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Exposure to infectious or non‐infectious immune activation during early development is a serious risk factor for long‐term behavioural dysfunctions. Mouse models of maternal immune activation (MIA) have increasingly been used to address neuronal and behavioural dysfunctions in response to prenatal infections. One commonly employed MIA model involves administering poly(I:C) (polyriboinosinic‐polyribocytdilic acid), a synthetic analogue of double‐stranded RNA, during gestation, which robustly induces an acute viral‐like inflammatory response. Using electroencephalography (EEG) and infrared (IR) activity recordings, we explored alterations in sleep/wake, circadian and locomotor activity patterns on the adult male offspring of poly(I:C)‐treated mothers. Our findings demonstrate that these offspring displayed reduced home cage activity during the (subjective) night under both light/dark or constant darkness conditions. In line with this finding, these mice exhibited an increase in non‐rapid eye movement (NREM) sleep duration as well as an increase in sleep spindles density. Following sleep deprivation, poly(I:C)‐exposed offspring extended NREM sleep duration and prolonged NREM sleep bouts during the dark phase as compared with non‐exposed mice. Additionally, these mice exhibited a significant alteration in NREM sleep EEG spectral power under heightened sleep pressure. Together, our study highlights the lasting effects of infection and/or immune activation during pregnancy on circadian activity and sleep/wake patterns in the offspring. [ABSTRACT FROM AUTHOR]

While it is generally known that metabolic disorders and circadian dysfunction are intertwined, how the two systems affect each other is not well understood, nor are the genetic factors that might exacerbate this pathological interaction. Blood chemistry is profoundly changed in metabolic disorders, and we have previously shown that serum factors change cellular clock properties. To investigate if circulating factors altered in metabolic disorders have circadian modifying effects, and whether these effects are of genetic origin, we measured circadian rhythms in U2OS cell in the presence of serum collected from diabetic, obese or control subjects. We observed that circadian period lengthening in U2OS cells was associated with serum chemistry that is characteristic of insulin resistance. Characterizing the genetic variants that altered circadian period length by genome‐wide association analysis, we found that one of the top variants mapped to the E3 ubiquitin ligase MARCH1 involved in insulin sensitivity. Confirming our data, the serum circadian modifying variants were also enriched in type 2 diabetes and chronotype variants identified in the UK Biobank cohort. Finally, to identify serum factors that might be involved in period lengthening, we performed detailed metabolomics and found that the circadian modifying variants are particularly associated with branched chain amino acids, whose levels are known to correlate with diabetes and insulin resistance. Overall, our multi‐omics data showed comprehensively that systemic factors serve as a path through which metabolic disorders influence circadian system, and these can be examined in human populations directly by simple cellular assays in common cultured cells. [ABSTRACT FROM AUTHOR]

N6‐methyladenosine (m6A) is the most abundant epitranscriptomic mark that regulates the fate of RNA molecules. Recent studies have revealed a bidirectional interaction between m6A modification and the circadian clock. However, the precise temporal dynamics of m6A global enrichment in the central circadian pacemaker have not been fully elucidated. Our study investigates the relationship between FTO demethylase and molecular clocks in primary cells of the suprachiasmatic nucleus (SCN). In addition, we examined the effects of lipopolysaccharide (LPS) on Fto expression and the role of FTO in LPS‐induced reactive oxygen species (ROS) production in primary SCN cell culture. We observed circadian rhythmicity in the global m6A levels, which mirrored the rhythmic expression of the Fto demethylase. Silencing FTO using siRNA reduced the mesor of Per2 rhythmicity in SCN primary cells and extended the period of the PER2 rhythm in SCN primary cell cultures from PER2::LUC mice. When examining the immune response, we discovered that exposure to LPS upregulated global m6A levels while downregulating Fto expression in SCN primary cell cultures. Interestingly, we found a loss of circadian rhythmicity in Fto expression following LPS treatment, indicating that the decrease of FTO levels may contribute to m6A upregulation without directly regulating its circadian rhythm. To explore potential protective mechanisms against neurotoxic inflammation, we examined ROS production following LPS treatment in SCN primary cell cultures pretreated with FTO siRNA. We observed a time‐dependent pattern of ROS induction, with significant peak at 32 h but not at 20 h after synchronization. Silencing the FTO demethylase abolished ROS induction following LPS exposure, supporting the hypothesis that FTO downregulation serves as a protective mechanism during LPS‐induced neuroinflammation in SCN primary cell cultures. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the behavioral responses and circadian rhythms of mice to both rapid and gradual increases in photoperiod, mimicking the transition from winter to summer, which is associated with a heightened prevalence of hospitalizations for mania and suicidal behavior. Behavioral tests were performed in C57BL/6 male mice exposed to a transitional photoperiod, from short to long durations. To determine if circadian rhythms are affected, we measured spontaneous locomotor activity and body temperature. Mice exhibited heightened exploratory and risk‐taking behaviors compared with equatorial and static long (16:8 h of light–dark cycle for several days) groups. These behaviors were prevented by lithium. Spontaneous locomotor activity and body temperature rhythms persisted and were effectively synchronized; however, the relative amplitude of activity and interdaily stability were diminished. Additionally, the animals displayed increased activity during the light phase. Photoperiodic transition modulates behavior and circadian rhythms, mirroring certain features observed in bipolar disorder patients. This study introduces an animal model for investigating mania‐like behavior induced by photoperiodic changes, offering potential insights for suicide prevention strategies and the management of mood disorders. [ABSTRACT FROM AUTHOR]

In mammals, intrinsic 24 h or circadian rhythms are primarily generated by the suprachiasmatic nuclei (SCN). Rhythmic daily changes in the transcriptome and proteome of SCN cells are controlled by interlocking transcription‐translation feedback loops (TTFLs) of core clock genes and their proteins. SCN cells function as autonomous circadian oscillators, which synchronize through intercellular neuropeptide signalling. Physiological and behavioural rhythms can be severely disrupted by genetic modification of a diverse range of genes and proteins in the SCN. With the advent of next generation sequencing, there is unprecedented information on the molecular profile of the SCN and how it is affected by genetically targeted alteration. However, whether the expression of some genes is more readily affected by genetic alteration of the SCN is unclear. Here, using publicly available datasets from recent RNA‐seq assessments of the SCN from genetically altered and control mice, we evaluated whether there are commonalities in transcriptome dysregulation. This was completed for four different phases across the 24 h cycle and was augmented by Gene Ontology Molecular Function (GO:MF) and promoter analysis. Common differentially expressed genes (DEGs) and/or enriched GO:MF terms included signalling molecules, their receptors, and core clock components. Finally, examination of the JASPAR database indicated that E‐box and CRE elements in the promoter regions of several commonly dysregulated genes. From this analysis, we identify differential expression of genes coding for molecules involved in SCN intra‐ and intercellular signalling as a potential cause of abnormal circadian rhythms. [ABSTRACT FROM AUTHOR]

Circadian clock function declines with ageing, which can aggravate ageing‐related diseases such as type 2 diabetes and neurodegenerative disorders. Understanding age‐related changes in the circadian system at a systemic level can contribute to the development of strategies to promote healthy ageing. The goal of this study was to investigate the impact of ageing on 24‐h rhythms in amine metabolites across four tissues in young (2 months of age) and old (22–25 months of age) mice using a targeted metabolomics approach. Liver, plasma, the suprachiasmatic nucleus (SCN; the location of the central circadian clock in the hypothalamus) and the paraventricular nucleus (PVN; a downstream target of the SCN) were collected from young and old mice every 4 h during a 24‐h period (n = 6–7 mice per group). Differential rhythmicity analysis revealed that ageing impacts 24‐h rhythms in the amine metabolome in a tissue‐specific manner. Most profound changes were observed in the liver, in which rhythmicity was lost in 60% of the metabolites in aged mice. Furthermore, we found strong correlations in metabolite levels between the liver and plasma and between the SCN and the PVN in young mice. These correlations were almost completely abolished in old mice. These results indicate that ageing is accompanied by a severe loss of the circadian coordination between tissues and by disturbed rhythmicity of metabolic processes. The tissue‐specific impact of ageing may help to differentiate mechanisms of ageing‐related disorders in the brain versus peripheral tissues and thereby contribute to the development of potential therapies for these disorders. [ABSTRACT FROM AUTHOR]

