humans, including insomnia, anxiety, and post traumatic stress disorder, which could help elucidate an underlying mechanism. This study has implications for the future of clinical trials, because there are commercially available drugs that could restore normal non‐REM sleep and potentially alleviate cognitive worsening.

Introduction Because regular sleep disruption can increase vulnerability to stress-related psychiatric disorders, there is a need to explore novel countermeasures to increase stress resilience after inadequate sleep. Immunization with heat-killed Mycobacterium vaccae NCTC11659 (MV), an environmental bacterium and immunomodulator, can increase resilience to chronic stress in mice. We therefore tested the hypothesis that MV immunization would prevent the negative impacts of five days of sleep disruption on stress-induced changes in sleep in mice. Methods 120 male C57BL/6N mice were implanted with EEG/EMG recording devices and given 3 weekly injections of either MV or vehicle before entering the experimental protocol (day 0). On days 1-5, sleep was disrupted by a slowly rotating bar, with an ad libitum sleep opportunity from ZT2-ZT6. At ZT4 of day 5, mice were exposed to a 1-hour episode of social defeat stress. Sleep recording continued for seven days after social defeat (day 12). Groups received just sleep disruption, just social defeat, both (‘double hit’), or neither. Results In vehicle-treated mice receiving just social defeat, an increase in NREM delta (0.5-4Hz) power compared to baseline was observed during the post-stress dark period (p=0.005, Wilcoxon signed rank test). However, this was absent in mice receiving the double hit, who instead had elevated power in the high frequency beta (15-30Hz) power band in both NREM (p=0.002) and REM (p=0.001). Mice receiving the double hit also had increased REM and sleep fragmentation compared to controls for at least 6 days post-stress (p<0.05, ANOVA). NREM beta power immediately post-stress correlated with REM sleep disturbances 6 days later. MV preimmunization prevented all double hit-induced sleep disturbances. Conclusion These results suggest repeated sleep disruption may increase vulnerability to an acute stressor in part by shifting the adaptive increase in delta power to a maladaptive increase in beta power during post-stress sleep. Importantly, these data provide further evidence supporting microbiota-based countermeasures to promote health. Support (If Any) Office of Naval Research Grant #N00014-15-1-2809; NIH Training Grant T32HL007909

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.

Disruption of circadian rhythms results in metabolic dysfunction. Casein kinase 1 epsilon (CK1[epsilon]) is a canonical circadian clock gene. Null and tau mutations in CK1[epsilon] show distinct effects on circadian period. To investigate the role of CK1[epsilon] 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 [CK1[epsilon].sup.-/-] and [CK1[epsilon].sup.tau/tau] mice on a standard 24 hr light-dark (LD) cycle. Given the abnormal entrainment of [CK1[epsilon].sup.tau/tau] mice on a 24 hr LD cycle, a separate set of [CK1[epsilon].sup.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 CK1[epsilon]~h and [CK1[epsilon].sup.tau/tau] mutants on a 24 hr LD cycle and [CK1[epsilon].sup.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, [CK1[epsilon].sup.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 CK1[epsilon] involved in the integration of circadian biology and metabolic physiology.

Affective behaviors and mental health are profoundly affected by disturbances in circadian rhythms. Casein kinase 1 epsilon (CSNK1E) is an essential component of the core 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 depressive-like behaviors in both male and female mice of these two different mutants. Compared with wild-type mice, we found reductions in fear and anxiety-like behaviors in both mutant lines and in both sexes, with the tau mutants exhibiting the greatest phenotypic changes. However, the depressive-like behaviors had distinct phenotypic patterns, with markedly less depressive-like behaviors in female null mutants, but not in tau mutants of either sex. To determine whether abnormal light entrainment of tau mutants to 24 hour light-dark cycles contributes to these phenotypic differences, we also examined these behaviors in tau mutants on a 20 hour light-dark cycle close to their endogenous circadian period. The normalized entrainment restored more wild-type-like behaviors for fear and anxiety, but it induced depressive-like behavior in tau mutant females. These data show that both mutations of Csnk1e broadly affect fear and anxiety-like behaviors, while the effects on depressive-like behavior vary with genetics, photoperiod, and sex, suggesting that the mechanisms by which Csnk1e affects fear and anxiety-like behaviors may be similar, but distinct from those affecting depressive-like behavior. 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 behaviors.