Clock In Suprachiasmatic Nucleus Research Articles

Light sets the brain's daily clock by regional quickening and slowing of the molecular clockworks at dawn and dusk.

How daily clocks in the brain are set by light to local environmental time and encode the seasons is not fully understood. The suprachiasmatic nucleus (SCN) is a central circadian clock in mammals that orchestrates physiology and behavior in tune with daily and seasonal light cycles. Here, we have found that optogenetically simulated light input to explanted mouse SCN changes the waveform of the molecular clockworks from sinusoids in free-running conditions to highly asymmetrical shapes with accelerated synthetic (rising) phases and extended degradative (falling) phases marking clock advances and delays at simulated dawn and dusk. Daily waveform changes arise under ex vivo entrainment to simulated winter and summer photoperiods, and to non-24 hr periods. Ex vivo SCN imaging further suggests that acute waveform shifts are greatest in the ventrolateral SCN, while period effects are greatest in the dorsomedial SCN. Thus, circadian entrainment is encoded by SCN clock gene waveform changes that arise from spatiotemporally distinct intrinsic responses within the SCN neural network.

Vasopressin Resets the Central Circadian Clock in a Manner Influenced by Sex and Vasoactive Intestinal Polypeptide Signaling

Background/Aims: Circadian rhythms in behavior and physiology are programmed by the suprachiasmatic nucleus (SCN) of the hypothalamus. A subset of SCN neurons produce the neuropeptide arginine vasopressin (AVP), but it remains unclear whether AVP signaling influences the SCN clock directly. Methods: Here, we test that AVP signaling acting through V1A and V1B receptors influences molecular rhythms in SCN neurons. V1 receptor agonists were applied ex vivo to PERIOD2::LUCIFERASE SCN slices, allowing for real-time monitoring of changes in molecular clock function. Results: V1A/B agonists reset the phase of the SCN molecular clock in a time-dependent manner, with larger magnitude responses by the female SCN. Further, we found evidence that both G_αq and G_αs signaling pathways interact with V1A/B-induced SCN resetting, and that this response requires vasoactive intestinal polypeptide (VIP) signaling. Conclusions: Collectively, this work indicates that AVP signaling resets SCN molecular rhythms in conjunction with VIP signaling and in a manner influenced by sex. This highlights the utility of studying clock function in both sexes and suggests that signal integration in central clock circuits regulates emergent properties important for the control of daily rhythms in behavior and physiology.

Identification of the suprachiasmatic nucleus venous portal system in the mammalian brain

There is only one known portal system in the mammalian brain - that of the pituitary gland, first identified in 1933 by Popa and Fielding. Here we describe a second portal pathway in the mouse linking the capillary vessels of the brain’s clock suprachiasmatic nucleus (SCN) to those of the organum vasculosum of the lamina terminalis (OVLT), a circumventricular organ. The localized blood vessels of portal pathways enable small amounts of important secretions to reach their specialized targets in high concentrations without dilution in the general circulatory system. These brain clock portal vessels point to an entirely new route and targets for secreted SCN signals, and potentially restructures our understanding of brain communication pathways.

The Circadian Clock Is Sustained in the Thyroid Gland of VIP Receptor 2 Deficient Mice.