The mammalian circadian timing system has a hierarchical architecture, with a central pacemaker located in the brain's suprachiasmatic nucleus orchestrating rhythms in behaviour and physiology. In cooperation with environmental cycles, it synchronizes the phases of peripheral oscillators operating in most cells of the body. Even cells kept in tissue culture harbour self‐sustained and cell‐autonomous circadian clocks that keep ticking throughout their lifespan. The master pacemaker in the suprachiasmatic nucleus is synchronized primarily by light–dark cycles, whereas peripheral oscillators are phase entrained by a multitude of systemic signalling pathways. These include pathways depending on feeding–fasting cycles, cellular actin polymerization dynamics, endocrine rhythms and, surprisingly, body temperature oscillations. Using tissue culture and murine models, Steve Brown was the first one to demonstrate that shallow rhythms of mammalian body temperature are timing cues (zeitgebers) for peripheral circadian clocks. [ABSTRACT FROM AUTHOR]

Patients with neurodevelopmental disorders, such as autism spectrum disorder, often display abnormal circadian rhythms. The role of the circadian system in these disorders has gained considerable attention over the last decades. Yet, it remains largely unknown how these disruptions occur and to what extent they contribute to the disorders' development. In this review, we examine circadian system dysregulation as observed in patients and animal models of neurodevelopmental disorders. Second, we explore whether circadian rhythm disruptions constitute a risk factor for neurodevelopmental disorders from studies in humans and model organisms. Lastly, we focus on the impact of psychiatric medications on circadian rhythms and the potential benefits of chronotherapy. The literature reveals that patients with neurodevelopmental disorders display altered sleep–wake cycles and melatonin rhythms/levels in a heterogeneous manner, and model organisms used to study these disorders appear to support that circadian dysfunction may be an inherent characteristic of neurodevelopmental disorders. Furthermore, the pre‐clinical and clinical evidence indicates that circadian disruption at the environmental and genetic levels may contribute to the behavioural changes observed in these disorders. Finally, studies suggest that psychiatric medications, particularly those prescribed for attention‐deficit/hyperactivity disorder and schizophrenia, can have direct effects on the circadian system and that chronotherapy may be leveraged to offset some of these side effects. This review highlights that circadian system dysfunction is likely a core pathological feature of neurodevelopmental disorders and that further research is required to elucidate this relationship. [ABSTRACT FROM AUTHOR]

The circadian clock orchestrates many physiological and behavioural rhythms in mammals with 24‐h periodicity, through a hierarchical organisation, with the central clock located in the suprachiasmatic nucleus (SCN) in the hypothalamus. The circuits of the SCN generate circadian rhythms with precision, relying on intrinsic coupling mechanisms, for example, neurotransmitters like arginine vasopressin (AVP), vasoactive intestinal peptide (VIP), neuronal gamma‐aminobutyric acid (GABA) signalling and astrocytes connected by gap junctions composed of connexins (Cx). In female rodents, the presence of estrogen receptors (ERs) in the dorsal SCN suggests an influence of estrogen (E2) on the circuit timekeeping that could regulate circadian rhythm and coupling. To investigate this, we used SCN explants together with hypothalamic neurons and astrocytes. First, we showed that E2 stabilised the circadian amplitude in the SCN when rAVPs (receptor‐associated vasopressin peptides) were inhibited. However, the phase delay induced by VIPAC2 (VIP receptors) inhibition remained unaffected by E2. We then showed that E2 exerted its effects in the SCN via ERβ (estrogen receptor beta), resulting in increased expression of Cx36 and Cx43. Notably, specific inhibition of both connexins resulted in a significant reduction in circadian amplitude within the SCN. Remarkably, E2 restored the period with inhibited Cx36 but not with Cx43 inhibition. This implies that the network between astrocytes and neurons, responsible for coupling in the SCN, can be reinforced through E2. In conclusion, these findings provide new insights into how E2 regulates circadian rhythms ex vivo in an ERβ‐dependent manner, underscoring its crucial role in fortifying the SCN's rhythm. [ABSTRACT FROM AUTHOR]

Temporal alignment of neural activity to rhythmic stimulation has been suggested to result from a resonating internal neural oscillator mechanism, but can also be explained by interval‐based temporal prediction. Here, we investigate behavioural and brain responses in the post‐stimulation period to compare an oscillatory versus an interval‐based account. Hickok et al.'s (2015) behavioural paradigm yielded results that relate to a neural oscillatory entrainment mechanism. We adapted the paradigm to an event‐related potential (ERP) suitable design: a periodic sequence was followed, in half of the trials, by near‐threshold targets embedded in noise. The targets were played in various phases in relation to the preceding sequences' period. Participants had to detect whether targets were played or not, and their EEG was recorded. Both behavioural results and the P300 component of the ERP were not only partially consistent with an oscillatory mechanism but also partially consistent with an interval‐based attentional gain mechanism. Instead, data obtained in the post‐entrainment period can best be explained with a combination of both mechanisms. [ABSTRACT FROM AUTHOR]

Although it is well recognized that the circadian timing system profoundly influences cognitive performance, the underlying molecular mechanisms remain poorly defined. Our previous work has found that the mitogen‐activated protein kinase‐interacting kinase (MNK)‐eukaryotic translation initiation factor 4E (eIF4E) axis, a conserved cellular signalling pathway regulating mRNA translation, modulates the function of the suprachiasmatic nucleus (SCN), the master circadian clock. Here, with the use of a combination of genetic, biochemical and behavioural approaches, we investigated the distribution and temporal regulation of eIF4E phosphorylation in the brain and its role in regulating the diurnal oscillations of some aspects of cognition in mice. We found that activities of the MNK‐eIF4E axis, as indicated by the level of eIF4E phosphorylation at Ser209, exhibited significant circadian oscillations in a variety of brain regions, including but not limited to the prefrontal cortex, the hippocampus, the amygdala and the cerebellum. Phosphorylated eIF4E was enriched in neurons but not in astrocytes or microglia. Mice lacking eIF4E phosphorylation (eIF4ES209A/S209A) or the MNKs (Mnk1−/−,2−/−), the kinases that phosphorylate eIF4E, exhibited impaired diurnal variations of novel object recognition, object location memory, Barnes maze learning and ambulatory activities. Together, these results suggest that circadian activities of the MNK‐eIF4E axis contribute to the diurnal rhythms of some cognitive functions, highlighting a role for rhythmic translational control in circadian regulation of cognitive performance. [ABSTRACT FROM AUTHOR]

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

Although aggression has been linked to disturbances of circadian rhythm, insight into the neural substrate of this association is currently lacking. The suprachiasmatic nucleus (SCN) of the hypothalamus, the master circadian clock, is regulated by clock genes and known to influence the secretion of cortisosterone and testosterone, important hormones implicated in aggression. Here, we investigated deviations in the regulation of the locomotor circadian rhythm and hormonal levels in a mouse model of abnormal aggression. We tested aggressive BALB/cJ and control BALB/cByJ mice in the resident–intruder paradigm and compared them on their locomotor circadian rhythm during a 12 h light/12 h dark cycle and constant darkness. State (serum) corticosterone and trait (hair) corticosterone and testosterone levels were determined, and immunohistochemistry was performed to assess the expression of important clock proteins, PER1 and PER2, in the core and shell of the SCN at the start of their active phase. Compared with BALB/cByJ mice, aggressive BALB/cJ mice displayed: (1) a shorter free‐running period in constant darkness; (2) reduced state corticosterone variability between circadian peak and trough but no differences in corticosterone trait levels; (3) lower testosterone trait levels; (4) higher PER1 expression in the SCN shell with no changes in PER2 in either SCN subregion during the early dark phase. Together, these results suggest that aggressive BALB/cJ mice have disturbances in different components encompassing the circadian and hormonal cycle, emphasizing their value for future investigation of the causal relationship between SCN function, circadian clocks and aggression. [ABSTRACT FROM AUTHOR]

