CSF-1R inhibitor PLX3397 attenuates peripheral and brain chronic GVHD and improves functional outcomes in mice.

Graft-versus-host disease (GVHD) is a serious complication of otherwise curative allogeneic haematopoietic stem cell transplants. Chronic GVHD induces pathological changes in peripheral organs as well as the brain and is a frequent cause of late morbidity and death after bone-marrow transplantation. In the periphery, bone-marrow-derived macrophages are key drivers of pathology, but recent evidence suggests that these cells also infiltrate into cGVHD-affected brains. Microglia are also persistently activated in the cGVHD-affected brain. To understand the involvement of these myeloid cell populations in the development and/or progression of cGVHD pathology, we here utilized the blood-brain-barrier permeable colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (pexidartinib) at varying doses to pharmacologically deplete both cell types. We demonstrate that PLX3397 treatment during the development of cGVHD (i.e., 30 days post-transplant) improves disease symptoms, reducing both the clinical scores and histopathology of multiple cGVHD target organs, including the sequestration of T cells in cGVHD-affected skin tissue. Cognitive impairments associated with cGVHD and neuroinflammation were also attenuated by PLX3397 treatment. PLX3397 treatment prior to the onset of cGVHD (i.e., immediately post-transplant) did not change in clinical scores or histopathology. Overall, our data demonstrate significant benefits of using PLX3397 for the treatment of cGVHD and associated organ pathologies in both the periphery and brain, highlighting the therapeutic potential of pexidartinib for this condition.

CircaCompare: a method to estimate and statistically support differences in mesor, amplitude and phase, between circadian rhythms.

MOTIVATION: A fundamental interest in chronobiology is to compare patterns between groups of rhythmic data. However, many existing methods are ill-equipped to derive statements concerning the statistical significance of differences between rhythms that may be visually apparent. This is attributed to both the form of data used (longitudinal versus cross-sectional) and the limitations of the statistical tests used to draw conclusions. RESULTS: To address this problem, we propose that a cosinusoidal curve with a particular parametrization be used to model and compare data of two sets of observations collected over a 24-h period. The novelty of our test is in the parametrization, which allows the explicit estimation of rhythmic parameters [mesor (the rhythm-adjusted mean level of a response variable around which a wave function oscillates), amplitude and phase], and simultaneously testing for statistical significance in all three parameters between two or more groups of datasets. A statistically significant difference between two groups, regarding each of these rhythmic parameters, is indicated by a P-value. The method is evaluated by applying the model to publicly available datasets, and is further exemplified by comparison to the currently recommended method, DODR. The results suggest that the method proposed may be highly sensitive to detect rhythmic differences between groups in phase, amplitude and mesor. AVAILABILITY AND IMPLEMENTATION: https://github.com/RWParsons/circacompare/.

At the Intersection of Microbiota and Circadian Clock: Are Sexual Dimorphism and Growth Hormones the Missing Link to Pathology?: Circadian Clock and Microbiota: Potential Egffect on Growth Hormone and Sexual Development.

Reciprocal interactions between the host circadian clock and the microbiota are evidenced by recent literature. Interestingly, dysregulation of either the circadian clock or microbiota is associated with common human pathologies such as obesity, type 2 diabetes, or neurological disorders. However, it is unclear to what extent a perturbation of pathways regulated by both the circadian clock and microbiota is involved in the development of these disorders. It is speculated that these perturbations are associated with impaired growth hormone (GH) secretion and sexual development. The GH axis is a broadly neglected pathway and could be the main converging point for the interaction of both circadian clock and microbiota. Here, the links between the circadian clock and microbiota are reviewed. Finally, the effects of chronodisruption and dysbiosis on physiology and pathology are discussed and it is speculated whether a common deregulation of the GH pathway could mediates those effects.

Pharmacological Neuroenhancement: Current Aspects of Categorization, Epidemiology, Pharmacology, Drug Development, Ethics, and Future Perspectives.

