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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 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.Significance StatementSleep and circadian rhythm disturbances are common features of Huntington’s disease (HD). Using an animal model of HD and EEG measures of sleep, we found that the males were more vulnerable to sleep/wake architecture alterations and sleep fragmentation. Homeostatic recovery from sleep loss did not appear to be altered at this stage of the disease. These findings raise the possibility that sex-specific factors play a role in the HD symptom progression and that hormone-based treatments may have therapeutic utility.

The objective of this randomized, double-blinded controlled trial was to evaluate the safety and relative effects of different formulations containing Cannabidiol (CBD) and melatonin, with and without the addition of minor cannabinoids, on sleep. Participants (N=1,793 adults experiencing symptoms of sleep disturbance) were assigned to receive a 4-week supply of 1 of 6 products (all capsules) containing either 15mg CBD or 5mg melatonin, alone or in combination with minor cannabinoids. Sleep disturbance was assessed using Patient-Reported Outcomes Measurement Information System (PROMIS™) Sleep Disturbance SF 8A, administered via weekly online surveys. 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

Alzheimer’s disease (AD) is a tragic neurodegenerative disease affecting more than 5 million Americans. Circadian disruptions impact nearly all AD patients, with reversal of sleep/wake cycles and agitation in the evening being common disturbances that manifest early in disease. These alterations support a role for circadian dysfunction as a driver of AD, emphasizing a critical need to investigate the therapeutic potential of circadian-modulating interventions. One of the most powerful regulators of the circadian system is the daily feed/fast cycle. Here we show that time-restricted feeding (TRF) without caloric restriction, improved key disease components including behavior, disease pathology and transcription in the APP23 mouse model of Alzheimer’s disease. We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and hyperactivity, and normalizing transcription of circadian, AD and neuroinflammation-associated genes in APP23 mice. Thus, our study unveils for the first time that circadian modulation through timed feeding has far-reaching effects beyond metabolism and affects the brain as the substrate for neurodegeneration. Since the pleiotropic effects of TRF can substantially modify disease trajectory, this intervention has immediate translational value, addressing the crucial need for accessible approaches to reduce or halt AD progression.

BACKGROUND: Sleep disturbance is common among individuals with Tourette’s Disorder (TD). Given that sleep is influenced by the circadian system, this study examined circadian rhythms and sleep in adults with TD, and explored the possible benefit of short-wavelength wearable morning light therapy. METHODS: Participants were 34 adults with TD (n=14) and age- and sex-matched healthy controls (HC; n=20). Participants were screened using clinician-rated diagnostic and tic severity interviews, and procedures lasted 3 consecutive weeks. Participants completed a baseline week of actigraphy. Adults with TD completed two weeks of Re-Timer(™) morning light therapy and continued actigraphy monitoring. Dim light melatonin onset (DLMO) phase assessment, tic severity interview, and measures of chronotype, sleep disturbance, daytime sleepiness, disability, depression, anxiety, and stress were completed at baseline and post-intervention. RESULTS: Adults with TD reported significantly greater eveningness and sleep disturbance relative to controls. Per wrist actigraphy, adults with TD exhibited significantly longer sleep onset latency, lower sleep efficiency, and greater sleep fragmentation than HC. Following morning light therapy there was significant advances in DLMO phase, but not self-report or actigraphy sleep variables. There were small, statistically significant decreases in tic severity and impairment. There were also significant reductions in daytime sleepiness, and self-reported anxiety, but not depression, stress, or disability. Participants reported minimal side effects and rated light therapy as acceptable and comfortable. CONCLUSIONS: Findings showed some benefits following brief light therapy in TD; further exploration of the impact of spectral tuning the photic environment as part of treatment for TD subjects is warranted.

