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Sleep disturbances are common features of neurodegenerative disorders including Huntington's disease (HD). Sleep and circadian disruptions are recapitulated in animal models, providing the opportunity to evaluate the effectiveness of circadian interventions as countermeasures for neurodegenerative disease. For instance, time restricted feeding (TRF) successfully improved activity rhythms, sleep behavior and motor performance in mouse models of HD. Seeking to determine if these benefits extend to physiological measures of sleep, electroencephalography (EEG) was used to measure sleep/wake states and polysomnographic patterns in male and female wild-type (WT) and bacterial artificial chromosome transgenic (BACHD) adult mice, under TRF and ad lib feeding (ALF). Our findings show that male, but not female, BACHD mice exhibited significant changes in the temporal patterning of wake and non-rapid eye movement (NREM) sleep. The TRF intervention reduced the inappropriate early morning activity by increasing NREM sleep in the male BACHD mice. In addition, the scheduled feeding reduced sleep fragmentation (# bouts) in the male BACHD mice. The phase of the rhythm in rapid-eye movement (REM) sleep was significantly altered by the scheduled feeding in a sex-dependent manner. The treatment did impact the power spectral curves during the day in male but not female mice regardless of the genotype. Sleep homeostasis, as measured by the response to six hours of gentle handling, was not altered by the diet. Thus, TRF improves the temporal patterning and fragmentation of NREM sleep without impacting sleep homeostasis. This work adds critical support to the view that sleep is a modifiable risk factor in neurodegenerative diseases.
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BACKGROUND: Sleep disturbances are a prevalent and complex comorbidity in neurodevelopmental disorders (NDDs). Dup15q syndrome (duplications of 15q11.2-13.1) is a genetic disorder highly penetrant for NDDs such as autism and intellectual disability and it is frequently accompanied by significant disruptions in sleep patterns. The 15q critical region harbors genes crucial for brain development, notably UBE3A and a cluster of gamma-aminobutyric acid type A receptor (GABAAR) genes. We previously described an electrophysiological biomarker of the syndrome, marked by heightened beta oscillations (12-30 Hz) in individuals with Dup15q syndrome, akin to electroencephalogram (EEG) alterations induced by allosteric modulation of GABAARs. Those with Dup15q syndrome exhibited increased beta oscillations during the awake resting state and during sleep, and they showed profoundly abnormal NREM sleep. This study aims to assess the translational validity of these EEG signatures and to delve into their neurobiological underpinnings by quantifying sleep physiology in chromosome-engineered mice with maternal (matDp/ + mice) or paternal (patDp/ + mice) inheritance of the full 15q11.2-13.1-equivalent duplication, and mice with duplication of just the UBE3A gene (Ube3a overexpression mice; Ube3a OE mice) and comparing the sleep metrics with their respective wildtype (WT) littermate controls. METHODS: We collected 48-h EEG/EMG recordings from 35 (23 male, 12 female) 12-24-week-old matDp/ + , patDp/ + , Ube3a OE mice, and their WT littermate controls. We quantified baseline sleep, sleep fragmentation, spectral power dynamics during sleep states, and recovery following sleep deprivation. Within each group, distinctions between Dup15q mutant mice and WT littermate controls were evaluated using analysis of variance (ANOVA) and student's t-test. The impact of genotype and time was discerned through repeated measures ANOVA, and significance was established at p < 0.05. RESULTS: Our study revealed that across brain states, matDp/ + mice mirrored the elevated beta oscillation phenotype observed in clinical EEGs from individuals with Dup15q syndrome. Time to sleep onset after light onset was significantly reduced in matDp/ + and Ube3a OE mice. However, NREM sleep between Dup15q mutant and WT littermate mice remained unaltered, suggesting a divergence from the clinical presentation in humans. Additionally, while increased beta oscillations persisted in matDp/ + mice after 6-h of sleep deprivation, recovery NREM sleep remained unaltered in all groups, thus suggesting that these mice exhibit resilience in the fundamental processes governing sleep-wake regulation. CONCLUSIONS: Quantification of mechanistic and translatable EEG biomarkers is essential for advancing our understanding of NDDs and their underlying pathophysiology. Our study of sleep physiology in the Dup15q mice underscores that the beta EEG biomarker has strong translational validity, thus opening the door for pre-clinical studies of putative drug targets, using the biomarker as a translational measure of drug-target engagement. The unaltered NREM sleep may be due to inherent differences in neurobiology between mice and humans. These nuanced distinctions highlight the complexity of sleep disruptions in Dup15q syndrome and emphasize the need for a comprehensive understanding that encompasses both shared and distinct features between murine models and clinical populations.