VIP/VPAC2-receptor signaling is crucial for functioning of the circadian clock in the suprachiasmatic nucleus (SCN) since the lack results in disrupted synchrony between SCN cells and altered locomotor activity, body temperature, hormone secretion and heart rhythm. Endocrine glands, including the thyroid, show daily oscillations in clock gene expression and hormone secretion, and SCN projections target neurosecretory hypothalamic thyroid-stimulating hormone (TSH)-releasing hormone cells. The aim of the study was to gain knowledge of mechanisms important for regulation of the thyroid clock by evaluating the impact of VIP/VPAC2-receptor signaling. Quantifications of mRNAs of three clock genes (Per1, Per2 and Bmal1) in thyroids of wild type (WT) and VPAC2-receptor deficient mice were done by qPCR. Tissues were taken every 4th h during 24-h 12:12 light-dark (LD) and constant darkness (DD) periods, both genders were used. PER1 immunoreactivity was visualized on sections of both WT and VPAC2 lacking mice during a LD cycle. Finally, TSH and the thyroid hormone T4 levels were measured in the sera by commercial ELISAs. During LD, rhythmic expression of all three mRNA was found in both the WT and knockout animals. In VPAC2-receptor knockout animals, the amplitudes were approximately halved compared to the ones in the WT mice. In the WT, Per1 mRNA peaked around “sunset”, Per2 mRNA followed with approximately 2 h, while Bmal1 mRNA was in antiphase with Per1. In the VPAC2 knockout mice, the phases of the mRNAs were advanced approximately 5 h compared to the WT. During DD, the phases of all the mRNAs were identical to the ones found during LD in both groups of mice. PER1 immunoreactivity was delayed compared to its mRNA and peaked during the night in follicular cells of both the thyroid and parathyroid glands in the WT animals. In WT animals, TSH was high around the transition to darkness compared to light-on, while T4 did not change during the 24 h cycle. In conclusion, sustained and identical rhythms (phases and amplitudes) of three clock genes were found in VPAC2 deficient mice during LD and DD suggesting high degree of independence of the thyroid clock from the master SCN clock.

Restoring the Molecular Clockwork within the Suprachiasmatic Hypothalamus of an Otherwise Clockless Mouse Enables Circadian Phasing and Stabilization of Sleep-Wake Cycles and Reverses Memory Deficits.

The timing and quality of sleep-wake cycles are regulated by interacting circadian and homeostatic mechanisms. Although the suprachiasmatic nucleus (SCN) is the principal clock, circadian clocks are active across the brain and the respective sleep-regulatory roles of SCN and local clocks are unclear. To determine the specific contribution(s) of the SCN, we used virally mediated genetic complementation, expressing Cryptochrome1 (Cry1) to establish circadian molecular competence in the suprachiasmatic hypothalamus of globally clockless, arrhythmic male Cry1/Cry2-null mice. Under free-running conditions, the rest/activity behavior of Cry1/Cry2-null controls expressing EGFP (SCNCon) was arrhythmic, whereas Cry1-complemented mice (SCNCry1) had coherent circadian behavior, comparable to that of Cry1,2-competent wild types (WTs). In SCNCon mice, sleep-wakefulness, assessed by electroencephalography (EEG)/electromyography (EMG), lacked circadian organization. In SCNCry1 mice, however, it matched WTs, with consolidated vigilance states [wake, rapid eye movement sleep (REMS) and non-REMS (NREMS)] and rhythms in NREMS δ power and expression of REMS within total sleep (TS). Wakefulness in SCNCon mice was more fragmented than in WTs, with more wake-NREMS-wake transitions. This disruption was reversed in SCNCry1 mice. Following sleep deprivation (SD), all mice showed a homeostatic increase in NREMS δ power, although the SCNCon mice had reduced NREMS during the inactive (light) phase of recovery. In contrast, the dynamics of homeostatic responses in the SCNCry1 mice were comparable to WTs. Finally, SCNCon mice exhibited poor sleep-dependent memory but this was corrected in SCNCry1mice. In clockless mice, circadian molecular competence focused solely on the SCN rescued the architecture and consolidation of sleep-wake and sleep-dependent memory, highlighting its dominant role in timing sleep.SIGNIFICANCE STATEMENT The circadian timing system regulates sleep-wake cycles. The hypothalamic suprachiasmatic nucleus (SCN) is the principal circadian clock, but the presence of multiple local brain and peripheral clocks mean the respective roles of SCN and other clocks in regulating sleep are unclear. We therefore used virally mediated genetic complementation to restore molecular circadian functions in the suprachiasmatic hypothalamus, focusing on the SCN, in otherwise genetically clockless, arrhythmic mice. This initiated circadian activity-rest cycles, and circadian sleep-wake cycles, circadian patterning to the intensity of non-rapid eye movement sleep (NREMS) and circadian control of REMS as a proportion of total sleep (TS). Consolidation of sleep-wake established normal dynamics of sleep homeostasis and enhanced sleep-dependent memory. Thus, the suprachiasmatic hypothalamus, alone, can direct circadian regulation of sleep-wake.