Recent pharmacoepidemiologic studies suggest that pharmacological neuroenhancement (pNE) and mood enhancement are globally expanding phenomena with distinctly different regional characteristics. Sociocultural and regulatory aspects, as well as health policies, play a central role in addition to medical care and prescription practices. The users mainly display self-involved motivations related to cognitive enhancement, emotional stability, and adaptivity. Natural stimulants, as well as drugs, represent substance abuse groups. The latter comprise purines, methylxanthines, phenylethylamines, modafinil, nootropics, antidepressants but also benzodiazepines, ß-adrenoceptor antagonists, and cannabis. Predominant pharmacodynamic target structures of these substances are the noradrenergic/dopaminergic and cholinergic receptor/transporter systems. Further targets comprise adenosine, serotonin, and glutamate receptors. Meta-analyses of randomized-controlled studies in healthy individuals show no or very limited verifiability of positive effects of pNE on attention, vigilance, learning, and memory. Only some members of the substance abuse groups, i.e., phenylethylamines and modafinil, display positive effects on attention and vigilance that are comparable to caffeinated drinks. However, the development of new antidementia drugs will increase the availability and the potential abuse of pNE. Social education, restrictive regulatory measures, and consistent medical prescription practices are essential to restrict the phenomenon of neuroenhancement with its social, medical, and ethical implications. This review provides a comprehensive overview of the highly dynamic field of pharmacological neuroenhancement and elaborates the dramatic challenges for the medical, sociocultural, and ethical fundaments of society.

Diet-altered body temperature rhythms are associated with altered rhythms of clock gene expression in peripheral tissues in vivo.

Temperature rhythms can act as potent signals for the modulation of the amplitude and phase of clock gene expression in peripheral organs in vitro, but the relevance of the circadian rhythm of core body temperature (Tc) as a modulating signal in vivo has not yet been investigated. Using calorie restriction and cafeteria feeding, we induced a larger and a dampened Tc amplitude, respectively, in male Wistar rats, and investigated the circadian expression profile of the core clock genes Bmal1, Per2, Cry1, and Rev-erbα, the heat-responsive genes heat shock protein 90 (Hsp90) and cold-inducible RNA binding protein (Cirbp), and Pgc1α, Pparα/γ/δ, Glut1/4, and Chop10 in the liver, skeletal muscle, white adipose tissue (WAT), and adrenal glands. Diet-altered Tc rhythms differentially affected the profiles of clock genes, Hsp90, and Cirbp expression in peripheral tissues. Greater Tc amplitudes elicited by calorie restriction were associated with large amplitudes of Hsp90 and Cirbp expression in the liver and WAT, in which larger amplitudes of clock gene expression were also observed. The amplitudes of metabolic gene expression were greater in the WAT, but not in the liver, in calorie-restricted rats. Conversely, diet-altered Tc rhythms were not translated to distinct changes in the amplitude of Hsp90, Cirbp, or clock or metabolic genes in the skeletal muscle or adrenal glands. While it was not possible to disentangle the effects of diet and temperature in this model, taken together with previous in vitro studies, our study presents novel data consistent with the notion that the circadian Tc rhythm can modulate the amplitude of circadian gene expression in vivo. The different responses of Hsp90 and Cirbp in peripheral tissues may be linked to the tissue-specific responses of peripheral clocks to diet and/or body temperature rhythms, but the association with the amplitude of metabolic gene expression is limited to the WAT.

Learned motivation drives circadian physiology in the absence of the master circadian clock.