DmMANF, Drosophila melanogaster mesencephalic astrocyte‐derived neurotrophic factor (DmMANF) is an evolutionarily conserved orthologue of mammalian MANF. This neurotrophic factor exerts many functions in the Drosophila brain, particularly those dependent on glial cells. As we found in our earlier study, downregulation of DmMANF in glia induces degeneration of glial cells in the first optic neuropil (lamina) where DmMANF abundance is especially high. In the present study, we observed that changes in the level of DmMANF in two types of glia, astrocyte‐like glia (AlGl) and ensheathing glia (EnGl), affect activity and sleep of flies. Interestingly, a proper level of DmMANF in AlGl seems to be important in guiding processes of pigment dispersing factor (PDF)‐expressing clock neurons. This is supported by our finding that DmMANF overexpression in AlGl leads to structural changes in the architecture of the PDF‐positive arborization in the brain. Finally, we detected that DmMANF also affects rhythms in glia themselves, as circadian oscillations in expression of the catalytic α subunit of the sodium pump in the lamina epithelial glia were abolished after DmMANF silencing. DmMANF expressed in AlGl and EnGl seems to affect the activity of neurons leading to changes in behaviour. [ABSTRACT FROM AUTHOR]

The hypothalamic suprachiasmatic nucleus (SCN) is the leading circadian pacemaker in mammals, which synchronizes with environmental light through the retinohypothalamic tract (RHT). Although the SCN regulates circadian rhythms before birth, postnatal synaptic changes are needed for the RHT‐SCN pathway to achieve total functional development. However, it is unknown whether visual experience affects developmental maturation. Here, we studied the effects of constant darkness (DD) rearing on the physiology (at pre‐ and postsynaptic levels) of glutamatergic neurotransmission between RHT and SCN during postnatal development in rats. Upon recording spontaneous and evoked excitatory postsynaptic currents (EPSCs) by electrical stimulation of RHT fibers, we found that DD animals at early postnatal ages (P3–19) exhibited different frequencies of spontaneous EPSCs and lower synaptic performance (short‐term depression, release sites, and recruitment of RHT fibers) when compared with their normal light/dark (LD) counterparts. At the oldest age evaluated (P30–35), there was a synaptic response strengthening (probability of release, vesicular re‐filling rate, and reduced synaptic depression) in DD rats, which functionally equaled (or surmounted) that of LD animals. Control experiments evaluating EPSCs in ventral SCN neurons of LD rats during day and night revealed no significant differences in spontaneous or evoked EPSCs by high‐frequency trains in the RHT at any postnatal age. Our results suggest that DD conditions induce a compensatory mechanism in the glutamatergic signaling of the circadian system to increase the chances of synchronization to light at adult ages, and that the synaptic properties of RHT terminals during postnatal development are not critically influenced by environmental light. [ABSTRACT FROM AUTHOR]

Circadian rhythms are regulated by a highly conserved transcriptional/translational feedback loop that maintains approximately 24‐hr periodicity from cellular to organismal levels. Much research effort is being devoted to understanding how the outputs of the master clock affect peripheral oscillators, and in turn, numerous biological processes. Recent studies have revealed roles for circadian timing in the regulation of numerous cellular behaviours in support of complex tissue regeneration. One such role involves the interaction between the circadian clockwork and the cell cycle. The molecular mechanisms that control the cell cycle create a system of regulation that allows for high fidelity DNA synthesis, mitosis and apoptosis. In recent years, it has become clear that clock gene products are required for proper DNA synthesis and cell cycle progression, and conversely, elements of the cell cycle cascade feedback to influence molecular circadian timing mechanisms. It is through this crosstalk that the circadian system orchestrates stem cell proliferation, niche exit and control of the signalling pathways that govern differentiation and self‐renewal. In this review, we discuss the evidence for circadian control of tissue homeostasis and repair and suggest new avenues for research. [ABSTRACT FROM AUTHOR]

The circadian rhythms are endogenous rhythms of about 24 h, and are driven by the circadian clock. The clock centre locates in the suprachiasmatic nucleus. Light signals from the retina shift the circadian rhythm in the suprachiasmatic nucleus, but there is a robust part of the suprachiasmatic nucleus that causes jet lag after an abrupt shift of the environmental lighting condition. To examine the effect of attenuated circadian rhythm on the duration of jet lag, we established a transgenic rat expressing BMAL1 dominant negative form under control by mouse Prnp‐based transcriptional regulation cassette [BMAL1 DN (+)]. The transgenic rats became active earlier than controls, just after light offset. Compared to control rats, BMAL1 DN (+) rats showed smaller circadian rhythm amplitudes in both behavioural and Per2 promoter driven luciferase activity rhythms. A light pulse during the night resulted in a larger phase shift of behavioural rhythm. Furthermore, at an abrupt shift of the light‐dark cycle, BMAL1 DN (+) rat showed faster entrainment to the new light‐dark cycle compared to controls. The circadian rhythm has been regarded as a limit cycle phenomenon, and our results support the hypothesis that modification of the amplitude of the circadian limit cycle leads to alteration in the length of the phase shift. [ABSTRACT FROM AUTHOR]

Circadian rhythms are endogenous biological cycles that synchronize physiology and behaviour to promote optimal function. These ~24‐hr internal rhythms are set to precisely 24 hr daily by exposure to the sun. However, the prevalence of night‐time lighting has the potential to dysregulate these biological functions. Hospital patients may be particularly vulnerable to the consequences of light at night because of their compromised physiological state. A mouse model of stroke (middle cerebral artery occlusion; MCAO) was used to test the hypothesis that exposure to dim light at night impairs responses to a major insult. Stroke lesion size was substantially larger among animals housed in dLAN after reperfusion than animals maintained in dark nights. Mice housed in dLAN for three days after the stroke displayed increased post‐stroke anxiety‐like behaviour. Overall, dLAN amplified pro‐inflammatory pathways in the CNS, which may have exacerbated neuronal damage. Our results suggest that exposure to LAN is detrimental to stroke recovery. [ABSTRACT FROM AUTHOR]

Organisms have developed a highly conserved and tightly regulated circadian system, to adjust their daily activities to day/night cycles. This system consists of a central clock, which is located in the hypothalamic suprachiasmatic nucleus, and the peripheral clocks that are ubiquitously expressed in all tissues. Both the central and peripheral clocks communicate with each other and achieve circadian oscillations of gene expression through transcriptional/translational loops mediated by clock transcription factors. It is worth mentioning that circadian non‐transcriptional/non‐translational rhythms also occur in non‐nucleated cells. Interestingly, sex has been identified as an important factor influencing the activity of the circadian system. Indeed, several sex differences have been documented in the anatomy, physiology and pathophysiology that pertain to circadian rhythms. In this review, we present the historical milestones of understanding circadian rhythms, describe the central and peripheral components of the circadian clock system, discuss representative examples of sexual dimorphism of circadian rhythms, and present the most relevant clinical implications. [ABSTRACT FROM AUTHOR]