Many patients with autism spectrum disorders (ASD) show disturbances in their sleep/wake cycles, and may be particularly vulnerable to the impact of circadian disruptors. We have previously shown that exposure to dim light at night (DLaN) in contactin associated protein-like 2 knock out (Cntnap2 KO) mice disrupts diurnal rhythms, increases repetitive behaviors while reducing social interactions. These negative effects of DLaN may be mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin, which is maximally sensitive to blue light (480nm). In this study, we used a light-emitting diode (LED) array that enabled us to shift the spectral properties of the DLaN while keeping the intensity at 10 lx. First, using wild-type (WT) mice, we confirmed that the short-wavelength enriched lighting produced strong acute suppression of locomotor activity (masking), robust light-induced phase shifts, and c-Fos expression in the suprachiasmatic nucleus, while the long-wavelength enriched lighting evoked much weaker responses. Furthermore, exposure of WT mice to the short-wavelength light at night reduced the amplitude of locomotor activity rhythms and impaired social interactions. Mice lacking the melanopsin expressing ipRGCs (Opn4DTA mice) were resistant to these negative effects of DLaN. Importantly, the shift of the DLaN stimulus to longer wavelengths ameliorated the negative impact on the activity rhythms and autistic behaviors (i.e. reciprocal social interactions, repetitive grooming) of the Cntnap2 KO model. The short-, but not the long-wavelength enriched, DLaN triggered cFos expression in the peri-habenula region as well as in the basolateral amygdala (BLA). Finally, DLaN-driven c-Fos induction in BLA glutamatergic neurons was about 3-fold higher in the Cntnap2 KO mice, suggesting that these cells may be particularly vulnerable to the effects of photic disruption. Broadly, our findings suggest that the spectral properties of light at night should be considered in the management of ASD and other neurodevelopmental disorders.

Salt sensitivity of blood pressure (SSBP) is a trait carrying strong prognostic implications for various cardiovascular diseases. To test the hypothesis that excessive maternal salt intake causes SSBP in offspring through a mechanism dependent upon arginine-vasopressin (AVP), we performed a series of experiments using offspring of the rat dams salt-loaded during pregnancy and lactation with 1.5% saline drink (“experimental offspring”) and those with normal perinatal salt exposure (“control offspring”). Salt challenge, given at 7–8 weeks of age with either 2% saline drink (3 days) or 8% NaCl-containing chow (4 weeks), had little or no effect on systolic blood pressure (SBP) in female offspring, whereas the salt challenge significantly raised SBP in male offspring, with the magnitude of increase being greater in experimental, than control, rats. Furthermore, the salt challenge not only raised plasma AVP level more and caused greater depressor responses to V1a and V2 AVP receptor antagonists to occur in experimental, than control, males, but it also made GABA excitatory in a significant proportion of magnocellular AVP neurons of experimental males by depolarizing GABA equilibrium potential. The effect of the maternal salt loading on the salt challenge-elicited SBP response in male offspring was precluded by maternal conivaptan treatment (non-selective AVP receptor antagonist) during the salt-loading period, whereas it was mimicked by neonatal AVP treatment. These results suggest that the excessive maternal salt intake brings about SSBP in male offspring, both the programming and the expression of which depend on increased AVP secretion that may partly result from excitatory GABAergic action.

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.

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.

Aim Abundant evidence indicates that estrogen (E2) plays a protective role against hypertension. Yet, the mechanism underlying the antihypertensive effect of E2 is poorly understood. In this study, we sought to determine the mechanism through which E2 inhibits salt-dependent hypertension. Methods and results To this end, we performed a series of in-vivo and in-vitro experiments employing a rat model of hypertension that is produced by deoxycorticosterone acetate (DOCA)-salt treatment after uninephrectomy. We found that E2 prevented DOCA-salt treatment from inducing hypertension, raising plasma arginine-vasopressin (AVP) level, enhancing the depressor effect of the V1a receptor antagonist (Phenylac1, D-Tyr(Et)2, Lys6, Arg8, des-Gly9)-vasopressin, and converting GABAergic inhibition to excitation in hypothalamic magnocellular AVP neurons. Moreover, we obtained results indicating that the E2 modulation of the activity and/or expression of NKCC1 (Cl- importer) and KCC2 (Cl- extruder) underpins the effect of E2 on the transition of GABAergic transmission in AVP neurons. Lastly, we discovered that, in DOCA-salt-treated hypertensive ovariectomized rats, CLP290 (prodrug of the KCC2 activator CLP257, intraperitoneal injections) lowered blood pressure and plasma AVP level and hyperpolarized GABA equilibrium potential to prevent GABAergic excitation from emerging in the AVP neurons of these animals. Conclusion Based on these results, we conclude that E2 inhibits salt-dependent hypertension by suppressing GABAergic excitation to decrease the hormonal output of AVP neurons. Translational perspective Numerous studies have shown that sex steroids can impact blood pressure (BP) and premenopausal women have a lower incidence of hypertension than age-matched men. Postmenopausal women no longer enjoy this beneficial difference. The causal mechanisms are not clear and hormone replacement therapy with estradiol (E2) does not consistently lower BP in postmenopausal women. In this study we showed that rats treated with CLP290 to control GABAergic excitation in AVP neurons have the same phenotype as E2-supplemented rats in BP and plasma AVP level. This result indicates that CLP290 leverages the same pathway of E2 protective effects against salt-dependent hypertension, and therefore, raises the possibility that classes of drugs like CLP290 may have some utility as alternative antihypertensives in persons resistant to or contraindicated for E2 therapy.