Circadian rhythms in the tissue-specificity from metabolism to immunity: insights from omics studies

Creatures on earth have the capacity to preserve homeostasis in response to changing environments. The circadian clock enables organisms to adapt to daily predictable rhythms in surrounding conditions. In mammals, circadian clocks constitute hierarchical network, where the central pacemaker in hypothalamic suprachiasmatic nucleus (SCN) serves as a time-keeping machinery and governs peripheral clocks in every other organ through descending neural and humoral factors. The central clock in SCN is reset by light, whilst peripheral clocks are entrained by feeding-fasting rhythms, emphasizing the point that temporal patterns of nutrient availability specifies peripheral clock functions. Indeed, emerging evidence revealed various types of diets or timing of food intake reprogram circadian rhythms in a tissue specific manner. This advancement in understanding of mechanisms underlying tissue specific responsiveness of circadian oscillators to nutrients at the genomic and epigenomic levels is largely owing to employment of state-of-the-art technologies. Specifically, high-throughput transcriptome, proteome, and metabolome have provided insights into how genes, proteins, and metabolites behave over circadian cycles in a given tissue under a certain dietary condition in an unbiased fashion. Additionally, combinations with specialized types of sequencing such as nascent-seq and ribosomal profiling allow us to dissect how circadian rhythms are generated or obliterated at each step of gene regulation. Importantly, chromatin immunoprecipitation followed by deep sequencing methods provide chromatin landscape in terms of regulatory mechanisms of circadian gene expression. In this review, we outline recent discoveries on temporal genomic and epigenomic regulation of circadian rhythms, discussing entrainment of the circadian rhythms by feeding as a fundamental new comprehension of metabolism and immune response, and as a potential therapeutic strategy of metabolic and inflammatory diseases.

Timed daily exercise remodels circadian rhythms in mice

Regular exercise is important for physical and mental health. An underexplored and intriguing property of exercise is its actions on the body’s 24 h or circadian rhythms. Molecular clock cells in the brain’s suprachiasmatic nuclei (SCN) use electrical and chemical signals to orchestrate their activity and convey time of day information to the rest of the brain and body. To date, the long-lasting effects of regular physical exercise on SCN clock cell coordination and communication remain unresolved. Utilizing mouse models in which SCN intercellular neuropeptide signaling is impaired as well as those with intact SCN neurochemical signaling, we examined how daily scheduled voluntary exercise (SVE) influenced behavioral rhythms and SCN molecular and neuronal activities. We show that in mice with disrupted neuropeptide signaling, SVE promotes SCN clock cell synchrony and robust 24 h rhythms in behavior. Interestingly, in both intact and neuropeptide signaling deficient animals, SVE reduces SCN neural activity and alters GABAergic signaling. These findings illustrate the potential utility of regular exercise as a long-lasting and effective non-invasive intervention in the elderly or mentally ill where circadian rhythms can be blunted and poorly aligned to the external world.

Peripheral clocks tick independently of their master.

The circadian system of mammals is hierarchically organized. The suprachiasmatic nucleus (SCN) in the hypothalamus is considered the master circadian clock adapting to environmental light-dark cycles and synchronizing subsidiary oscillators in peripheral organs. While being an attractive concept, this has never been convincingly shown in vivo. New findings by Sinturel and colleagues (pp. 329-334) in this issue of Genes & Development now show the requirement of the SCN for temporal orchestration of the periphery in living animals. Surprisingly, this study also found that even in the absence of SCN or extra-SCN clocks, peripheral clocks remain rhythmic, indicating previously controversial circadian oscillator coupling within peripheral tissues.

Circadian Chimeric Mice Reveal an Interplay Between the Suprachiasmatic Nucleus and Local Brain Clocks in the Control of Sleep and Memory.