Shift‐work and jet‐lag–related disorders are caused by the limited flexibility of the suprachiasmatic nucleus (SCN), a master circadian clock in the hypothalamus, to adjust to new light–dark (LD) cycles. Recent findings confirmed here establish that behavioral jet lag after simulated time‐zone travel is virtually eliminated following bifurcated circadian entrainment under a novel and atypical 24‐h light:dark:light:dark (LDLD) cycle. To investigate the mechanisms of this fast resetting, we examined the oscillatory stability of the SCN and peripheral tissues in LDLD‐bifurcated mice employing the dissection procedure as a perturbing resetting stimulus. SCN, lung, liver, and adrenal tissue were extracted at times throughout the day from female and male PER2::Luciferase knock‐in mice entrained to either LDLD or a normal LD cycle. Except for adrenals, the phase of the cultured explants was more strongly set by dissection under LDLD than under normal LD. Acute bioluminescence levels of SCN explants indicate that the rhythm amplitude of PER2 is reduced and phase is altered in LDLD. Real‐time quantitative PCR suggests that amplitude and rhythmicity of canonical clock genes in the lung, liver, and kidney are also significantly reduced in LDLD in vivo. Furthermore, spatiotemporal patterns of PER2 peak time in cultured SCN were altered in LDLD. These results suggest that altered gene expression patterns in the SCN caused by bifurcation likely result in fast resetting of behavior and cultured explants, consistent with previously reported mathematical models. Thus, non‐invasive, simple light manipulations can make circadian rhythms more adaptable to abrupt shifts in the environmental LD cycle. [ABSTRACT FROM AUTHOR]

A single phase advance of the light:dark (LD) cycle can temporarily disrupt synchrony of neural circadian rhythms within the suprachiasmatic nucleus (SCN) and between the SCN and peripheral tissues. Compounding this, modern life can involve repeated disruptive light conditions. To model chronic disruption to the circadian system, we exposed male mice to more than a month of a 20‐hr light cycle (LD10:10), which mice typically cannot entrain to. Control animals were housed under LD12:12. We measured locomotor activity and body temperature rhythms in vivo, and rhythms of PER2::LUC bioluminescence in SCN and peripheral tissues ex vivo. Unexpectedly, we discovered strong effects of the time of dissection on circadian phase of PER2::LUC bioluminescent rhythms, which varied across tissues. White adipose tissue was strongly reset by dissection, while thymus phase appeared independent of dissection timing. Prior light exposure impacted the SCN, resulting in strong resetting of SCN phase by dissection for mice housed under LD10:10, and weak phase shifts by time of dissection in SCN from control LD12:12 mice. These findings suggest that exposure to circadian disruption may desynchronize SCN neurons, increasing network sensitivity to perturbations. We propose that tissues with a weakened circadian network, such as the SCN under disruptive light conditions, or with little to no coupling, for example, some peripheral tissues, will show increased resetting effects. In particular, exposure to light at inconsistent circadian times on a recurring weekly basis disrupts circadian rhythms and alters sensitivity of the SCN neural pacemaker to dissection time. [ABSTRACT FROM AUTHOR]

Per‐Arnt‐Sim (PAS) domain‐containing proteins are critical to homeostatic regulatory networks that mediate responsiveness to environmental change. PAS domains are multifunctional structural motifs that allow protein‐protein interactions amongst family members, typically forming heterodimeric transcription factors to affect the transcription of target genes. Prototypical PAS domain‐dependent pathways include the circadian clock network and metabolic regulation of the xenobiotic response through the aryl hydrocarbon receptor (AhR). Both pathways are increasingly linked to health, and alteration in their function contributes to development of disease. The AhR demonstrates promiscuity in ligand binding and selectivity during heterodimer formation, which allows varied combinations of protein‐protein interactions with other Per‐Arnt‐Sim (PAS) domain‐containing proteins and crosstalk amongst signalling pathways, including the molecular clockworks. AhR and the circadian signalling pathways are highly integrated and reciprocally regulated. AhR exhibits a rhythmic expression and time‐dependent sensitivity to activation by AhR agonists. Conversely, AhR influences amplitude and phase of rhythms in circadian clock genes, hormones, and behaviour. Understanding the molecular interactions between AhR and the clock provides insight into physiological regulation of rhythmic processes and provides an innovative approach to development of therapeutics. [ABSTRACT FROM AUTHOR]

Disruption to sleep and circadian rhythms can impact on metabolism. The study aimed to investigate the effect of acute sleep deprivation on plasma melatonin, cortisol and metabolites, to increase understanding of the metabolic pathways involved in sleep/wake regulation processes. Twelve healthy young female participants remained in controlled laboratory conditions for ~92 hr with respect to posture, meals and environmental light (18:00–23:00 hr and 07:00‐09:00 hr <8 lux; 23:00–07:00 hr 0 lux (sleep opportunity) or <8 lux (continuous wakefulness); 09:00–18:00 hr ~90 lux). Regular blood samples were collected for 70 hr for plasma melatonin and cortisol, and targeted liquid chromatography–mass spectrometry metabolomics. Timepoints between 00:00 and 06:00 hr for day 1 (baseline sleep), day 2 (sleep deprivation) and day 3 (recovery sleep) were analysed. Cosinor analysis and MetaCycle analysis were performed for detection of rhythmicity. Night‐time melatonin levels were significantly increased during sleep deprivation and returned to baseline levels during recovery sleep. No significant differences were observed in cortisol levels. Of 130 plasma metabolites quantified, 41 metabolites were significantly altered across the study nights, with the majority decreasing during sleep deprivation, most notably phosphatidylcholines. In cosinor analysis, 58 metabolites maintained their rhythmicity across the study days, with the majority showing a phase advance during acute sleep deprivation. This observation differs to that previously reported for males. Our study is the first of metabolic profiling in females during sleep deprivation and recovery sleep, and offers a novel view of human sleep/wake regulation and sex differences. [ABSTRACT FROM AUTHOR]

Mood disorders are often characterised by alterations in circadian rhythms, sleep disturbances and seasonal exacerbation. Conversely, chronobiological treatments utilise zeitgebers for circadian rhythms such as light to improve mood and stabilise sleep, and manipulations of sleep timing and duration as rapid antidepressant modalities. Although sleep deprivation ("wake therapy") can act within hours, and its mood‐elevating effects be maintained by regular morning light administration/medication/earlier sleep, it has not entered the regular guidelines for treating affective disorders as a first‐line treatment. The hindrances to using chronotherapeutics may lie in their lack of patentability, few sponsors to carry out large multi‐centre trials, non‐reimbursement by medical insurance and their perceived difficulty or exotic "alternative" nature. Future use can be promoted by new technology (single‐sample phase measurements, phone apps, movement and sleep trackers) that provides ambulatory documentation over long periods and feedback to therapist and patient. Light combinations with cognitive behavioural therapy and sleep hygiene practice may speed up and also maintain response. The urgent need for new antidepressants should hopefully lead to reconsideration and implementation of these non‐pharmacological methods, as well as further clinical trials. We review the putative neurochemical mechanisms underlying the antidepressant effect of sleep deprivation and light therapy, and current knowledge linking clocks and sleep with affective disorders: neurotransmitter switching, stress and cortico‐limbic reactivity, clock genes, cortical neuroplasticity, connectomics and neuroinflammation. Despite the complexity of multi‐system mechanisms, more insight will lead to fine tuning and better application of circadian and sleep‐related treatments of depression. [ABSTRACT FROM AUTHOR]

Aging leads to changes in circadian rhythms, including decreased amplitude or robustness, altered synchrony with the environment, and reduced coordination of rhythms within body. These circadian rhythm alterations are more pronounced in age‐associated neurodegenerative disorders such as Alzheimer's disease (AD), in which they often precede the onset of other symptoms by many years. As well as their early onset, the findings that fragmentation of daily rest‐activity rhythms in non‐demented older subjects is associated earlier cognitive decline, increased risk of incident AD, and preclinical AD neuropathology, suggest that circadian rhythm disruption may contribute to the development and progression of the neuropathological changes occurring in AD. Conversely, other studies have implicated amyloid‐beta, a prominent neurotoxin that accumulates in AD, in the impairment of circadian rhythms. Thus, circadian rhythm disruption and AD‐associated neurodegeneration may interact to form a deleterious cycle. This article reviews the neural and molecular mechanisms underlying the age‐ and AD‐related changes in circadian rhythms. It also explores therapeutic strategies proposed to ameliorate circadian rhythm deficits in elderly and demented individuals. [ABSTRACT FROM AUTHOR]

