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The European Journal of Neuroscience Jun 2024The mammalian circadian timing system has a hierarchical architecture, with a central pacemaker located in the brain's suprachiasmatic nucleus orchestrating rhythms in...
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.
PubMed: 38837456
DOI: 10.1111/ejn.16431 -
Nature Metabolism Jun 2024The daily light-dark cycle is a key zeitgeber (time cue) for entraining an organism's biological clock, whereby light sensing by retinal photoreceptors, particularly... (Review)
Review
The daily light-dark cycle is a key zeitgeber (time cue) for entraining an organism's biological clock, whereby light sensing by retinal photoreceptors, particularly intrinsically photosensitive retinal ganglion cells, stimulates the suprachiasmatic nucleus of the hypothalamus, a central pacemaker that in turn orchestrates the rhythm of peripheral metabolic activities. Non-rhythmic effects of light on metabolism have also been long known, and their transduction mechanisms are only beginning to unfold. Here, we summarize emerging evidence that, in mammals, light exposure or deprivation profoundly affects glucose homeostasis, thermogenesis and other metabolic activities in a clock-independent manner. Such light regulation could involve melanopsin-based, intrinsically photosensitive retinal ganglion cell-initiated brain circuits via the suprachiasmatic nucleus of the hypothalamus and other nuclei, or direct stimulation of opsins expressed in the hypothalamus, adipose tissue, blood vessels and skin to regulate sympathetic tone, lipolysis, glucose uptake, mitochondrial activation, thermogenesis, food intake, blood pressure and melanogenesis. These photic signalling events may coordinate with circadian-based mechanisms to maintain metabolic homeostasis, with dysregulation of this system underlying metabolic diseases caused by aberrant light exposure, such as environmental night light and shift work.
Topics: Animals; Circadian Rhythm; Light; Humans; Mammals; Suprachiasmatic Nucleus; Homeostasis; Thermogenesis; Glucose; Photoperiod; Rod Opsins
PubMed: 38831000
DOI: 10.1038/s42255-024-01051-6 -
Journal of Neuroendocrinology Jun 2024Reproduction in all mammalian species depends on the growth and maturation of ovarian follicles, that is, folliculogenesis. Follicular development can culminate with the...
Reproduction in all mammalian species depends on the growth and maturation of ovarian follicles, that is, folliculogenesis. Follicular development can culminate with the rupture of mature follicles and the consequent expulsion of their oocytes (ovulation) or in atresia, characterized by the arrest of development and eventual degeneration. These processes are regulated by different neuroendocrine signals arising at different hypothalamic nuclei, including the suprachiasmatic nucleus (SCN). In the later, the activation of muscarinic receptors (mAChRs) and nicotinic receptors (nAChRs) by acetylcholine is essential for the regulation of the pre-ovulatory signals that stimulate the rupture of mature follicles. To evaluate the participation of the nAChRs in the SCN throughout the oestrous cycle in the regulation of the hypothalamic-pituitary-ovarian axis. For this purpose, 90-day-old adult female rats in metoestrus, dioestrus, proestrus or oestrus were microinjected into the left- or right-SCN with 0.3 μL of saline solution as vehicle or with 0.225 μg of mecamylamine (Mec), a non-selective antagonist of the nicotinic receptors, diluted in 0.3 μL of vehicle. The animals were sacrificed when they presented vaginal cornification, indicative of oestrus stage, and the effects of the unilateral pharmacological blockade of the nAChRs in the SCN on follicular development, ovulation and secretion of oestradiol and follicle-stimulating hormone (FSH) were evaluated. The microinjection of Mec decreased the serum levels of FSH, which resulted in a lower number of growing and healthy follicles and an increase in atresia. The higher percentage of atresia in pre-ovulatory follicles was related to a decrease in the number of ova shed and abnormalities in oestradiol secretion. We also detected asymmetric responses between the left and right treatments that depended on the stage of the oestrous cycle. The present results allow us to suggest that during all the stages of the oestrous cycle, cholinergic signals that act on the nAChRs in the SCN are pivotal to modulate the secretion of gonadotropins and hence the physiology of the ovaries. Further research is needed to determine if such signals are generated by the cholinergic neurons in the SCN or by cholinergic afferents to the SCN.