The suprachiasmatic nucleus (SCN)-often referred to as the master circadian clock-is essential in generating physiologic rhythms and orchestrating synchrony among circadian clocks. This study tested the hypothesis that periodic motivation induced by rhythmically pairing 2 reinforcing stimuli [methamphetamine (Meth) and running wheel (RW)] restores autonomous circadian activity in arrhythmic SCN-lesioned (SCNX) C3H/HeN mice. Sham-surgery and SCNX mice were treated with either Meth (1.2 mg/kg, i.p.) or vehicle in association, dissociation, or absence of an RW. Only the association of Meth treatment and restricted RW access successfully reestablished entrained circadian rhythms in mice with SCNX. RW-likely acting as a link between the circadian and reward systems-promotes circadian entrainment of activity. We conclude that a conditioned drug response is a powerful tool to entrain, drive, and restore circadian physiology. Furthermore, an RW should be recognized as a potent input signal in addition to the conventional use as an output signal.-Rawashdeh, O., Clough, S. J., Hudson, R. L., Dubocovich, M. L. Learned motivation drives circadian physiology in the absence of the master circadian clock.

Clocking In Time to Gate Memory Processes: The Circadian Clock Is Part of the Ins and Outs of Memory.

Learning, memory consolidation, and retrieval are processes known to be modulated by the circadian (circa: about; dies: day) system. The circadian regulation of memory performance is evolutionarily conserved, independent of the type and complexity of the learning paradigm tested, and not specific to crepuscular, nocturnal, or diurnal organisms. In mammals, long-term memory (LTM) formation is tightly coupled to de novo gene expression of plasticity-related proteins and posttranslational modifications and relies on intact cAMP/protein kinase A (PKA)/protein kinase C (PKC)/mitogen-activated protein kinase (MAPK)/cyclic adenosine monophosphate response element-binding protein (CREB) signaling. These memory-essential signaling components cycle rhythmically in the hippocampus across the day and night and are clearly molded by an intricate interplay between the circadian system and memory. Important components of the circadian timing mechanism and its plasticity are members of the Period clock gene family (Per1, Per2). Interestingly, Per1 is rhythmically expressed in mouse hippocampus. Observations suggest important and largely unexplored roles of the clock gene protein PER1 in synaptic plasticity and in the daytime-dependent modulation of learning and memory. Here, we review the latest findings on the role of the clock gene Period 1 (Per1) as a candidate molecular and mechanistic blueprint for gating the daytime dependency of memory processing.

Ribosomal RNA - a tail wagging the dog?

It is an intriguing hypothesis that the complex organization of neuronal dynamics important for a memory engram is largely underpinned by the regulation of nucleolar functioning. This Editorial highlights a study by Capitano and coworkers in this issue of the Journal of Neurochemistry, in which the authors tackle this hypothesis with a behavioral approach. The study investigates the role of axo-dendritic mRNAs within learning-induced plasticity and in vivo modulation of rRNA transcription in response to spatial learning. The authors confirm with their in vivo approach what is known from many earlier in vitro experiments: efficient learning and memory requires a proper homeostasis of hippocampal neurons in general, which, however, depends crucially on proper integrity of the nucleolus. Read the highlighted article 'RNA polymerase I transcription is modulated by spatial learning in different brain regions' on page 706.

Period1 gates the circadian modulation of memory-relevant signaling in mouse hippocampus by regulating the nuclear shuttling of the CREB kinase pP90RSK.