ObjectiveThis study examined sleep disorders and sleep medication use rates, nighttime tics, and sleep and chronotype in relation to tic and co-occurring symptoms in adults with persistent tic disorders (PTDs), including Tourette's disorder (TD).MethodsOne hundred twenty-five adult internet survey respondents rated sleep history, sleep, chronotype, tic severity, impairment, attention deficit hyperactivity disorder, obsessive-compulsive symptoms, anxiety, depression, and emotional and behavioral dyscontrol.ResultsBruxism, insomnia, tic-related difficulty falling asleep, and melatonin use were commonly endorsed. Sleep disturbance correlated with impairment, obsessive-compulsive symptoms, and emotional and behavioral dyscontrol. Eveningness correlated with vocal and total tic severity only in TD. Controlling for age and sex, age, impairment, and obsessive-compulsive symptoms predicted sleep disturbance, and age and tic severity predicted chronotype.ConclusionsImpairment and obsessive-compulsive symptoms play a role in sleep disturbance in adults with PTDs, and may be intervention targets. Eveningness relates to tic severity, which may suggest the utility of interventions to advance chronotype.

Circadian rhythms in core body temperature (CBT) have been widely studied, but fewer studies have explored higher-frequency (ultradian) rhythms in detail. We analyzed CBT recordings from young and middle-aged wild-type mice as well as from the Q175 model of Huntington's disease (HD), at sufficient temporal resolution to address the question of ultradian rhythms. We used model selection methods to show that the overall circadian pattern was better fit by a square wave than a sine wave. Then, using Fourier analysis of the CBT rhythms, we identified the spectral signature of an 8-hour oscillation that occurs in the night but not the day, an observation that can be confirmed by direct inspection of the rhythms. This diurnal amplitude modulation of the 8-hour rhythm was lost with aging as well as in the HD model. Thus, the impact of aging and disease is seen here in the loss of the ability to separate rhythms into a daytime phase and a nighttime phase. These findings raise the possibility that ultradian rhythms in CBT may be a useful biomarker for the pathology within the central nervous system.

The dorsal striatum forms part of the basal ganglia circuit that is a major regulator of voluntary motor behavior. Dysfunction in this circuit is a critical factor in the pathology of neurological (Parkinson's and Huntington's disease) as well as psychiatric disorders. In this study, we employed in vivo real-time monitoring of multiple unit neural activity (MUA) in the dorsal striatum of freely moving mice. We demonstrate that the striatum exhibits robust diurnal and circadian rhythms in MUA that peak in the night. These rhythms are dependent upon the central circadian clock located in the suprachiasmatic nucleus (SCN) as lesions of this structure caused the loss of rhythmicity measured in the striatum. Nonetheless, chronic treatment of methamphetamine (METH) makes circadian rhythms appear in MUA recorded from the striatum of SCN-lesioned mice. These data demonstrate that the physiological properties of neurons in the dorsal striatum are regulated by the circadian system and that METH drives circadian rhythms in striatal physiology in the absence of the SCN. The finding of SCN-driven circadian rhythms in striatal physiology has important implications for an understanding of the temporal regulation of motor control as well as revealing how disease processes may disrupt this regulation., Highlights • Dorsal striatum exhibits robust circadian rhythms in MUA in freely moving animals. • Suprachiasmatic nucleus (SCN) lesions caused the loss of rhythmicity measured in the striatum. • METH treatment made newly striatal MUA rhythms appear after SCN lesions. • METH treatment reduced the amplitude and delayed the offset of SCN rhythms.