PubMed: 38826071
DOI: 10.1111/jne.13421 -
Frontiers in Genetics 2024Circadian rhythms, essential 24-hour cycles guiding biological functions, synchronize organisms with daily environmental changes. These rhythms, which are evolutionarily... (Review)
Review
Circadian rhythms, essential 24-hour cycles guiding biological functions, synchronize organisms with daily environmental changes. These rhythms, which are evolutionarily conserved, govern key processes like feeding, sleep, metabolism, body temperature, and endocrine secretion. The central clock, located in the suprachiasmatic nucleus (SCN), orchestrates a hierarchical network, synchronizing subsidiary peripheral clocks. At the cellular level, circadian expression involves transcription factors and epigenetic remodelers, with environmental signals contributing flexibility. Circadian disruption links to diverse diseases, emphasizing the urgency to comprehend the underlying mechanisms. This review explores the communication between the environment and chromatin, focusing on histone post-translational modifications. Special attention is given to the significance of histone methylation in circadian rhythms and metabolic control, highlighting its potential role as a crucial link between metabolism and circadian rhythms. Understanding these molecular intricacies holds promise for preventing and treating complex diseases associated with circadian disruption.
PubMed: 38818037
DOI: 10.3389/fgene.2024.1343030 -
Frontiers in Endocrinology 2024This article discusses data showing that mammals, including humans, have two sources of melatonin that exhibit different functions. The best-known source of melatonin,... (Review)
Review
This article discusses data showing that mammals, including humans, have two sources of melatonin that exhibit different functions. The best-known source of melatonin, herein referred to as Source #1, is the pineal gland. In this organ, melatonin production is circadian with maximal synthesis and release into the blood and cerebrospinal fluid occurring during the night. Of the total amount of melatonin produced in mammals, we speculate that less than 5% is synthesized by the pineal gland. The melatonin rhythm has the primary function of influencing the circadian clock at the level of the suprachiasmatic nucleus (the CSF melatonin) and the clockwork in all peripheral organs (the blood melatonin) via receptor-mediated actions. A second source of melatonin (Source # 2) is from multiple tissues throughout the body, probably being synthesized in the mitochondria of these cells. This constitutes the bulk of the melatonin produced in mammals and is concerned with metabolic regulation. This review emphasizes the action of melatonin from peripheral sources in determining re-dox homeostasis, but it has other critical metabolic effects as well. Extrapineal melatonin synthesis does not exhibit a circadian rhythm and it is not released into the blood but acts locally in its cell of origin and possibly in a paracrine matter on adjacent cells. The factors that control/influence melatonin synthesis at extrapineal sites are unknown. We propose that the concentration of melatonin in these cells is determined by the subcellular redox state and that melatonin synthesis may be inducible under stressful conditions as in plant cells.
Topics: Melatonin; Humans; Animals; Circadian Rhythm; Pineal Gland; Suprachiasmatic Nucleus
PubMed: 38808108
DOI: 10.3389/fendo.2024.1414463 -
Fluids and Barriers of the CNS May 2024Choroid plexus (ChP), the brain structure primarily responsible for cerebrospinal fluid production, contains a robust circadian clock, whose role remains to be...