Memory performance varies over a 24-h day/night cycle. While the detailed underlying mechanisms are yet unknown, recent evidence suggests that in the mouse hippocampus, rhythmic phosphorylation of mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate response element-binding protein (CREB) are central to the circadian (~ 24 h) regulation of learning and memory. We recently identified the clock protein PERIOD1 (PER1) as a vehicle that translates information encoding time of day to hippocampal plasticity. We here elaborate how PER1 may gate the sensitivity of memory-relevant hippocampal signaling pathways. We found that in wild-type mice (WT), spatial learning triggers CREB phosphorylation only during the daytime, and that this effect depends on the presence of PER1. The time-of-day-dependent induction of CREB phosphorylation can be reproduced pharmacologically in acute hippocampal slices prepared from WT mice, but is absent in preparations made from Per1-knockout (Per1(-/-) ) mice. We showed that the PER1-dependent CREB phosphorylation is regulated downstream of MAPK. Stimulation of WT hippocampal neurons triggered the co-translocation of PER1 and the CREB kinase pP90RSK (pMAPK-activated ribosomal S6 kinase) into the nucleus. In hippocampal neurons from Per1(-/-) mice, however, pP90RSK remained perinuclear. A co-immunoprecipitation assay confirmed a high-affinity interaction between PER1 and pP90RSK. Knocking down endogenous PER1 in hippocampal cells inhibited adenylyl cyclase-dependent CREB activation. Taken together, the PER1-dependent modulation of cytoplasmic-to-nuclear signaling in the murine hippocampus provides a molecular explanation for how the circadian system potentially shapes a temporal framework for daytime-dependent memory performance, and adds a novel facet to the versatility of the clock gene protein PER1. We provide evidence that the circadian clock gene Period1 (Per1) regulates CREB phosphorylation in the mouse hippocampus, sculpturing time-of-day-dependent memory formation. This molecular mechanism constitutes the functional link between circadian rhythms and learning efficiency. In hippocampal neurons of wild-type mice, pP90RSK translocates into the nucleus upon stimulation with forskolin (left), whereas in Period1-knockout (Per1(-/-) ) mice (right) the kinase is trapped at the nuclear periphery, unable to efficiently phosphorylate nuclear CREB. Consequently, the presence of PER1 in hippocampal neurons is a prerequisite for the time-of-day-dependent phosphorylation of CREB, as it regulates the shuttling of pP90RSK into the nucleus. Representative immunofluorescence images show a temporal difference in phosphorylated cAMP response element-binding protein (pCREB; green color) levels in all regions of the dorsal hippocampus between a wild-type C3H mouse (WT; left) and a Period1-knockout (Per1(-/-) ; right) mouse. Images were taken 2 h after lights on, thus, when fluctuating levels of pCREB peak in WT mouse hippocampus. Insets show a representative hippocampal neuron, in response to activating cAMP signaling, stained for the neuronal marker NeuN (red), the nuclear marker DAPI (blue) and the activated CREB kinase pP90RSK (green). The image was taken 2 h after light onset (at the peak of the endogenous CREB phosphorylation that fluctuates with time of day). Magnification: 100X, inset 400X. Read the Editorial Highlight for this article on page 650. Cover image for this issue: doi: 10.1111/jnc.13332.

PERIOD1 coordinates hippocampal rhythms and memory processing with daytime.

In species ranging from flies to mammals, parameters of memory processing, like acquisition, consolidation, and retrieval are clearly molded by time of day. However, mechanisms that regulate and adapt these temporal differences are elusive, with an involvement of clock genes and their protein products suggestive. Therefore, we analyzed initially in mouse hippocampus the daytime-dependent dynamics of parameters, known to be important for proper memory formation, like phosphorylation of the "memory molecule" cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB) and chromatin remodeling. Next, in an effort to characterize the mechanistic role of clock genes within hippocampal molecular dynamics, we compared the results obtained from wildtype (WT) -mice and mice deficient for the archetypical clock gene Period1 (Per1(-/-) -mice). We detected that the circadian rhythm of CREB phosphorylation in the hippocampus of WT mice disappeared completely in mice lacking Per1. Furthermore, we found that the here for the first time described profound endogenous day/night rhythms in histone modifications in the hippocampus of WT-mice are markedly perturbed in Per1(-/-) -mice. Concomitantly, both, in vivo recorded LTP, a cellular correlate for long-term memory, and hippocampal gene expression were significantly altered in the absence of Per1. Notably, these molecular perturbations in Per1(-/-) -mice were accompanied by the loss of daytime-dependent differences in spatial working memory performance. Our data provide a molecular blueprint for a novel role of PER1 in temporally shaping the daytime-dependency of memory performance, likely, by gating CREB signaling, and by coupling to downstream chromatin remodeling.