Sleep is regulated by circadian and homeostatic processes. Whereas the suprachiasmatic nucleus (SCN) is viewed as the principal mediator of circadian control, the contributions of sub-ordinate local circadian clocks distributed across the brain are unknown. To test whether the SCN and local brain clocks interact to regulate sleep, we used intersectional genetics to create temporally chimeric CK1ε Tau mice, in which dopamine 1a receptor (Drd1a)-expressing cells, a powerful pacemaking sub-population of the SCN, had a cell-autonomous circadian period of 24 h whereas the rest of the SCN and the brain had intrinsic periods of 20 h. We compared these mice with non-chimeric 24 h wild-types (WT) and 20 h CK1ε Tau mutants. The periods of the SCN ex vivo and the in vivo circadian behavior of chimeric mice were 24 h, as with WT, whereas other tissues in the chimeras had ex vivo periods of 20 h, as did all tissues from Tau mice. Nevertheless, the chimeric SCN imposed its 24 h period on the circadian patterning of sleep. When compared to 24 h WT and 20 h Tau mice, however, the sleep/wake cycle of chimeric mice under free-running conditions was disrupted, with more fragmented sleep and an increased number of short NREMS and REMS episodes. Even though the chimeras could entrain to 20 h light:dark cycles, the onset of activity and wakefulness was delayed, suggesting that SCN Drd1a-Cre cells regulate the sleep/wake transition. Chimeric mice also displayed a blunted homeostatic response to 6 h sleep deprivation (SD) with an impaired ability to recover lost sleep. Furthermore, sleep-dependent memory was compromised in chimeras, which performed significantly worse than 24 h WT and 20 h Tau mice. These results demonstrate a central role for the circadian clocks of SCN Drd1a cells in circadian sleep regulation, but they also indicate a role for extra-SCN clocks. In circumstances where the SCN and sub-ordinate local clocks are temporally mis-aligned, the SCN can maintain overall circadian control, but sleep consolidation and recovery from SD are compromised. The importance of temporal alignment between SCN and extra-SCN clocks for maintaining vigilance state, restorative sleep and memory may have relevance to circadian misalignment in humans, with environmental (e.g., shift work) causes.

GABA from vasopressin neurons regulates the time at which suprachiasmatic nucleus molecular clocks enable circadian behavior

The suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals, is a network structure composed of multiple types of γ-aminobutyric acid (GABA)-ergic neurons and glial cells. However, the roles of GABA-mediated signaling in the SCN network remain controversial. Here, we report noticeable impairment of the circadian rhythm in mice with a specific deletion of the vesicular GABA transporter in arginine vasopressin (AVP)-producing neurons. These mice showed disturbed diurnal rhythms of GABAA receptor-mediated synaptic transmission in SCN neurons and marked lengthening of the activity time in circadian behavioral rhythms due to the extended interval between morning and evening locomotor activities. Synchrony of molecular circadian oscillations among SCN neurons did not significantly change, whereas the phase relationships between SCN molecular clocks and circadian morning/evening locomotor activities were altered significantly, as revealed by PER2::LUC imaging of SCN explants and in vivo recording of intracellular Ca2+ in SCN AVP neurons. In contrast, daily neuronal activity in SCN neurons in vivo clearly showed a bimodal pattern that correlated with dissociated morning/evening locomotor activities. Therefore, GABAergic transmission from AVP neurons regulates the timing of SCN neuronal firing to temporally restrict circadian behavior to appropriate time windows in SCN molecular clocks.

Modulation of single cell circadian response to NMDA by diacylglycerol lipase inhibition reveals a role of endocannabinoids in light entrainment of the suprachiasmatic nucleus

Suprachiasmatic nucleus (SCN) of the hypothalamus is the master clock that drives circadian rhythms in physiology and behavior and adjusts their timing to external cues. Neurotransmitter glutamate and glutamatergic receptors sensitive to N-methyl-d-aspartate (NMDA) play a dual role in the SCN by coupling astrocytic and neuronal single cell oscillators and by resetting their phase in response to light. Recent reports suggested that signaling by endogenous cannabinoids (ECs) participates in both of these functions. We have previously shown that ECs, such as 2-arachidonoylglycerol (2-AG), act via CB1 receptors to affect the SCN response to light-mimicking NMDA stimulus in a time-dependent manner. We hypothesized that this ability is linked to the circadian regulation of EC signaling. We demonstrate that circadian clock in the rat SCN regulates expression of 2-AG transport, synthesis and degradation enzymes as well as its receptors. Inhibition of the major 2-AG synthesis enzyme, diacylglycerol lipase, enhanced the phase delay and lowered the amplitude of explanted SCN rhythm in response to NMDAR activation. Using microscopic PER2 bioluminescence imaging, we visualized how individual single cell oscillators in different parts of the SCN respond to the DAGL inhibition/NMDAR activation and shape response of the whole pacemaker. Additionally, we present strong evidence that the zero amplitude behavior of the SCN in response to single NMDA stimulus in the middle of subjective night is the result of a loss of rhythm in individual SCN cells. The paper provides new insights into the modulatory role of endocannabinoid signaling during the light entrainment of the SCN.