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Cromossomos Humanos Par 15 , Modelos Animais de Doenças , Eletroencefalografia , Animais , Camundongos , Cromossomos Humanos Par 15/genética , Masculino , Feminino , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/fisiopatologia , Sono/fisiologia , Sono/genética , Trissomia/fisiopatologia , Trissomia/genética , Aberrações Cromossômicas , Deficiência IntelectualRESUMO
The influence of light spectral properties on circadian rhythms is of substantial interest to laboratory-based investigation of the circadian system and to field-based understanding of the effects of artificial light at night. The trade-offs between intensity and spectrum regarding masking behaviors are largely unknown, even for well-studied organisms. We used a custom LED illumination system to document the response of wild-type house mice (Mus musculus) to 1-h nocturnal exposure of all combinations of four intensity levels (0.01, 0.5, 5 and 50â lx) and three correlated color temperatures (CCT; 1750, 1950 and 3000â K). Higher intensities of light (50â lx) suppressed cage activity substantially, and consistently more for the higher CCT light (91% for 3000â K, 53% for 1750â K). At the lowest intensity (0.01â lx), mean activity was increased, with the greatest increases for the lowest CCT (12.3% increase at 1750â K, 3% increase at 3000â K). Multiple linear regression confirmed the influence of both CCT and intensity on changes in activity, with the scaled effect size of intensity 3.6 times greater than that of CCT. Activity suppression was significantly lower for male than for female mice. Assessment of light-evoked cFos expression in the suprachiasmatic nucleus at 50â lx showed no significant difference between high and low CCT exposure. The significant differences by spectral composition illustrate a need to account for light spectrum in circadian studies of behavior, and confirm that spectral controls can mitigate some, but certainly not all, of the effects of light pollution on species in the wild.
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Ritmo Circadiano , Luz , Iluminação , Animais , Camundongos/fisiologia , Masculino , Ritmo Circadiano/fisiologia , Ritmo Circadiano/efeitos da radiação , Feminino , Comportamento Animal/efeitos da radiação , Comportamento Animal/fisiologia , Atividade Motora/efeitos da radiação , TemperaturaRESUMO
Sleep disturbances are common features of neurodegenerative disorders including Huntington's disease (HD). The sleep and circadian disruptions are recapitulated in animal models, and these models provide the opportunity to evaluate whether circadian interventions can be effective countermeasures for neurodegenerative disease. Time restricted feeding (TRF) interventions successfully improve activity rhythms, sleep behavior and motor performance in mouse models of HD. Seeking to determine if these benefits of scheduled feeding extend to physiological measures of sleep, electroencephalography (EEG) was used to measure sleep/wake states and polysomnographic patterns in adult mice (six mo-old) under TRF and ad lib feeding (ALF). With each diet, both male and female wild-type (WT) and bacterial artificial chromosome transgenic (BACHD) mice were evaluated. Our findings show that male, but not female, BACHD mice exhibited significant changes in the temporal patterning of wake and nonrapid eye movement (NREM) sleep. The TRF intervention reduced the inappropriate early morning activity by increasing NREM sleep in the male BACHD mice. In addition, the scheduled feeding reduced sleep fragmentation (# bouts) in the male BACHD mice. The phase of the rhythm in rapid-eye movement (REM) sleep was significantly altered by the scheduled feeding. The treatment did impact the power spectral curves during the day in male but not female mice. Sleep homeostasis, as measured by the response to six hours of gentle handling, was not altered by the diet. Thus, TRF improves the temporal patterning and fragmentation of NREM sleep without impacting sleep homeostasis. This work adds critical support to the view that sleep is a modifiable risk factor in neurodegenerative diseases.