Long-term effects of maternal separation on the responsiveness of the circadian system to melatonin in the diurnal nonhuman primate (Macaca mulatta).

Depression is often linked to early-life adversity and circadian disturbances. Here, we assessed the long-term impact of early-life adversity, particularly preweaning mother-infant separation, on the circadian system's responsiveness to a time giver or synchronizer (Zeitgeber). Mother-reared (MR) and peer-reared (PR) rhesus monkeys were subjected to chronic jet-lag, a forced desynchrony protocol of 22 hr T-cycles [11:11 hr light:dark (LD) cycles] to destabilize the central circadian organization. MR and PR monkeys subjected to the T-cycles showed split locomotor activity rhythms with periods of ~22 hr (entrained) and ~24 hr (free-running), simultaneously. Continuous melatonin treatment in the drinking water (20 µg/mL) gradually increased the amplitude of the entrained rhythm at the expense of the free-running rhythm, reaching complete entrainment by 1 wk. Upon release into constant dim light, a rearing effect on anticipation for both the predicted light onset and food presentation was observed. In MR monkeys, melatonin did not affect the amplitude of anticipatory behavior. Interestingly, however, PR macaques showed light onset and food anticipatory activities in response to melatonin treatment. These results demonstrate for the first time a rearing-dependent effect of maternal separation in macaques, imprinting long-term plastic changes on the circadian system well into late adulthood. These effects could be counteracted by the synchronizer molecule melatonin. We conclude that the melatonergic system is targeted by early-life adversity of maternal separation and that melatonin supplementation ameliorates the negative impact of stress on the circadian system.

Targeting sleep and the circadian system as a novel treatment strategy for Parkinson's disease.

There is a growing appreciation of the wide range of sleep-wake disturbances that occur frequently in Parkinson's disease. These are known to be associated with a range of motor and non-motor symptoms and significantly impact not only on the quality of life of the patient, but also on their bed partner. The underlying causes for fragmented sleep and daytime somnolence are no doubt multifactorial but there is clear evidence for circadian disruption in Parkinson's disease. This appears to be occurring not only as a result of the neuropathological changes that occur across a distributed neural network, but even down to the cellular level. Such observations indicate that circadian changes may in fact be a driver of neurodegeneration, as well as a cause for some of the sleep-wake symptoms observed in Parkinson's disease. Thus, efforts are now required to evaluate approaches including the prescription of precision medicine to modulate photoreceptor activation ratios that reflect daylight inputs to the circadian pacemaker, the use of small molecules to target clock genes, the manipulation of orexin pathways that could help restore the circadian system, to offer novel symptomatic and novel disease modifying strategies.

Tuning of liver circadian transcriptome rhythms by thyroid hormone state in male mice.

Thyroid hormones (THs) are important regulators of systemic energy metabolism. In the liver, they stimulate lipid and cholesterol turnover and increase systemic energy bioavailability. It is still unknown how the TH state interacts with the circadian clock, another important regulator of energy metabolism. We addressed this question using a mouse model of hypothyroidism and performed circadian analyses. Low TH levels decreased locomotor activity, food intake, and body temperature mostly in the active phase. Concurrently, liver transcriptome profiling showed only subtle effects compared to elevated TH conditions. Comparative circadian transcriptome profiling revealed alterations in mesor, amplitude, and phase of transcript levels in the livers of low-TH mice. Genes associated with cholesterol uptake, biosynthesis, and bile acid secretion showed reduced mesor. Increased and decreased cholesterol levels in the serum and liver were identified, respectively. Combining data from low- and high-TH conditions allowed the identification of 516 genes with mesor changes as molecular markers of the liver TH state. We explored these genes and created an expression panel that assesses liver TH state in a time-of-day dependent manner. Our findings suggest that the liver has a low TH action under physiological conditions. Circadian profiling reveals genes as potential markers of liver TH state.

Poor sleep versus exercise: A duel to decide whether pain resolves or persists after injury.