Challenging the Integrity of Rhythmic Maternal Signals Revealed Gene-Specific Responses in the Fetal Suprachiasmatic Nuclei.

During fetal stage, maternal circadian system sets the phase of the developing clock in the suprachiasmatic nuclei (SCN) via complex pathways. We addressed the issue of how impaired maternal signaling due to a disturbed environmental light/dark (LD) cycle affects the fetal SCN. We exposed pregnant Wistar rats to two different challenges – a 6-h phase shift in the LD cycle on gestational day 14, or exposure to constant light (LL) throughout pregnancy – and detected the impact on gene expression profiles in 19-day-old fetuses. The LD phase shift, which changed the maternal SCN into a transient state, caused robust downregulation of expression profiles of clock genes (Per1, Per2, and Nr1d1), clock-controlled (Dbp) genes, as well as genes involved in sensing various signals, such as c-fos and Nr3c1. Removal of the rhythmic maternal signals via exposure of pregnant rats to LL abolished the rhythms in expression of c-fos and Nr3c1 in the fetal SCN. We identified c-fos as the gene primarily responsible for sensing rhythmic maternal signals because its expression profile tracked the shifted or arrhythmic maternal SCN clock. Pathways related to the maternal rhythmic behavioral state were likely not involved in driving the c-fos expression rhythm. Instead, introduction of a behavioral rhythm to LL-exposed mothers via restricted feeding regime strengthened rhythm in Vip expression in the fetal SCN. Our results revealed for the first time that the fetal SCN is highly sensitive in a gene-specific manner to various changes in maternal signaling due to disturbances of environmental cycles related to the modern lifestyle in humans.

Chapter 22 - Melatonin and the circadian system: Keys for health with a focus on sleep

Melatonin (MLT), secreted during the night by the pineal gland, is an efferent hormonal signal of the master circadian clock located in the suprachiasmatic nucleus (SCN). Consequently, it is a reliable phase marker of the SCN clock. If one defines as "chronobiotic," a drug able to influence the phase and/or the period of the circadian clock, MLT is a very potent one. The most convincing data obtained so far come from studies on totally blind individuals. Exogenous MLT administered daily entrains the sleep-wake cycle of these individuals to a 24-h cycle. MLT, however, is not essential to sleep. In nocturnally, active mammals, MLT is released during the night concomitantly with the daily period of wakefulness. Therefore, MLT cannot be simply considered as a sleep hormone, but rather as a signal of darkness. Its role in the circadian system is to reinforce nighttime physiology, including timing of the sleep-wake cycle and other circadian rhythms. MLT exerts its effects on the sleep cycle especially by a direct action on the master circadian clock. The sleep-wake cycle is depending not only on the circadian clock but also on an orchestrated network of different centers in the brain. Thus, the control of sleep-wake rhythm might be explained by a parallel and concomitant action of MLT on the master clock (chronobiotic effect) and on sleep-related structures within the brain. MLT acts through two high-affinity membrane receptors (MT1 and MT2) with striking differences in their distribution pattern. MLT is a powerful synchronizer of human circadian rhythms, thus justifying the use of MLT and MLT agonists in clinical medicine as pharmacological tools to manipulate the sleep-wake cycle, and to treat sleep disorders and other circadian disorders. Available MLT analogs/drugs are all nonspecific MT1/MT2 agonists. The development of new ligands which are highly selectivity for each subtype is clearly a new challenge for the field and will be at the root of new therapeutic agents for curing specific pathologies, including sleep disorders.