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The present study examined rates of sleep disorders and sleep medication use, and predictors of sleep disturbance in children with persistent tic disorders (PTD). Sixty-three parents of children aged 10 to 17 years with PTDs completed an internet survey evaluating sleep patterns and clinical symptoms. Insomnia (19.4%), nightmares (16.1%), and bruxism (13.1%) were the most commonly reported lifetime sleep disorders. Fifty-two percent endorsed current sleep medication use. Higher ADHD severity, overall life impairment, and female sex predicted greater sleep disturbance. Findings suggest the utility of clinical management of co-occurring ADHD and impairment to mitigate sleep disturbance in children with PTDs.
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Study Objectives: Sleep loss contributes to various health issues and impairs neurological function. Molecular hydrogen has recently gained popularity as a nontoxic ergogenic and health promoter. The effect of molecular hydrogen on sleep and sleep-related neural systems remains unexplored. This study investigates the impact of hydrogen-rich water (HRW) on sleep behavior and neuronal activation in sleep-deprived mice. Methods: Adult C57BL/6J mice were implanted with electroencephalography (EEG) and electromyography (EMG) recording electrodes and given HRW (0.7-1.4 mM) or regular water for 7 days ad libitum. Sleep-wake cycles were recorded under baseline conditions and after acute sleep loss. Neuronal activation in sleep- and wake-related regions was assessed using cFos immunostaining. Results: HRW increased sleep consolidation in undisturbed mice and increased non-rapid-eye movement and rapid-eye-movement sleep amount in sleep-deprived mice. HRW also decreased the average amount of time for mice to fall asleep after light onset. Neuronal activation in the lateral septum, medial septum, ventrolateral preoptic area, and median preoptic area was significantly altered in all mice treated with HRW. Conclusions: HRW improves sleep consolidation and increases neuronal activation in sleep-related brain regions. It may serve as a simple, effective treatment to improve recovery after sleep loss.
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Sleep and circadian rhythm disturbances are common features of Huntington's disease (HD). HD is an autosomal dominant neurodegenerative disorder that affects men and women in equal numbers, but some epidemiological studies as well as preclinical work indicate there may be sex differences in disease presentation and progression. Since sex differences in HD could provide important insights to understand cellular and molecular mechanism(s), we used the bacterial artificial chromosome transgenic mouse model of HD (BACHD) to examine whether sex differences in sleep/wake cycles are detectable in an animal model of the disease. Electroencephalography/electromyography (EEG/EMG) was used to measure sleep/wake states and polysomnographic patterns in young adult (12-week-old) male and female wild-type and BACHD mice. Our findings show that male, but not female, BACHD mice exhibited increased variation in phases of the rhythms as compared to age- and sex-matched wild-types. For both rapid-eye movement (REM) and non-rapid eye movement (NREM) sleep, genotypic and sex differences were detected. In particular, the BACHD males spent less time in NREM sleep and exhibited a more fragmented sleep than the other groups. Finally, in response to 6 h of sleep deprivation, both genotypes and sexes displayed the predicted homeostatic responses to sleep loss. These findings suggest that females are relatively protected early in disease progression in this HD model.