Poor sleep is thought to enhance pain via increasing peripheral and/or central sensitization. Aerobic exercise, conversely, relives pain via reducing sensitization, among other mechanisms. This raises two clinical questions: (1) does poor sleep contribute to the transition from acute-to-persistent pain, and (2) can exercise protect against this transition? This study tested these questions and explored underlying mechanisms in a controlled injury model. Twenty-nine adult female Sprague-Dawley rats performed an intensive lever-pulling task for 4 weeks to induce symptoms consistent with clinical acute-onset overuse injury. Rats were then divided into three groups and exposed for 4 weeks to either: voluntary exercise via access to a running wheel, sleep disturbance, or both. Pain-related behaviours (forepaw mechanical sensitivity, reflexive grip strength), systemic levels of brain derived neurotrophic factor (BDNF), estradiol and corticosterone, and white blood cells (WBC) were assessed pre-injury, post-injury and post-intervention. Mechanical sensitivity increased post-injury and remained elevated with sleep disturbance alone, but decreased to pre-injury levels with exercise both with and without sleep disturbance. Reflexive grip strength decreased post-injury but recovered post-intervention-more with exercise than sleep disturbance. BDNF increased with sleep disturbance alone, remained at pre-injury levels with exercise regardless of sleep, and correlated with mechanical sensitivity. WBCs and estradiol increased with exercise alone and together with sleep disturbance, respectively. Corticosterone was not impacted by injury/intervention. Findings provide preliminary evidence for a role of poor sleep in the transition from acute-to-persistent pain, and the potential for aerobic exercise to counter these effects. BDNF might have a role in these relationships.

Sleep and circadian rhythms in α-synucleinopathies-Perspectives for disease modification.

The global north is facing an unprecedented rise in the prevalence of neurodegenerative diseases. The increasing incidence of Parkinson's disease is being referred to as a pandemic. The reason for the enormous increase is only partly understood. Lifestyle factors are known to play a role, but they alone cannot account for the surge. One factor that-although being recognized as important-has not been explored in detail so far is the influence of circadian rhythms. Sleep and circadian rhythm disruption are known as key factors in neurodegeneration, and their occurrence during early disease stages suggests a causal role in the pathogenesis. Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) has been identified as a prodromal state of α-synucleinopathies, such as Parkinson's disease, Lewy body dementia, and multiple system atrophy offering a window for insights into the early development of these diseases. Even though REM sleep is the sleep state most pronounced, driven and modulated by the circadian timing system, specific circadian abnormalities have not been described in iRBD. Novel experimental and clinical approaches exploiting the molecular circuitry underlying circadian timekeeping hold promise to disentangle some of the pathophysiologic mechanisms of α-synucleinopathies. In this review, we summarize current knowledge on sleep and circadian rhythm disruptions in α-synucleinopathies with an emphasis on molecular aspects and therapeutic potentials. These insights might contribute to our understanding of the pathogenesis of neurodegenerative diseases and may allow therapeutic interventions addressing the disturbed circadian system at the early stage of disease.

Sleep and circadian rhythms in Parkinson's disease and preclinical models.

The use of animals as models of human physiology is, and has been for many years, an indispensable tool for understanding the mechanisms of human disease. In Parkinson's disease, various mouse models form the cornerstone of these investigations. Early models were developed to reflect the traditional histological features and motor symptoms of Parkinson's disease. However, it is important that models accurately encompass important facets of the disease to allow for comprehensive mechanistic understanding and translational significance. Circadian rhythm and sleep issues are tightly correlated to Parkinson's disease, and often arise prior to the presentation of typical motor deficits. It is essential that models used to understand Parkinson's disease reflect these dysfunctions in circadian rhythms and sleep, both to facilitate investigations into mechanistic interplay between sleep and disease, and to assist in the development of circadian rhythm-facing therapeutic treatments. This review describes the extent to which various genetically- and neurotoxically-induced murine models of Parkinson's reflect the sleep and circadian abnormalities of Parkinson's disease observed in the clinic.