In mammals, the central pacemaker that coordinates 24‐hr rhythms is located in the suprachiasmatic nucleus (SCN). Individual neurons of the SCN have a molecular basis for rhythm generation and hence, they function as cell autonomous oscillators. Communication and synchronization among these neurons are crucial for obtaining a coherent rhythm at the population level, that can serve as a pace making signal for brain and body. Hence, the ability of single SCN neurons to produce circadian rhythms is equally important as the ability of these neurons to synchronize one another, to obtain a bona fide pacemaker at the SCN tissue level. In this chapter we will discuss the mechanisms underlying synchronization, and plasticity herein, which allows adaptation to changes in day length. Furthermore, we will discuss deterioration in synchronization among SCN neurons in aging, and gain in synchronization by voluntary physical activity or exercise. [ABSTRACT FROM AUTHOR]

Circadian rhythm disorders have been classically associated with disorders of abnormal timing of the sleep–wake cycle, however circadian dysfunction can play a role in a wide range of pathology, ranging from the increased risk for cardiometabolic disease and malignancy in shift workers, prompting the need for a new field focused on the larger concept of circadian medicine. The relationship between circadian disruption and human health is bidirectional, with changes in circadian amplitude often preceding the classical symptoms of neurodegenerative disorders. As our understanding of the importance of circadian dysfunction in disease grows, we need to develop better clinical techniques for identifying circadian rhythms and also develop circadian based strategies for disease management. Overall this review highlights the need to bring the concept of time to all aspects of medicine, emphasizing circadian medicine as a prime example of both personalized and precision medicine. [ABSTRACT FROM AUTHOR]

Circadian clocks are widespread among eukaryotes and generally involve feedback loops coupled with metabolic processes and redox balance. The organising power of these oscillations has not only allowed organisms to anticipate day–night cycles, but also acts to temporally compartmentalise otherwise incompatible processes, enhance metabolic efficiency, make the system more robust to noise and propagate signals among cells. While daily rhythms and the function of the circadian transcription‐translation loop have been the subject of extensive research over the past four decades, cycles of shorter period and respiratory oscillations, with which they are intertwined, have received less attention. Here, we describe features of yeast respiratory oscillations, which share many features with daily and 12 hr cellular oscillations in animal cells. This relatively simple system enables the analysis of dynamic rhythmic changes in metabolism, independent of cellular oscillations that are a product of the circadian transcription‐translation feedback loop. Knowledge gained from studying ultradian oscillations in yeast will lead to a better understanding of the basic mechanistic principles and evolutionary origins of oscillatory behaviour among eukaryotes. [ABSTRACT FROM AUTHOR]

Behaviors, such as sleeping, foraging, and learning, are controlled by different regions of the rat brain, yet they occur rhythmically over the course of day and night. They are aligned adaptively with the day‐night cycle by an endogenous circadian clock in the suprachiasmatic nucleus (SCN), but local mechanisms of rhythmic control are not established. The SCN expresses a ~24‐hr oscillation in reduction‐oxidation that modulates its own neuronal excitability. Could circadian redox oscillations control neuronal excitability elsewhere in the brain? We focused on the CA1 region of the rat hippocampus, which is known for integrating information as memories and where clock gene expression undergoes a circadian oscillation that is in anti‐phase to the SCN. Evaluating long‐term imaging of endogenous redox couples and biochemical determination of glutathiolation levels, we observed oscillations with a ~24 hr period that is 180° out‐of‐phase to the SCN. Excitability of CA1 pyramidal neurons, primary hippocampal projection neurons, also exhibits a rhythm in resting membrane potential that is circadian time‐dependent and opposite from that of the SCN. The reducing reagent glutathione rapidly and reversibly depolarized the resting membrane potential of CA1 neurons; the magnitude is time‐of‐day‐dependent and, again, opposite from the SCN. These findings extend circadian redox regulation of neuronal excitability from the SCN to the hippocampus. Insights into this system contribute to understanding hippocampal circadian processes, such as learning and memory, seizure susceptibility, and memory loss with aging. [ABSTRACT FROM AUTHOR]

Circadian rhythms are generated in mammals by a central clock located in the suprachiasmatic nucleus of the hypothalamus, which regulates the homeostasis of many biological processes. At the molecular level, the regulation of circadian rhythms is under the control of transcriptional‐translational feedback loops composed of clock factors, including transcription factors. In the brain, synaptic plasticity has been shown to vary with a 24‐h rhythm. Also, when measured at a given time‐of‐day, synaptic plasticity has been observed to be disrupted by dysregulation of clock factors. This could suggest a regulation of synaptic functions by the clock machinery. Interestingly, many studies provide support for direct and indirect transcriptional regulation by core clock factors, including rhythmic gene expression, for a variety of synaptic components. Indeed, the gene of several neuropeptides, neurotransmitter regulators, receptors and transporters, ion channels, vesicle proteins, and adhesion and scaffolding molecules present evidence to be clock‐controlled. We here present, while considering different regions of the mammalian brain, an overview of the extent of the transcriptional control of synaptic components by the clock machinery. [ABSTRACT FROM AUTHOR]

Large molecular machines regulate daily cycles of transcriptional activity and help generate rhythmic behavior. In recent years, structural and biochemical analyses have elucidated a number of principles guiding the interactions of proteins that form the basis of circadian timing. In its simplest form, the circadian clock is composed of a transcription/translation feedback loop. However, this description elides a complicated process of activator recruitment, chromatin decompaction, recruitment of coactivators, expression of repressors, formation of a repressive complex, repression of the activators, and ultimately degradation of the repressors and reinitiation of the cycle. Understanding the core principles underlying the clock requires careful examination of molecular and even atomic level details of these processes. Here, we review major structural and biochemical findings in circadian biology and make the argument that shared protein interfaces within the clockwork are critical for both the generation of rhythmicity and timing of the clock. [ABSTRACT FROM AUTHOR]

A key feature of circadian rhythms is the sleep/wake cycle. Sleep causes reduced responsiveness to the environment, which puts animals in a particularly vulnerable state; yet sleep has been conserved throughout evolution, indicating that it fulfils a vital purpose. A core function of sleep across species has not been identified, but substantial advances in sleep research have been made in recent years using the genetically tractable model organism, Drosophila melanogaster. This review describes the universality of sleep, the regulation of sleep, and current theories on the function of sleep, highlighting a historical and often overlooked theory called the Free Radical Flux Theory of Sleep. Additionally, we summarize our recent work with short‐sleeping Drosophila mutants and other genetic and pharmacological tools for manipulating sleep which supports an antioxidant theory of sleep and demonstrates a bi‐directional relationship between sleep and oxidative stress. [ABSTRACT FROM AUTHOR]

Adult rabbits show robust circadian rhythms of: nursing, food and water intake, hard faeces excretion, locomotion, body temperature, blood and intraocular pressure, corticosteroid secretion, and sleep. Control of several circadian rhythms involves a light‐entrained circadian clock and a food‐entrained oscillator. Nursing periodicity, however, relies on a suckling stimulation threshold. Brain structures regulating this activity include the paraventricular nucleus and preoptic area, as determined by lesions and quantification of cFOS‐ and PER1 clock gene‐immunoreactive proteins. Melatonin synthesis in the rabbit pineal gland shows a diurnal rhythm, with highest values at night and lowest ones during the day. In kits the main zeitgeber is milk intake, which synchronizes locomotor activity, body temperature, and corticosterone secretion. Brain regions involved in these effects include the median preoptic nucleus and several olfactory structures. As models for particular human illnesses rabbits have been valuable for studying glaucoma and cardiovascular disease. Circadian variations in intraocular pressure (main risk factor for glaucoma) have been found, with highest values at night, which depend on sympathetic innervation. Rabbits fed a high fat diet develop cholesterol plaques and high blood pressure, as do humans, and such increased fat intake directly modulates cardiovascular homeostasis and circadian patterns, independently of white adipose tissue accumulation. Rabbits have also been useful to investigate the characteristics of sleep across the day and its modulation by infections, cytokines and other endogenous humoral factors. Rabbit circadian biology warrants deeper investigation of the role of the suprachiasmatic nucleus in regulating most behavioral and physiological rhythms described above. [ABSTRACT FROM AUTHOR]