Neurodegenerative diseases encompass a large group of conditions that are clinically and pathologically diverse yet are linked by a shared pathology of misfolded proteins. The accumulation of insoluble aggregates is accompanied by a progressive loss of vulnerable neurons. For some patients, the symptoms are motor focused (ataxias), while others experience cognitive and psychiatric symptoms (dementias). Among the shared symptoms of neurodegenerative diseases is a disruption of the sleep/wake cycle that occurs early in the trajectory of the disease and may be a risk factor for disease development. In many cases, the disruption in the timing of sleep and other rhythmic physiological markers immediately raises the possibility of neurodegeneration-driven disruption of the circadian timing system. The aim of this Review is to summarize the evidence supporting the hypothesis that circadian disruption is a core symptom within neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, and Parkinson's disease, and to discuss the latest progress in this field. The Review discusses evidence that neurodegenerative processes may disrupt the structure and function of the circadian system and describes circadian-based interventions as well as timed drug treatments that may improve a wide range of symptoms associated with neurodegenerative disorders. It also identifies key gaps in our knowledge.

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.

Trichotillomania (TTM; hair-pulling disorder) is characterized by an irresistible urge or desire to pull out one's own hair, and a sense of pleasure when hair is pulled out. Evidence from translational neuroscience has shown that 'wanting' (motivation to seek a reward) and 'liking' (enjoyment when reward is received) are each mediated by overlapping but distinct neural circuitry, and that 'wanting' contributes to addictive/compulsive behaviors more so than 'liking'. In the present study, we developed the Hair Pulling Reward Scale (HPRS), a self-report measure that consists of two subscales designed to assess (a) cue-triggered urges and appetitive motivation to pull hair (i.e., putative correlates of 'wanting'), and (b) momentary pleasure and gratification during pulling episodes (i.e., putative correlates of 'liking'). We administered the HPRS to 259 individuals with TTM and examined its psychometric properties. Confirmatory factor analysis supported a two-factor model reflecting correlated Wanting and Liking scales. Consistent with predictions, Wanting, much more than Liking, had robust correlations with TTM severity, impulsiveness, difficulties in emotion regulation, psychiatric symptoms, and sleep dysfunction. The results suggest that the HPRS is a psychometrically sound instrument that can be used as a symptom-level measure of reward processing in TTM.

In mammals, the part of the nervous system responsible for most circadian behavior can be localized to a bilaterally paired structure in the hypothalamus known as the suprachiasmatic nucleus (SCN). Understanding the mammalian circadian system will require a detailed multilevel analysis of neural SCN circuits ex vivo and in vivo. Many of the techniques and approaches that are used for the analysis of the circuitry driving circadian oscillations in the SCN are similar to those employed in other brain regions. There is, however, one fundamental difference that needs to be taken into consideration, that is, the physiological, cell, and molecular properties of SCN neurons vary with the time of day. In this chapter, we will consider the preparations and electrophysiological techniques that we have used to analyze the SCN circuit focusing on the acute brain slice and intact, freely moving animal.

In mammals, the part of the nervous system responsible for most circadian behavior can be localized to a bilaterally paired structure in the hypothalamus known as the suprachiasmatic nucleus (SCN). Understanding the mammalian circadian system will require a detailed multilevel analysis of neural SCN circuits ex vivo and in vivo. Many of the techniques and approaches that are used for the analysis of the circuitry driving circadian oscillations in the SCN are similar to those employed in other brain regions. There is, however, one fundamental difference that needs to be taken into consideration, that is, the physiological, cell, and molecular properties of SCN neurons vary with the time of day. In this chapter, we will consider the preparations and electrophysiological techniques that we have used to analyze the SCN circuit focusing on the acute brain slice and intact, freely moving animal.

Nighttime light pollution is linked to metabolic and cognitive dysfunction. Many patients with autism spectrum disorders (ASD) show disturbances in their sleep/wake cycle, and may be particularly vulnerable to the impact of circadian disruptors. In this study, we examined the impact of exposure to dim light at night (DLaN, 5lx) in a model of ASD: the contactin associated protein-like 2 knock out (Cntnap2 KO) mice. DLaN was sufficient to disrupt locomotor activity rhythms, exacerbate the excessive grooming and diminish the social preference in Cntnap2 mutant mice. On a molecular level, DLaN altered the phase and amplitude of PER2:LUC rhythms in a tissue-specific manner in vitro. Daily treatment with melatonin reduced the excessive grooming of the mutant mice to wild-type levels and improved activity rhythms. Our findings suggest that common circadian disruptors such as light at night should be considered in the management of ASD.