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Doença de Huntington , Caracteres Sexuais , Adulto Jovem , Feminino , Masculino , Humanos , Animais , Camundongos , Doença de Huntington/genética , Sono , Modelos Animais de Doenças , Camundongos TransgênicosRESUMO
BACKGROUND: Clinical evidence on the use of cannabidiol (CBD) for sleep remains limited. Even fewer studies have tested the comparative effectiveness of cannabinoid formulations found within CBD products used for sleep or how they compare to other complementary therapies such as melatonin. METHODS: Participants (N = 1,793 adults experiencing symptoms of sleep disturbance) were randomly assigned to receive a 4-week supply of 1 of 6 products (all capsules) containing either 15 mg CBD or 5 mg melatonin, alone or in combination with minor cannabinoids. Sleep disturbance was assessed over a period of 5 weeks (baseline week and 4 weeks of product use) using Patient-Reported Outcomes Measurement Information System (PROMIS™) Sleep Disturbance SF 8A, administered via weekly online surveys. A linear mixed-effects regression model was used to assess the differences in the change in sleep disturbance through time between each active product arm and CBD isolate. RESULTS: All formulations exhibited a favorable safety profile (12% of participants reported a side effect and none were severe) and led to significant improvements in sleep disturbance (p < 0.001 in within-group comparisons). Most participants (56% to 75%) across all formulations experienced a clinically important improvement in their sleep quality. There were no significant differences in effect, however, between 15 mg CBD isolate and formulations containing 15 mg CBD and 15 mg cannabinol (CBN), alone or in combination with 5 mg cannabichromene (CBC). There were also no significant differences in effect between 15 mg CBD isolate and formulations containing 5 mg melatonin, alone or in combination with 15 mg CBD and 15 mg CBN. CONCLUSIONS: Our findings suggest that chronic use of a low dose of CBD is safe and could improve sleep quality, though these effects do not exceed that of 5 mg melatonin. Moreover, the addition of low doses of CBN and CBC may not improve the effect of formulations containing CBD or melatonin isolate.
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Canabidiol , Canabinoides , Melatonina , Adulto , Humanos , Melatonina/efeitos adversos , Canabinoides/efeitos adversos , Canabinol , Canabidiol/efeitos adversos , SonoRESUMO
Subcortical white matter stroke (WMS) is a progressive disorder which is demarcated by the formation of small ischemic lesions along white matter tracts in the CNS. As lesions accumulate, patients begin to experience severe motor and cognitive decline. Despite its high rate of incidence in the human population, our understanding of the cause and outcome of WMS is extremely limited. As such, viable therapies for WMS remain to be seen. This study characterizes myelin recovery following stroke and motor learning-based rehabilitation in a mouse model of subcortical WMS. Following WMS, a transient increase in differentiating oligodendrocytes occurs within the peri-infarct in young male adult mice, which is completely abolished in male aged mice. Compound action potential recording demonstrates a decrease in conduction velocity of myelinated axons at the peri-infarct. Animals were then tested on one of three distinct motor learning-based rehabilitation strategies (skilled reach, restricted access to a complex running wheel, and unrestricted access to a complex running wheel) for their capacity to induce repair. These studies determined that unrestricted access to a complex running wheel alone increases the density of differentiating oligodendrocytes in infarcted white matter in young adult male mice, which is abolished in aged male mice. Unrestricted access to a complex running wheel was also able to enhance conduction velocity of myelinated axons at the peri-infarct to a speed comparable to naive controls suggesting functional recovery. However, there was no evidence of motor rehabilitation-induced remyelination or myelin protection.SIGNIFICANCE STATEMENT White matter stroke is a common disease with no medical therapy. A form of motor rehabilitation improves some aspects of white matter repair and recovery.