Light Input to the Mammalian Circadian Clock.

Circadian rhythms are 24-hcycles in physiology and behavior that occur in virtually all organisms. These processes are not simply driven by changes in the external environment as they persist under constant conditions, providing evidence for an internal biological clock. In mammals, this clock is located in the hypothalamic suprachiasmatic nuclei (SCN) and is based upon an intracellular mechanism composed of a transcriptional-translational feedback loop composed of a number of core clock genes. However, a clock is of no use unless it can be set to the correct time. The primary time cue for the molecular clock in the SCN is light detected by the eye. The photoreceptors involved in this process include the rods and cones that mediate vision, as well as the recently identified melanopsin-expressing photosensitive retinal ganglion cells (pRGCs). Light information is conveyed to the SCN via the retinohypothalamic tract, resulting in an intracellular signaling cascade which converges on cAMP-response elements in the promoters of several key clock genes. Over the last two decades a number of studies have investigated the transcriptional response of the SCN to light stimuli with the aim of further understanding these molecular signaling pathways. Here we provide an overview of these studies and provide protocols for studying the molecular responses to light in the SCN clock.

SynGAP is expressed in the murine suprachiasmatic nucleus and regulates circadian-gated locomotor activity and light-entrainment capacity.

The suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master circadian clock. The phasing of the SCN oscillator is locked to the daily solar cycle, and an intracellular signaling cassette from the small GTPase Ras to the p44/42 mitogen-activated protein kinase (ERK/MAPK) pathway is central to thisentrainmentprocess. Here, we analyzed the expression and function of SynGAP-a GTPase-activating protein that serves as a negative regulator of Ras signaling-within the murine SCN. Using a combination of immunohistochemical and Western blotting approaches, we show that SynGAP is broadly expressed throughout the SCN. In addition, temporal profiling assays revealed that SynGAP expression is regulated over the circadian cycle, with peak expression occurring during the circadian night. Further, time-of-day-gated expression of SynGAP was not observed in clock arrhythmicBMAL1null mice, indicating that the daily oscillation in SynGAP is driven by the inherent circadian timing mechanism. We also show that SynGAP phosphorylation at serine 1138-an event that has been found to modulate its functional efficacy-is regulated by clock time and is responsive to photic input. Finally, circadian phenotypic analysis ofSyngap1heterozygous mice revealed enhanced locomotor activity, increased sensitivity to light-evoked clock entrainment, and elevated levels of light-evoked MAPK activity, which is consistent with the role of SynGAP as a negative regulator of MAPK signaling. These findings reveal that SynGAP functions as a modulator of SCN clock entrainment, an effect that may contribute to sleep and circadian abnormalities observed in patients withSYNGAP1gene mutations.

Rapid Jetlag Resetting of Behavioral, Physiological, and Molecular Rhythms in Proestrous Female Mice.

A gradual adaptation to a shifted light-dark (LD) cycle is a key element of the circadian clock system and believed to be controlled by the central circadian pacemaker, the suprachiasmatic nucleus (SCN). Endocrine factors have a strong influence on the regulation of the circadian clock network and alter acute photic responses of the SCN clock. In females, endocrine function depends on the stage of the ovarian cycle. So far, however, little is known about the effect of the estrous cycle on behavioral and molecular responses to shifts in the LD rhythm. Based on this, we investigated whether estrous state affects the kinetics of phase shift during jetlag in behavior, physiology, and molecular clock rhythms in the SCN and in peripheral tissues. Female mice exposed to an advanced LD phase at proestrous or metestrous showed different phase-shift kinetics, with proestrous females displaying accelerated adaptation in behavior and physiology. Constant darkness release experiments suggest that these fast phase shifts do not reflect resetting of the SCN pacemaker. Explant experiments on SCN, adrenal gland, and uterus confirmed this finding with proestrous females showing significantly faster clock phase shifts in peripheral tissues compared with the SCN. Together, these findings provide strong evidence for an accelerated adaptation of proestrous compared with metestrous females to new LD conditions that is accompanied by rapid behavioral, physiological, and molecular rhythm resetting. Not only do these findings open up a new avenue to understand the effect of estrous cycle on the clock network under changing environmental conditions but also imply a greater susceptibility in proestrous females.