Disturbances in sleep/wake cycle are a common complaint of individuals with Huntington's disease (HD) and are displayed by HD mouse models. The underlying mechanisms, including the possible role of the circadian timing system, are not well established. The BACHD mouse model of HD exhibits disrupted behavioral and physiological rhythms, including decreased electrical activity in the central circadian clock (suprachiasmatic nucleus, SCN). In this study, electrophysiological techniques were used to explore the ionic underpinning of the reduced spontaneous neural activity in male mice. We found that SCN neural activity rhythms were lost early in the disease progression and was accompanied by loss of the normal daily variation in resting membrane potential in the mutant SCN neurons. The low neural activity could be transiently reversed by direct current injection or application of exogenous N-methyl-d-aspartate (NMDA) thus demonstrating that the neurons have the capacity to discharge at WT levels. Exploring the potassium currents known to regulate the electrical activity of SCN neurons, our most striking finding was that these cells in the mutants exhibited an enhancement in the large-conductance calcium activated K+ (BK) currents. The expression of the pore forming subunit (Kcnma1) of the BK channel was higher in the mutant SCN. We found a similar decrease in daytime electrical activity and enhancement in the magnitude of the BK currents early in disease in another HD mouse model (Q175). These findings suggest that SCN neurons of both HD models exhibit early pathophysiology and that dysregulation of BK current may be responsible.

Huntington’s disease (HD) patients suffer from progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular, and motor dysfunction. Disturbances in sleep-wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and excessive fatigue. The BACHD mouse model exhibits many HD core symptoms including circadian dysfunction. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early interventions that improve circadian rhythmicity could benefit HD symptoms and delay disease progression. We evaluated the effects of time-restricted feeding (TRF) on the BACHD mouse model. At 3 months of age, the animals were divided into 2 groups: ad lib and TRF. The TRF-treated BACHD mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle (ZT 15-21) of the period when mice are normally active (ZT 12-24). Following 3 months of treatment (when mice reached the early disease stage), the TRF-treated BACHD mice showed improvements in their locomotor activity and sleep behavioral rhythms. Furthermore, we found improved heart rate variability, suggesting that their autonomic nervous system dysfunction was improved. On a molecular level, TRF altered the phase but not the amplitude of the PER2::LUC rhythms measured in vivo and in vitro. Importantly, treated BACHD mice exhibited improved motor performance compared with untreated BACHD controls, and the motor improvements were correlated with improved circadian output. It is worth emphasizing that HD is a genetically caused disease with no known cure. Lifestyle 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 circadian-based treatment strategies in a preclinical model of HD.

Development of cell replacement therapies in diabetes requires understanding of the molecular underpinnings of β-cell maturation. The circadian clock regulates diverse cellular functions important for regulation of β-cell function and turnover. However, postnatal ontogenesis of the islet circadian clock and its potential role in β-cell maturation remain unknown. To address this, we studied wild-type Sprague-Dawley as well as Period1 luciferase transgenic (Per1:LUC) rats to determine circadian clock function, clock protein expression, and diurnal insulin secretion during islet development and maturation process. We additionally studied β-cell–specific Bmal1-deficient mice to elucidate a potential role of this key circadian transcription factor in β-cell functional and transcriptional maturation. We report that emergence of the islet circadian clock 1) occurs during the early postnatal period, 2) depends on the establishment of global behavioral circadian rhythms, and 3) leads to the induction of diurnal insulin secretion and gene expression. Islet cell maturation was also characterized by induction in the expression of circadian transcription factor BMAL1, deletion of which altered postnatal development of glucose-stimulated insulin secretion and the associated transcriptional network. Postnatal development of the islet circadian clock contributes to early-life β-cell maturation and should be considered for optimal design of future β-cell replacement strategies in diabetes.