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Acidente Vascular Cerebral , Substância Branca , Humanos , Masculino , Camundongos , Animais , Idoso , Substância Branca/patologia , Acidente Vascular Cerebral/patologia , Bainha de Mielina/patologia , Oligodendroglia/fisiologia , Infarto/patologia , Atividade MotoraRESUMO
Inadequate sleep is a global health concern. Sleep is multidimensional and complex; new multi-ingredient agents are needed. This study assessed the comparative effects of two multi-ingredient supplements on sleep relative to placebo. Adults (N = 620) seeking better sleep were randomly assigned to receive one of three study products. Sleep A (contained lower (0.35 mg THC and higher levels of botanicals (75 mg each hops oil and valerian oil), Sleep B (contained higher THC (0.85 mg) and lower botanicals (20 mg each hops oil and valerian oil) or placebo) for 4 weeks. Sleep disturbance was assessed at baseline and weekly using NIH's Patient-Reported Outcomes Measurement Information System (PROMIS™) Sleep Disturbance SF 8A survey. Anxiety, stress, pain, and well-being were assessed using validated measures at baseline and weekly. A linear mixed-effects regression model was used to assess the change in health outcome score between active product groups and the placebo. There was a significant difference in sleep disturbance, anxiety, stress, and well-being between Sleep A and placebo. There was no significant difference in any health parameter between Sleep B and placebo. Side effects were mild or moderate. There were no significant differences in the frequency of side effects between the study groups. A botanical blend containing a low concentration of THC improved sleep disturbance, anxiety, stress, and well-being in healthy individuals that reported better sleep as a primary health concern.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Transtornos do Sono-Vigília , Humanos , Adulto , Sono , Privação do Sono , Ansiedade , Transtornos do Sono-Vigília/tratamento farmacológico , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Purpose of review: Sleep disturbance is common in TD. However, our understanding of the pathophysiological mechanisms involved is preliminary. This review summarizes findings from neuroimaging, genetic, and animal studies to elucidate potential underlying mechanisms of sleep disruption in TD. Recent findings: Preliminary neuroimaging research indicates increased activity in the premotor cortex, and decreased activity in the prefrontal cortex is associated with NREM sleep in TD. Striatal dopamine exhibits a circadian rhythm; and is influenced by the suprachiasmatic nucleus via multiple molecular mechanisms. Conversely, dopamine receptors regulate circadian function and striatal expression of circadian genes. The association of TD with restless legs syndrome and periodic limb movements indicates shared pathophysiology, including iron deficiency, and variants in the BTDB9 gene. A mutations in the L-Histidine Decarboxylase gene in TD, suggests the involvement of the histaminergic system, implicated in arousal, in TD. Summary: These biological markers have implications for application of novel, targeted interventions, including noninvasive neuromodulation, iron supplementation, histamine receptor antagonists, and circadian-based therapies for tic symptoms and/or sleep and circadian rhythms in TD.
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Circadian disruptions impact nearly all people with Alzheimer's disease (AD), emphasizing both their potential role in pathology and the critical need to investigate the therapeutic potential of circadian-modulating interventions. Here, we show that time-restricted feeding (TRF) without caloric restriction improved key disease components including behavioral timing, disease pathology, hippocampal transcription, and memory in two transgenic (TG) mouse models of AD. We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aß42 clearance, improving sleep and memory, and normalizing daily transcription patterns of multiple genes, including those associated with AD and neuroinflammation. Thus, our study unveils for the first time the pleiotropic nature of timed feeding on AD, which has far-reaching effects beyond metabolism, ameliorating neurodegeneration and the misalignment of circadian rhythmicity. Since TRF can substantially modify disease trajectory, this intervention has immediate translational potential, addressing the urgent demand for accessible approaches to reduce or halt AD progression.
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Doença de Alzheimer , Camundongos , Animais , Humanos , Doença de Alzheimer/terapia , Doença de Alzheimer/genética , Camundongos Transgênicos , Modelos Animais de Doenças , Ritmo Circadiano , Encéfalo/metabolismo , Peptídeos beta-AmiloidesRESUMO
Sleep and circadian rhythm disturbances are common features of Huntington's disease (HD). HD is an autosomal dominant neurodegenerative disorder that affects men and women in equal numbers, but some epidemiological studies as well as preclinical work indicate there may be sex differences in disease progression. Since sex differences in HD could provide important insights to understand cellular and molecular mechanism(s), we used the bacterial artificial chromosome transgenic mouse model of HD (BACHD) to examine whether sex differences in sleep/wake cycles are detectable in an animal model of the disease. Electroencephalography/electromyography (EEG/EMG) was used to measure sleep/wake states and polysomnographic patterns in young adult (12 week-old) male and female wild-type and BACHD mice. Our findings show that male, but not female, BACHD mice exhibited increased variation in phases of the rhythms as compared to age and sex matched wild-types. For both Rapid-eye movement (REM) and Non-rapid eye movement (NREM) sleep, genotypic and sex differences were detected. In particular, the BACHD males spent less time in NREM and exhibited a more fragmented sleep than the other groups. Both male and female BACHD mice exhibited significant changes in delta but not in gamma power compared to wild-type mice. Finally, in response to a 6-hrs sleep deprivation, both genotypes and sexes displayed predicted homeostatic responses to sleep loss. These findings suggest that females are relatively protected early in disease progression in this HD model.