P.353 Peripheral melatonin levels in bipolar disorder: preliminary results of a cross-sectional analysis

Recently, correlations of different physiological processes in humans with variations in the local lunisolar gravitational tide force have been observed under highly controlled laboratory conditions. Understanding of the physical nature of this phenomenon needs a comprehensive study of its possible molecular mechanisms. One of the possible timing cues is the strong periodic variation of the emanation fields of radon-222 and its progeny produced by tidal deformations of geological environment. In the present work, we argue that this variation could induce temporal modulation of radiation-induced bystander signaling pathways associated with fundamental regulators of gene expression in the suprachiasmatic nucleus clock.

Astrocytic Modulation of Neuronal Activity in the Suprachiasmatic Nucleus: Insights from Mathematical Modeling.

The suprachiasmatic nucleus (SCN) of the hypothalamus consists of a highly heterogeneous neuronal population networked together to allow precise and robust circadian timekeeping in mammals. While the critical importance of SCN neurons in regulating circadian rhythms has been extensively studied, the roles of SCN astrocytes in circadian system function are not well understood. Recent experiments have demonstrated that SCN astrocytes are circadian oscillators with the same functional clock genes as SCN neurons. Astrocytes generate rhythmic outputs that are thought to modulate neuronal activity through pre- and postsynaptic interactions. In this study, we developed an in silico multicellular model of the SCN clock to investigate the impact of astrocytes in modulating neuronal activity and affecting key clock properties such as circadian rhythmicity, period, and synchronization. The model predicted that astrocytes could alter the rhythmic activity of neurons via bidirectional interactions at tripartite synapses. Specifically, astrocyte-regulated extracellular glutamate was predicted to increase neuropeptide signaling from neurons. Consistent with experimental results, we found that astrocytes could increase the circadian period and enhance neural synchronization according to their endogenous circadian period. The impact of astrocytic modulation of circadian rhythm amplitude, period, and synchronization was predicted to be strongest when astrocytes had periods between 0 and 2 h longer than neurons. Increasing the number of neurons coupled to the astrocyte also increased its impact on period modulation and synchrony. These computational results suggest that signals that modulate astrocytic rhythms or signaling (e.g., as a function of season, age, or treatment) could cause disruptions in circadian rhythm or serve as putative therapeutic targets.

Tidal variations of background ionizing radiation and circadian timing of the suprachiasmatic nucleus clock

Recently, correlations of different physiological processes in humans with variations in the local lunisolar gravitational tide force have been observed under highly controlled laboratory conditions. Understanding of the physical nature of this phenomenon needs a comprehensive study of its possible molecular mechanisms. One of the possible timing cues is the strong periodic variation of the emanation fields of radon-222 and its progeny produced by tidal deformations of geological environment. In the present work, we argue that this variation could induce temporal modulation of radiation-induced bystander signaling pathways associated with fundamental regulators of gene expression in the suprachiasmatic nucleus clock.

Mice Hypomorphic for <i>Pitx3</i> Define a Minimal Dopamine Neuron Population Sufficient for Entraining Behavior and Metabolism to Scheduled Feeding

Pitx3ak mice lack a functioning retina and nearly all dopamine neurons of the substantia nigra (SN). del Rio-Marten et al (2019) reported that entrainment of circadian rhythms to daily light-dark and feeding schedules is absent in these mice. With food limited to 12h/day, food anticipatory circadian rhythms failed to emerge, and metabolic rhythms failed to synchronize with locomotor and feeding rhythms. The authors propose that retinal innervation of the suprachiasmatic nucleus clock is required for development of cyclic metabolic homeostasis, but methodological issues limit interpretation of the results. Using standardized feeding schedules and procedures for distinguishing free-running from entrained circadian rhythms, we confirm that behavioral and metabolic rhythms in Pitx3ak mice do not entrain to LD cycles, but we find no desynchrony between these rhythms nor a deficit in entrainment to daily feeding schedules. SN dopamine neurons surviving in Pitx3ak mice may define a mininum population sufficient for food entrainment.