Temperature Profile and Adverse Outcomes After Discharge From the Intensive Care Unit.

BACKGROUND: A predictive model that uses the rhythmicity of core body temperature (CBT) could be an easily accessible clinical tool to ultimately improve outcomes among critically ill patients. OBJECTIVES: To assess the relation between the 24-hour CBT profile (CBT-24) before intensive care unit (ICU) discharge and clinical events in the step-down unit within 7 days of ICU discharge. METHODS: This retrospective cohort study in a tertiary ICU at a single center included adult patients requiring acute invasive ventilation for more than 48 hours and assessed major clinical adverse events (MCAEs) and rapid response system activations (RRSAs) within 7 days of ICU discharge (MCAE-7 and RRSA-7, respectively). RESULTS: The 291 enrolled patients had a median mechanical ventilation duration of 139 hours (IQR, 50-862 hours) and at admission had a median Acute Physiology and Chronic Health Evaluation II score of 22 (IQR, 7-42). At least 1 MCAE or RRSA occurred in 64% and 22% of patients, respectively. Independent predictors of an MCAE-7 were absence of CBT-24 rhythmicity (odds ratio, 1.78 [95% CI, 1.07-2.98]; P = .03), Sequential Organ Failure Assessment score at ICU discharge (1.10 [1.00-1.21]; P = .05), male sex (1.72 [1.04-2.86]; P = .04), age (1.02 [1.00-1.04]; P = .02), and Charlson Comorbidity Index (0.87 [0.76-0.99]; P = .03). Age (1.03 [1.01-1.05]; P = .006), sepsis at ICU admission (2.02 [1.13-3.63]; P = .02), and Charlson Comorbidity Index (1.18 [1.02-1.36]; P = .02) were independent predictors of an RRSA-7. CONCLUSIONS: Use of CBT-24 rhythmicity can assist in stratifying a patient's risk of subsequent deterioration during general care within 7 days of ICU discharge.

Rewiring of liver diurnal transcriptome rhythms by triiodothyronine (T3) supplementation.

Diurnal (i.e., 24 hr) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (T3) state was induced in mice by supplementing T3 in the drinking water, which affected body temperature, and oxygen consumption in a time-of-day-dependent manner. A 24-hr transcriptome profiling of liver tissue identified 37 robustly and time independently T3-associated transcripts as potential TH state markers in the liver. Such genes participated in xenobiotic transport, lipid and xenobiotic metabolism. We also identified 10-15% of the liver transcriptome as rhythmic in control and T3 groups, but only 4% of the liver transcriptome (1033 genes) were rhythmic across both conditions - amongst these, several core clock genes. In-depth rhythm analyses showed that most changes in transcript rhythms were related to mesor (50%), followed by amplitude (10%), and phase (10%). Gene set enrichment analysis revealed TH state-dependent reorganization of metabolic processes such as lipid and glucose metabolism. At high T3 levels, we observed weakening or loss of rhythmicity for transcripts associated with glucose and fatty acid metabolism, suggesting increased hepatic energy turnover. In summary, we provide evidence that tonic changes in T3 levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.