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In mammals, photic information delivered to the suprachiasmatic nucleus (SCN) via the retinohypothalamic tract (RHT) plays a crucial role in synchronizing the master circadian clock located in the SCN to the solar cycle. It is well known that glutamate released from the RHT terminals initiates the synchronizing process by activating ionotropic glutamate receptors (iGluRs) on retinorecipient SCN neurons. The potential role of metabotropic glutamate receptors (mGluRs) in modulating this signaling pathway has received less attention. In this study, using extracellular single-unit recordings in mouse SCN slices, we investigated the possible roles of the Gq/11 protein-coupled mGluRs, mGluR1 and mGluR5, in photic resetting. We found that mGluR1 activation in the early night produced phase advances in neural activity rhythms in the SCN, while activation in the late night produced phase delays. In contrast, mGluR5 activation had no significant effect on the phase of these rhythms. Interestingly, mGluR1 activation antagonized phase shifts induced by glutamate through a mechanism that was dependent upon CaV1.3 L-type voltage-gated Ca2+ channels (VGCCs). While both mGluR1-evoked phase delays and advances were inhibited by knockout (KO) of CaV1.3 L-type VGCCs, different signaling pathways appeared to be involved in mediating these effects, with mGluR1 working via protein kinase G in the early night and via protein kinase A signaling in the late night. We conclude that, in the mouse SCN, mGluR1s function to negatively modulate glutamate-evoked phase shifts.
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Many patients with autism spectrum disorders (ASD) show disturbances in their sleep/wake cycles, and they may be particularly vulnerable to the impact of circadian disruptors. We have previously shown that a 2-weeks exposure to dim light at night (DLaN) disrupts diurnal rhythms, increases repetitive behaviors and reduces social interactions in contactin-associated protein-like 2 knock out (Cntnap2 KO) mice. The deleterious effects of DLaN may be mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin, which is maximally sensitive to blue light (480 nm). In this study, the usage of a light-emitting diode array enabled us to shift the spectral properties of the DLaN while keeping the intensity of the illumination at 10 lx. First, we confirmed that the short-wavelength enriched lighting produced strong acute suppression of locomotor activity (masking), robust light-induced phase shifts, and cFos expression in the suprachiasmatic nucleus in wild-type (WT) mice, while the long-wavelength enriched lighting evoked much weaker responses. Opn4DTA mice, lacking the melanopsin expressing ipRGCs, were resistant to DLaN effects. Importantly, shifting the DLaN stimulus to longer wavelengths mitigated the negative impact on the activity rhythms and 'autistic' behaviors (i.e. reciprocal social interactions, repetitive grooming) in the Cntnap2 KO as well as in WT mice. The short-, but not the long-wavelength enriched, DLaN triggered cFos expression in in the basolateral amygdala (BLA) as well as in the peri-habenula region raising that possibility that these cell populations may mediate the effects. Broadly, our findings are consistent with the recommendation that spectral properties of light at night should be considered to optimize health in neurotypical as well as vulnerable populations.
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Ritmo Circadiano , Células Ganglionares da Retina , Camundongos , Animais , Ritmo Circadiano/fisiologia , Células Ganglionares da Retina/metabolismo , Núcleo Supraquiasmático , Luz , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismoRESUMO
Disturbances in sleep/wake cycles are common among patients with neurodegenerative diseases including Huntington's disease (HD) and represent an appealing target for chrono-nutrition-based interventions. In the present work, we sought to determine whether a low-carbohydrate, high-fat diet would ameliorate the symptoms and delay disease progression in the BACHD mouse model of HD. Adult WT and BACHD male mice were fed a normal or a ketogenic diet (KD) for 3 months. The KD evoked a robust rhythm in serum levels of ß-hydroxybutyrate and dramatic changes in the microbiome of male WT and BACHD mice. NanoString analysis revealed transcriptional changes driven by the KD in the striatum of both WT and BACHD mice. Disturbances in sleep/wake cycles have been reported in mouse models of HD and are common among HD patients. Having established that the KD had effects on both the WT and mutant mice, we examined its impact on sleep/wake cycles. KD increased daytime sleep and improved the timing of sleep onset, while other sleep parameters were not altered. In addition, KD improved activity rhythms, including rhythmic power, and reduced inappropriate daytime activity and onset variability. Importantly, KD improved motor performance on the rotarod and challenging beam tests. It is worth emphasizing that HD is a genetically caused disease with no known cure. Life-style changes that not only improve the quality of life but also delay disease progression for HD patients are greatly needed. Our study demonstrates the therapeutic potential of diet-based treatment strategies in a pre-clinical model of HD.