Shift work, defined as work occurring outside typical daytime working hours, is associated with an increased risk of various non‐communicable diseases, including diabetes and cardiovascular disease. Disruption of the internal circadian timing system and concomitant sleep disturbances is thought to play a critical role in the development of these health problems. Indeed, controlled laboratory studies have shown that short‐term circadian misalignment and sleep restriction independently impair physiological processes, including insulin sensitivity, energy expenditure, immune function, blood pressure and cardiac modulation by the autonomous nervous system. If allowed to persist, these acute effects may lead to the development of cardiometabolic diseases in the long term. Here, we discuss the evidence for the contributions of circadian disruption and associated sleep disturbances to the risk of metabolic and cardiovascular health problems in shift workers. Improving the understanding of the physiological mechanisms affected by circadian misalignment and sleep disturbance will contribute to the development and implementation of strategies that prevent or mitigate the cardiometabolic impact of shift work. [ABSTRACT FROM AUTHOR]

The mammalian retina is the most unique tissue among those that display robust circadian/diurnal oscillations. The retina is not only a light sensing tissue that relays light information to the brain, it has its own circadian "system" independent from any influence from other circadian oscillators. While all retinal cells and retinal pigment epithelium (RPE) possess circadian oscillators, these oscillators integrate by means of neural synapses, electrical coupling (gap junctions), and released neurochemicals (such as dopamine, melatonin, adenosine, and ATP), so the whole retina functions as an integrated circadian system. Dysregulation of retinal clocks not only causes retinal or ocular diseases, it also impacts the circadian rhythm of the whole body, as the light information transmitted from the retina entrains the brain clock that governs the body circadian rhythms. In this review, how circadian oscillations in various retinal cells are integrated, and how retinal diseases affect daily rhythms. [ABSTRACT FROM AUTHOR]

Mood disorders, including major depression, bipolar disorder, and seasonal affective disorder, are debilitating disorders that affect a significant portion of the global population. Individuals suffering from mood disorders often show significant disturbances in circadian rhythms and sleep. Moreover, environmental disruptions to circadian rhythms can precipitate or exacerbate mood symptoms in vulnerable individuals. Circadian clocks exist throughout the central nervous system and periphery, where they regulate a wide variety of physiological processes implicated in mood regulation. These processes include monoaminergic and glutamatergic transmission, hypothalamic–pituitary–adrenal axis function, metabolism, and immune function. While there seems to be a clear link between circadian rhythm disruption and mood regulation, the mechanisms that underlie this association remain unclear. This review will touch on the interactions between the circadian system and each of these processes and discuss their potential role in the development of mood disorders. While clinical studies are presented, much of the review will focus on studies in animal models, which are attempting to elucidate the molecular and cellular mechanisms in which circadian genes regulate mood. [ABSTRACT FROM AUTHOR]

Dopamine has been implicated in circadian timing underlying the food entrainable oscillator (FEO) circuitry and overexpression of the dopamine D2 receptor (D2R) in the striatum has been reported to reduce motivation to obtain food rewards in operant tasks. In the present study, we explored both of these mechanisms by examining food anticipatory activity (FAA) in dopamine D2 receptor‐overexpressing (D2R‐OE) mice under various durations of food availability. First, we noted that at baseline, there were no differences between D2R‐OE mice and their littermates in activity level, food intake, and body weight or in circadian activity. Under conditions of very restricted food availability (4 or 6 hr), both genotypes displayed FAA. In contrast, under 8‐hr food availability, control mice showed FAA, but D2R‐OE mice did not. Normalization of D2R by administration of doxycycline, a tetracycline analogue, rescued FAA under 8‐hr restricted food. We next tested for circadian regulation of FAA. When given ad libitum access to food, neither D2R‐OE nor controls were active during the daytime. However, after an interval of food restriction, all mice showed elevated locomotor activity at the time of previous food availability in the day, indicating circadian timing of anticipatory activity. In summary, motivation is reduced in D2R‐OE mice but circadian timing behavior is not affected. We conclude that an increase in striatal D2R reduces FAA by modulating motivation and not by acting on a clock mechanism. [ABSTRACT FROM AUTHOR]

The mammalian circadian clock in the suprachiasmatic nucleus (SCN) is very robust, able to coordinate our daily physiological and behavioral rhythms with exquisite accuracy. Simultaneously, the SCN clock is highly sensitive to environmental timing cues such as the solar cycle. This duality of resiliency and sensitivity may be sustained in part by a complex intertwining of three cellular oscillators: transcription/translation, metabolic/redox, and membrane excitability. We suggest here that one of the links connecting these oscillators may be forged from copper (Cu). Cellular Cu levels are highly regulated in the brain and peripherally, and Cu affects cellular metabolism, redox state, cell signaling, and transcription. We have shown that both Cu chelation and application induce nighttime phase shifts of the SCN clock in vitro and that these treatments affect glutamate, N‐methyl‐D‐aspartate receptor, and associated signaling processes differently. More recently we found that Cu induces mitogen‐activated protein kinase‐dependent phase shifts, while the mechanisms by which Cu removal induces phase shifts remain unclear. Lastly, we have found that two Cu transporters are expressed in the SCN, and that one of these transporters (ATP7A) exhibits a day/night rhythm. Our results suggest that Cu homeostasis is tightly regulated in the SCN, and that changes in Cu levels may serve as a time cue for the circadian clock. We discuss these findings in light of the existing literature and current models of multiple coupled circadian oscillators in the SCN. [ABSTRACT FROM AUTHOR]

Circadian rhythms are physiological and behavioral processes that exhibit a 24‐hr cycle. These daily rhythms are essential for living organisms to align their behavior and physiology with the environment to increase the likelihood of survival. In mammals, circadian rhythms synchronize with the environment primarily by the suprachiasmatic nucleus, a hypothalamic brain region that integrates exogenous and endogenous timing cues. Sex steroid hormones, including estrogens, are thought to modulate sexually dimorphic behaviors through developmental programming of the brain (i.e., organization), as well as acute receptor signaling during adulthood (i.e., activation). Importantly, there are known sex differences in the expression of circadian locomotor activity and molecular organization of the suprachiasmatic nucleus, likely due, in part, to the actions of circulating estrogens. Circadian locomotor rhythms, which are coordinated by the suprachiasmatic nucleus, have been shown to be regulated by developmental and adult levels of circulating estrogens. Further, increasing evidence suggests that estrogens can modulate expression of circadian clock genes that are essential for orchestration of circadian rhythms by the suprachiasmatic nucleus. In this review, we will discuss the organizational and activational modulation of the circadian timekeeping system by estrogens through estrogen receptor signaling. [ABSTRACT FROM AUTHOR]

The temporal niche that an animal occupies includes a coordinated suite of behavioral and physiological processes that set diurnal and nocturnal animals apart. The daily rhythms of the two chronotypes are regulated by both the circadian system and direct responses to light, a process called masking. Here we review the literature on circadian regulations and masking responses in diurnal mammals, focusing on our work using the diurnal Nile grass rat (Arvicanthis niloticus) and comparing our findings with those derived from other diurnal and nocturnal models. There are certainly similarities between the circadian systems of diurnal and nocturnal mammals, especially in the phase and functioning of the principal circadian oscillator within the hypothalamic suprachiasmatic nucleus (SCN). However, the downstream pathways, direct or indirect from the SCN, lead to drastic differences in the phase of extra‐SCN oscillators, with most showing a complete reversal from the phase seen in nocturnal species. This reversal, however, is not universal and in some cases the phases of extra‐SCN oscillators are only a few hours apart between diurnal and nocturnal species. The behavioral masking responses in general are opposite between diurnal and nocturnal species, and are matched by differential responses to light and dark in several retinorecipient sites in their brain. The available anatomical and functional data suggest that diurnal brains are not simply a phase‐reversed version of nocturnal ones, and work with diurnal models contribute significantly to a better understanding of the circadian and photic modulation of daily rhythms in our own diurnal species. [ABSTRACT FROM AUTHOR]