Patients with Huntington's disease (HD) exhibit movement disorders, psychiatric disturbance and cognitive impairments as the disease progresses. Abnormal sleep/wake cycles are common among HD patients with reports of delayed sleep onset, fatigue during the day, and a delayed pattern of melatonin secretion all of which suggest circadian dysfunction. Mouse models of HD confirm disrupted circadian rhythms with pathophysiology found in the central circadian clock (suprachiasmatic nucleus). Importantly, circadian dysfunction manifests early in disease, even before the classic motor symptoms, in both patients and mouse models. Therefore, we hypothesize that the circadian dysfunction may interact with the disease pathology and exacerbate the HD symptoms. If correct, early intervention may benefit patients and delay disease progression. One test of this hypothesis is to determine whether light therapy designed to strengthen this intrinsic timing system can delay the disease progression in mouse models. Therefore, we determined the impact of blue wavelength-enriched light on two HD models: the BACHD and Q175 mice. Both models received 6 h of blue-light at the beginning of their daily light cycle for 3 months. After treatment, both genotypes showed improvements in their locomotor activity rhythm without significant change to their sleep behavior. Critically, treated mice of both lines exhibited improved motor performance compared to untreated controls. Focusing on the Q175 genotype, we sought to determine whether the treatment altered signaling pathways in brain regions known to be impacted by HD using NanoString gene expression assays. We found that the expression of several HD relevant markers was altered in the striatum and cortex of the treated mice. Our study demonstrates that strengthening the circadian system can delay the progression of HD in pre-clinical models. This work suggests that lighting conditions should be considered when managing treatment of HD and other neurodegenerative disorders., Highlights • Blue-enriched lighting improves locomotor activity rhythms in mouse models of HD. • Blue-enriched lighting improves some measures of motor performance in the HD mice. • Blue-enriched lighting alters the expression of HD relevant markers in the cortex and striatum. • Findings suggest that environmental lighting conditions should be considered in the management of HD.

In Drosophila, well-delineated circuits control circadian rhythms, but the electrophysiological patterns that occur within these circuits are not well understood. In this issue, Tabuchi et al. clarify the temporal coding within a circuit, linking patterns of neural activity to sleep behavior.

Disturbances in sleep/wake cycle are a common complaint of individuals with Huntington’s disease (HD) and are displayed by HD mouse models. The underlying mechanisms, including the possible role of the circadian timing system, have been the topic of a number of recent studies. The (z)Q175 mouse is a knock-in model in which the human exon 1 sequence of the huntingtin gene is inserted into the mouse DNA with approximately 190 CAG repeats. Among the numerous models available, the heterozygous Q175 offers strong construct validity with a single copy of the mutation, genetic precision of the insertion and control of mutation copy number. In this review, we will summarize the evidence that this model exhibits disrupted diurnal and circadian rhythms in locomotor activity. We found overwhelming evidence for autonomic dysfunction including blunted daily rhythms in heart rate and core body temperature, reduced heart rate variability, and almost a complete failure of the sympathetic arm of the autonomic nervous system to function during the baroreceptor reflex. Mechanistically, the Q175 mouse model exhibits deficits in the neural output of the central circadian clock, the suprachiasmatic nucleus (SCN) along with an enhancement of at least one type of potassium current in these neurons. Finally, we report a novel network analysis examining the phase coherence between activity, core body temperature, and cardiovascular measures. Such analyses found that even young Q175 mutants (heterozygous or homozygous) show coherence degradation, and suggests that loss of phase coherence is a variable that should be considered as a possible biomarker for HD.

Huntington’s disease (HD) patients suffer from a progressive neurodegenerative disorder that inflicts both motor and non-motor symptoms. HD is caused by a CAG repeat expansion within the first exon of the huntingtin (HTT) gene that produces a polyglutamine repeat that leads to protein misfolding, soluble aggregates, and inclusion bodies detected throughout the body. Both clinical and preclinical research indicate that cardiovascular dysfunction should be considered a core symptom in at least a subset of HD patients. There is strong evidence for dysautonomia (dysfunctional autonomic nervous system, ANS) in HD patients that can be detected early in the disease progression. The temporal patterning of ANS function is controlled by the circadian timing system based in the anterior hypothalamus. Patients with neurodegenerative diseases including HD exhibit disrupted sleep/wake cycle and, in preclinical models, there is compelling evidence that the circadian timing system is compromised early in the disease process. Here we review data from preclinical models of HD that explore the intersection between disruption of circadian rhythms and dysautonomia. This work will lead to new therapeutic strategies and standards of care for HD and other neurodegenerative diseases.