Many environmental conditions, including light and temperature, vary with a daily rhythm that affects how animals interact with their surroundings. Indeed, most species have developed so-called circadian clocks: internal molecular timers that cycle approximately every 24 hours and regulate many bodily functions, including digestion, energy metabolism and sleep. The energy metabolism of the liver ­ the chemical reactions that occur in the organ to produce energy from nutrients ­ is controlled both by the circadian clock system, and by the hormones produced by a gland in the neck called the thyroid. However, the interaction between these two regulators is poorly understood. To address this question, de Assis, Harder et al. elevated the levels of thyroid hormones in mice by adding these hormones to their drinking water. Studying these mice showed that, although thyroid hormone levels were good indicators of how much energy mice burn in a day, they do not reflect daily fluctuations in metabolic rate faithfully. Additionally, de Assis, Harder et al. showed that elevating T₃, the active form of thyroid hormone, led to a rewiring of the daily rhythms at which genes were turned on and off in the liver, affecting the daily timing of processes including fat and cholesterol metabolism. This occurred without changing the circadian clock of the liver directly. De Assis, Harder et al.'s results indicate that time-of-day critically affects the action of thyroid hormones in the liver. This suggests that patients with hypothyroidism, who produce low levels of thyroid hormones, may benefit from considering time-of-day as a factor in disease diagnosis, therapy and, potentially, prevention. Further data on the rhythmic regulation of thyroid action in humans, including in patients with hypothyroidism, are needed to further develop this approach.

Cholinergic basal forebrain degeneration due to sleep-disordered breathing exacerbates pathology in a mouse model of Alzheimer's disease.

Although epidemiological studies indicate that sleep-disordered breathing (SDB) such as obstructive sleep apnea is a strong risk factor for the development of Alzheimer's disease (AD), the mechanisms of the risk remain unclear. Here we developed a method of modeling SDB in mice that replicates key features of the human condition: altered breathing during sleep, sleep disruption, moderate hypoxemia, and cognitive impairment. When we induced SDB in a familial AD model, the mice displayed exacerbation of cognitive impairment and the pathological features of AD, including increased levels of amyloid-beta and inflammatory markers, as well as selective degeneration of cholinergic basal forebrain neurons. These pathological features were not induced by chronic hypoxia or sleep disruption alone. Our results also revealed that the cholinergic neurodegeneration was mediated by the accumulation of nuclear hypoxia inducible factor 1 alpha. Furthermore, restoring blood oxygen levels during sleep to prevent hypoxia prevented the pathological changes induced by the SDB. These findings suggest a signaling mechanism whereby SDB induces cholinergic basal forebrain degeneration.

Circadian Rhythmicity of Vital Signs at Intensive Care Unit Discharge and Outcome of Traumatic Brain Injury.

BACKGROUND: Physiological functions with circadian rhythmicity are often disrupted during illness. OBJECTIVE: To assess the utility of circadian rhythmicity of vital signs in predicting outcome of traumatic brain injury (TBI). METHODS: A retrospective single-center cohort study of adult intensive care unit (ICU) patients with largely isolated TBI to explore the relationship between the circadian rhythmicity of vital signs during the last 24 hours before ICU discharge and clinical markers of TBI severity and score on the Glasgow Outcome Scale 6 months after injury (GOS-6). RESULTS: The 130 study participants had a median age of 39.0 years (IQR, 23.0-59.0 years), a median Glasgow Coma Scale score at the scene of 8.0 (IQR, 3.0-13.0), and a median Rotterdam score on computed tomography of the head of 3 (IQR, 3-3), with 105 patients (80.8%) surviving to hospital discharge. Rhythmicity was present for heart rate (30.8% of patients), systolic blood pressure (26.2%), diastolic blood pressure (20.0%), and body temperature (26.9%). Independent predictors of a dichotomized GOS-6 ≥4 were the Rotterdam score (odds ratio [OR], 0.38 [95% CI, 0.18-0.81]; P = .01), Glasgow Coma Scale score at the scene (OR, 1.22 [95% CI, 1.05-1.41]; P = .008), age (OR, 0.95 [95% CI, 0.92-0.98]; P = .003), oxygen saturation <90% in the first 24 hours (OR, 0.19 [95% CI, 0.05-0.73]; P = .02), serum sodium level <130 mmol/L (OR, 0.20 [95% CI, 0.05-0.70]; P = .01), and active intracranial pressure management (OR, 0.16 [95% CI, 0.04-0.62]; P = .008), but not rhythmicity of any vital sign. CONCLUSION: Circadian rhythmicity of vital signs at ICU discharge is not predictive of GOS-6 in patients with TBI.