A central question in the circadian biology field concerns the mechanisms that translate ~24‐hr oscillations of the molecular clock into overt rhythms. Drosophila melanogaster is a powerful system that provided the first understanding of how molecular clocks are generated and is now illuminating the neural basis of circadian behavior. The identity of ~150 clock neurons in the Drosophila brain and their roles in shaping circadian rhythms of locomotor activity have been described before. This review summarizes mechanisms that transmit time‐of‐day signals from the clock, within the clock network as well as downstream of it. We also discuss the identification of functional multisynaptic circuits between clock neurons and output neurons that regulate locomotor activity. [ABSTRACT FROM AUTHOR]

Neurons of the hypothalamic suprachiasmatic nucleus (SCN) express clock genes, which regulate their own transcription and generate daily output signals driving circadian rhythmic behavior and physiology. The neuropeptide VIP and its specific receptor, the VPAC2 receptor, are important for synchronization of clock neurons. In the present study, we characterized PER1 and PER2 expressing neurons in wild‐type and VPAC2‐deficient mice. We found evidence for distinct spatiotemporal circadian oscillation in the expression of the PER genes in two separate clusters of SCN neurons. In wild‐type mice corresponding to the SCN shell and ventral core, high expression of PER was found at lights‐off most likely representing an evening clock (E‐clock). In another smaller cluster of neurons located in the central core of the SCN, PER expression peaks in antiphase at lights‐on and could represent a morning clock (M‐clock). BMAL1 immunoreactivity was found to be expressed in antiphase to PER in M and E neurons, respectively. PER was found in 98% of neurons expressing vasopressin (AVP) and in 92% of VIP neurons. The chemotype of M neurons was not identified. M but not E cells were responsive to long but not short photoperiods. The expression of the VPAC2 receptor was found in both M and E cells, and VPAC2‐deficient mice displayed markedly blunted PER expression in both cell clusters of the SCN. Conclusion: These observations support the existence of M and E clocks involved in circadian and seasonal adaptation, which seem dependent on intact VIP/VPAC2 signaling in the SCN. [ABSTRACT FROM AUTHOR]

Mammalian circadian rhythms are entrained by photic stimuli that are relayed by retinal projections to the core of the suprachiasmatic nucleus (SCN). Neuronal activation, as demonstrated by expression of the immediate early gene c‐fos, leads to transcription of the core clock gene per1. The duper mutation in hamsters shortens circadian period and amplifies light‐induced phase shifts. We performed two experiments to compare the number of c‐FOS immunoreactive (ir) and PER1‐ir cells, and the intensity of staining, in the SCN of wild‐type (WT) and duper hamsters at various intervals after presentation of a 15‐min light pulse in the early subjective night. Light‐induced c‐FOS‐ir within 1 hr in the dorsocaudal SCN of duper, but not WT hamsters. In cells that express vasoactive intestinal peptide (VIP), which plays a critical role in synchronization of SCN cellular oscillators, light‐induced c‐FOS‐ir was greater in duper than WT hamsters. After the light pulse, PER1‐ir cells were found in more medial portions of the SCN than FOS‐ir, and appeared with a longer latency and over a longer time course, in VIP cells of duper than wild‐type hamsters. Our results indicate that the duper allele alters SCN function in ways that may contribute to changes in free running period and phase resetting. Duper mutant hamsters have a fast circadian clock and enhanced phase delays in response to a light pulse delivered in the early subjective night (Circadian Time 15). Top, the light signal is relayed from the eye to the suprachiasmatic nucleus (SCN), which serves as a master pacemaker. Subordinate circadian oscillators in other brain areas, including the paraventricular nucleus (PVN), adjust their phase in response to SCN input. As a result, behavioral rhythms show a phase delay (horizontal red arrow) that is greater in duper (middle panel) than wild‐type (bottom panel) hamsters. Resetting of the pacemaker of mutant hamsters differs from that in wild type: dupers show increased activation (as reflected by greater c‐FOS immunoreactivity) and clock gene expression (as reflected by PER1 immunoreactivity) in the ventral core (green) and dorsal shell (blue) neurons of the SCN at various time points sampled after the light pulse (vertical arrows). Activation of VIP neurons of the core SCN is specifically affected by the duper mutation. [ABSTRACT FROM AUTHOR]

Artificial light at night induces circadian disruptions and causes cognitive impairment and mood disorders; yet very little is known about the neural and molecular correlates of these effects in diurnal animals. We manipulated the night environment and examined cellular and molecular changes in hippocampus, the brain region involved in cognition and mood, of Indian house crows (Corvus splendens) exposed to 12 hr light (150 lux): 12 hr darkness (0 lux). Diurnal corvids are an ideal model species with cognitive abilities at par with mammals. Dim light (6 lux) at night (dLAN) altered daily activity:rest pattern, reduced sleep, and induced depressive‐like responses (decreased eating and self‐grooming, self‐mutilation, and reduced novel object exploration); return to an absolute dark night reversed these negative effects. dLAN suppressed nocturnal melatonin levels; however, diurnal corticosterone levels were unaffected. Concomitant reduction of immunoreactivity for DCX and BDNF suggested dLAN‐induced suppression of hippocampal neurogenesis and compromised neuronal health. dLAN also negatively influenced hippocampal expression of genes associated with depressive‐like responses (bdnf, il‐1β, tnfr1, nr4a2), but not of those associated with neuronal plasticity (egr1, creb, syngap, syn2, grin2a, grin2b), cellular oxidative stress (gst, sod3, cat1) and neuronal death (caspase2, caspase3, foxo3). Furthermore, we envisaged the role of BDNF and showed epigenetic modification of bdnf gene by decreased histone H3 acetylation and increased hdac4 expression under dLAN. These results demonstrate transcriptional and epigenetic bases of dLAN‐induced negative effects in diurnal crows, and provide insights into the risks of exposure to illuminated nights to animals including humans in an urban setting. Artificial light at night induces cognitive impairment and mood disorders. We manipulated the night environment and examined cellular and molecular changes in the hippocampus of Indian house crows exposed to 12 hr light (150 lux): 12 hr darkness (0 or 6 lux). Our results demonstrate dLAN‐induced negative effects on BDNF expression and hippocampal neurogenesis in diurnal crows, and suggest an epigenetic modification of bdnf gene by increased hdac4 expression and decreased histone H3 acetylation. [ABSTRACT FROM AUTHOR]

Neuronal oscillations of the brain, such as those observed in the cortices and hippocampi of behaving animals and humans, span across wide frequency bands, from slow delta waves (0.1 Hz) to ultra‐fast ripples (600 Hz). Here, we focus on ultra‐slow neuronal oscillators in the hypothalamic suprachiasmatic nuclei (SCN), the master daily clock that operates on interlocking transcription‐translation feedback loops to produce circadian rhythms in clock gene expression with a period of near 24 h (< 0.001 Hz). This intracellular molecular clock interacts with the cell's membrane through poorly understood mechanisms to drive the daily pattern in the electrical excitability of SCN neurons, exhibiting an up‐state during the day and a down‐state at night. In turn, the membrane activity feeds back to regulate the oscillatory activity of clock gene programs. In this review, we emphasise the circadian processes that drive daily electrical oscillations in SCN neurons, and highlight how mathematical modelling contributes to our increasing understanding of circadian rhythm generation, synchronisation and communication within this hypothalamic region and across other brain circuits. Neuronal oscillations of the brain span across wide frequency bands. Here, we focus on the ultra‐slow neuronal oscillators in the mammalian master clock, the suprachiasmatic nuclei (SCN). We emphasise the circadian processes driving daily oscillations in SCN neurons, discuss SCN oscillations in the context of brain‐wide oscillators, and highlight how mathematical modelling contributes to our increasing understanding of circadian rhythm generation, synchronisation and communication across brain circuits. [ABSTRACT FROM AUTHOR]