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Brain tissue transcriptomes may be organized into gene coexpression networks, but their underlying biological drivers remain incompletely understood. Here, we undertook a large-scale transcriptomic study using 508 wild-type mouse striatal tissue samples dissected exclusively in the afternoons to define 38 highly reproducible gene coexpression modules. We found that 13 and 11 modules are enriched in cell-type and molecular complex markers, respectively. Importantly, 18 modules are highly enriched in daily rhythmically expressed genes that peak or trough with distinct temporal kinetics, revealing the underlying biology of striatal diurnal gene networks. Moreover, the diurnal coexpression networks are a dominant feature of daytime transcriptomes in the mouse cortex. We next employed the striatal coexpression modules to decipher the striatal transcriptomic signatures from Huntington's disease models and heterozygous null mice for 52 genes, uncovering novel functions for Prkcq and Kdm4b in oligodendrocyte differentiation and bipolar disorder-associated Trank1 in regulating anxiety-like behaviors and nocturnal locomotion.
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Doença de Huntington , Transcriptoma , Animais , Camundongos , Proteína Quinase C-theta/genética , Redes Reguladoras de Genes , Doença de Huntington/genética , EncéfaloRESUMO
Light is a potent circadian entraining agent. For many people, daily light exposure is fundamentally dysregulated with reduced light during the day and increased light into the late evening. This lighting schedule promotes chronic disruption to circadian physiology resulting in a myriad of impairments. Developmental changes in sleep-wake physiology suggest that such light exposure patterns may be particularly disruptive for adolescents and further compounded by lifestyle factors such as early school start times. This narrative review describes evidence that reduced light exposure during the school day delays the circadian clock, and longer exposure durations to light-emitting electronic devices in the evening suppress melatonin. While home lighting in the evening can suppress melatonin secretion and delay circadian phase, the patterning of light exposure across the day and evening can have moderating effects. Photic countermeasures may be flexibly and scalably implemented to support sleep-wake health; including manipulations of light intensity, spectra, duration and delivery modality across multiple contexts. An integrative approach addressing physiology, attitudes, and behaviors will support optimization of light-driven sleep-wake outcomes in adolescents.
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Relógios Circadianos , Melatonina , Adolescente , Ritmo Circadiano/fisiologia , Humanos , Iluminação , Sono/fisiologiaRESUMO
In Huntington's disease (HD), the uninterrupted CAG repeat length, but not the polyglutamine length, predicts disease onset. However, the underlying pathobiology remains unclear. Here, we developed bacterial artificial chromosome (BAC) transgenic mice expressing human mutant huntingtin (mHTT) with uninterrupted, and somatically unstable, CAG repeats that exhibit progressive disease-related phenotypes. Unlike prior mHTT transgenic models with stable, CAA-interrupted, polyglutamine-encoding repeats, BAC-CAG mice show robust striatum-selective nuclear inclusions and transcriptional dysregulation resembling those in murine huntingtin knockin models and HD patients. Importantly, the striatal transcriptionopathy in HD models is significantly correlated with their uninterrupted CAG repeat length but not polyglutamine length. Finally, among the pathogenic entities originating from mHTT genomic transgenes and only present or enriched in the uninterrupted CAG repeat model, somatic CAG repeat instability and nuclear mHTT aggregation are best correlated with early-onset striatum-selective molecular pathogenesis and locomotor and sleep deficits, while repeat RNA-associated pathologies and repeat-associated non-AUG (RAN) translation may play less selective or late pathogenic roles, respectively.