The suprachiasmatic nucleus (SCN) is a collection of about 10 000 neurons, each of which functions as a circadian clock with slightly different periods and phases, that work in concert with form and maintain the master circadian clock for the organism. The diversity among neurons confers on the SCN the ability to robustly encode both the 24‐h light pattern as well as the seasonal time. Cluster synchronization brings the different neurons into line and reduces the large population to essentially two oscillators, coordinated by a macroscopic network motif of asymmetric repulsive‐attractive coupling. We recount the steps leading to this simplification and rigorously examine the two‐oscillator case by seeking an analytical solution. Through these steps, we identify physiologically relevant parameters that shape the behaviour of the SCN network and delineate its ability to store past details of seasonal variation in photoperiod. Asymmetric GABA excitation and inhibition can lead to two clusters of circadian oscillators in the SCN. In the phase oscillator formalism, its network dynamics can be summarized by phase attraction of the ventral SCN (oscillator V) towards the dorsal SCN (oscillator D) and phase repulsion on the oscillator D by the oscillator V. The two‐oscillator model explains seasonal encoding in the SCN, but with mathematically definable limits. [ABSTRACT FROM AUTHOR]

Abstract: Nuclear receptor subfamily 1, group D, member 1 (Nr1d1) (also known as Rev‐erb alpha) has been linked to circadian rhythm regulation, mood‐related behaviour and disorders associated with social deficits. Recent work from our laboratory found striking decreases in Nr1d1 in the nucleus accumbens (NAc) in the maternal condition and indirect evidence that Nr1d1 was interacting with numerous addiction and reward‐related genes to modulate social reward. In this study, we applied our insights from the maternal state to nonparental adult mice to determine whether decreases in Nr1d1 expression in the NAc via adeno‐associated viral (AAV) vectors and short hairpin RNA (shRNA)‐mediated gene knockdown were sufficient to modulate social behaviours and mood‐related behaviours. Knockdown of Nr1d1 in the NAc enhanced sociability and reduced anxiety, but did not affect depressive‐like traits in female mice. In male mice, Nr1d1 knockdown had no significant behavioural effects. Microarray analysis of Nr1d1 knockdown in females identified changes in circadian rhythm and histone deacetylase genes and suggested possible drugs, including histone deacetylase inhibitors, that could mimic actions of Nr1d1 knockdown. Quantitative real‐time PCR (qPCR) analysis confirmed expression upregulation of gene period circadian clock 1 (Per1) and period circadian clock 2 (Per2) with Nr1d1 knockdown. The evidence for roles for opioid‐related genes opioid receptor, delta 1 (Oprd1) and preproenkephalin (Penk) was also found. Together, these results suggest that Nr1d1 in the NAc modulates sociability and anxiety‐related behaviour in a sex‐specific manner, and circadian, histone deacetylase and opioid‐related genes may be involved in the expression of these behavioural phenotypes. [ABSTRACT FROM AUTHOR]

Abstract: A total of 668 single units were recorded in the mouse periaqueductal gray (PAG) and adjacent deep mesencephalic nucleus (DpMe) to determine their role in the switching of sleep–wake states, that is, wakefulness (W), slow‐wave sleep (SWS) and paradoxical (or rapid eye movement) sleep (PS) in general, and, in particular, to determine whether PS‐on and PS‐off neurons involved in PS state switching are present in these structures and to identify neuronal substrates for the SWS‐PS switching mediated by DpMe neurons. Both structures were found to contain similar percentages of W/PS‐active neurons, which discharge at a higher rate during W and PS than during SWS, while W‐active neurons, which discharge maximally during W, were found mainly in the PAG. Both also contained similar percentages of SWS/PS‐active neurons, which discharge at higher rates during SWS and PS than during W, and PS‐active neurons, which discharge maximally during PS, while SWS‐active neurons, which discharge maximally during SWS, were found almost exclusively in the PAG. Both structures contained virtually no PS‐on or PS‐off neurons, which, respectively, discharge or cease firing selectively and tonically just prior to, and during, PS. Unlike the PAG, the DpMe contained many SWS/PS‐on neurons, which discharge selectively at high rates during SWS and PS, but show a decrease in discharge rate at the transition from SWS to PS. Analysis of discharge profiles and trends in spike activity at the state transitions strongly suggests that PAG and DpMe neurons play an important role in the W‐SWS, SWS‐PS and/or PS‐W switches. [ABSTRACT FROM AUTHOR]

Abstract: In the Madeira cockroach, pigment‐dispersing factor‐immunoreactive (PDF‐ir) neurons innervating the circadian clock, the accessory medulla (AME) in the brain′s optic lobes, control circadian behaviour. Circadian activity rhythms are entrained to daily light–dark cycles only by compound eye photoreceptors terminating in the lamina and medulla. Still, it is unknown which neurons connect the photoreceptors to the clock to allow for light entrainment. Here, we characterized by multiple‐label immunocytochemistry the serotonin (5‐HT)‐ir anterior fibre fan and GABA‐ir pathways connecting the AME‐ and optic lobe neuropils. Colocalization of 5‐HT with PDF was confirmed in PDF‐ir lamina neurons (PDFLAs). Double‐labelled fibres were traced to the AME originating from colabelled PDFLAs branching in accessory laminae and proximal lamina. The newly discovered GABA‐ir medial layer fibre tract connected the AME to the medulla′s medial layer fibre system, and the distal tract fibres connected the AME to the medulla. With Ca2+ imaging on primary cell cultures of the AME and with loose‐patch‐clamp recordings in vivo, we showed that both neurotransmitters either excite or inhibit AME clock neurons. Because we found no colocalization of GABA and 5‐HT in any optic lobe neuron, GABA‐ and 5‐HT neurons form separate clock input circuits. Among others, both pathways converged also on AME neurons that coexpressed mostly inhibitory GABA‐ and excitatory 5‐HT receptors. Our physiological and immunocytochemical studies demonstrate that GABA‐ and 5‐HT‐immunoreactive neurons constitute parallel excitatory or inhibitory pathways connecting the circadian clock either to the lamina or medulla where photic information from the compound eye is processed. [ABSTRACT FROM AUTHOR]

The mammalian circadian clock is synchronized to the day : night cycle by light. Serotonin modulates the circadian effects of light, with agonists inhibiting response to light and antagonists enhancing responses to light. A special class of serotonergic compounds, the mixed 5- HT1A agonist/antagonists, potentiates light-induced phase advances by up to 400% when administered acutely. In this study, we examine the effects of one of these mixed 5- HT1A agonist/antagonists, BMY7378, when administered chronically. Thirty adult male hamsters were administered either vehicle or BMY7378 via surgically implanted osmotic mini pumps over a period of 28 days. In a light : dark cycle, chronic BMY7378 advanced the phase angle of entrainment, prolonged the duration of the active phase and attenuated the amplitude of the wheel-running rhythm during the early night. In constant darkness, chronic treatment with BMY7378 significantly attenuated light-induced phase advances, but had no significant effect on light-induced phase delays. Non-photic phase shifts to daytime administration of a 5- HT1A/7 agonist were also attenuated by chronic BMY7378 treatment. qRT- PCR analysis revealed that chronic BMY7378 treatment upregulated mRNA for 5- HT1A and 5- HT1B receptors in the hypothalamus and downregulated mRNA for 5- HT1A and monoamine oxidase-A in the brainstem. These results highlight adaptive changes of serotonin receptors in the brain to chronic treatment with BMY7378 and link such up- and downregulation to changes in important circadian parameters. Such long-term changes to the circadian system should be considered when patients are treated chronically with drugs that alter serotonergic function. [ABSTRACT FROM AUTHOR]