Choroid plexus (ChP), the brain structure primarily responsible for cerebrospinal fluid production, contains a robust circadian clock, whose role remains to be elucidated. The aim of our study was to [1] identify rhythmically controlled cellular processes in the mouse ChP and [2] assess the role and nature of signals derived from the master clock in the suprachiasmatic nuclei (SCN) that control ChP rhythms. To accomplish this goal, we used various mouse models (WT, mPer2, ChP-specific Bmal1 knockout) and combined multiple experimental approaches, including surgical lesion of the SCN (SCNx), time-resolved transcriptomics, and single cell luminescence microscopy. In ChP of control (Ctrl) mice collected every 4 h over 2 circadian cycles in darkness, we found that the ChP clock regulates many processes, including the cerebrospinal fluid circadian secretome, precisely times endoplasmic reticulum stress response, and controls genes involved in neurodegenerative diseases (Alzheimer's disease, Huntington's disease, and frontotemporal dementia). In ChP of SCNx mice, the rhythmicity detected in vivo and ex vivo was severely dampened to a comparable extent as in mice with ChP-specific Bmal1 knockout, and the dampened cellular rhythms were restored by daily injections of dexamethasone in mice. Our data demonstrate that the ChP clock controls tissue-specific gene expression and is strongly dependent on the presence of a functional connection with the SCN. The results may contribute to the search for a novel link between ChP clock disruption and impaired brain health.
Topics: Animals; Suprachiasmatic Nucleus; Choroid Plexus; Circadian Clocks; Mice; Mice, Inbred C57BL; Circadian Rhythm; Male; Mice, Knockout; ARNTL Transcription Factors
PubMed: 38802875
DOI: 10.1186/s12987-024-00547-3 -
The European Journal of Neuroscience May 2024Circadian clock function declines with ageing, which can aggravate ageing-related diseases such as type 2 diabetes and neurodegenerative disorders. Understanding...
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.
PubMed: 38802069
DOI: 10.1111/ejn.16428 -
Experimental Eye Research Jul 2024Orexin A and B (OXA and OXB) and their receptors are expressed in the majority of retinal neurons in humans, rats, and mice. Orexins modulate signal transmission between...
Orexin A and B (OXA and OXB) and their receptors are expressed in the majority of retinal neurons in humans, rats, and mice. Orexins modulate signal transmission between the different layers of the retina. The suprachiasmatic nucleus (SCN) and the retina are central and peripheral components of the body's biological clocks; respectively. The SCN receives photic information from the retina through the retinohypothalamic tract (RHT) to synchronize bodily functions with environmental changes. In present study, we aimed to investigate the impact of inhibiting retinal orexin receptors on the expression of retinal Bmal1 and c-fos, as well as hypothalamic c-fos, Bmal1, Vip, and PACAP at four different time-points (Zeitgeber time; ZT 3, 6, 11, and ZT-0). The intravitreal injection (IVI) of OX1R antagonist (SB-334867) and OX2R antagonist (JNJ-10397049) significantly up-regulated c-fos expression in the retina. Additionally, compared to the control group, the combined injection of SB-334867 and JNJ-10397049 showed a greater increase in retinal expression of this gene. Moreover, the expression of hypothalamic Vip and PACAP was significantly up-regulated in both the SB-334867 and JNJ-10397049 groups. In contrast, the expression of Bmal1 was down-regulated. Furthermore, the expression of hypothalamic c-fos was down-regulated in all groups treated with SB-334867 and JNJ-10397049. Additionally, the study demonstrated that blocking these receptors in the retina resulted in alterations in circadian rhythm parameters such as mesor, amplitude, and acrophase. Finally, it affected the phase of gene expression rhythms in both the retina and hypothalamus, as identified through cosinor analysis and the zero-amplitude test. This study represents the initial exploration of how retinal orexin receptors influence expression of rhythmic genes in the retina and hypothalamus. These findings could provide new insights into how the retina regulates the circadian rhythm in both regions and illuminate the role of the orexinergic system expression within the retina.
Topics: Animals; Male; Rats; Proto-Oncogene Proteins c-fos; Hypothalamus; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats, Wistar; Orexin Receptors; Retina; Vasoactive Intestinal Peptide; Naphthyridines; ARNTL Transcription Factors; Gene Expression Regulation; Orexin Receptor Antagonists; Benzoxazoles; Urea; Circadian Rhythm; Suprachiasmatic Nucleus; Dioxanes; Isoquinolines; Phenylurea Compounds; Pyridines
PubMed: 38797259
DOI: 10.1016/j.exer.2024.109943 -
Neuropharmacology Sep 2024Feeding, like many other biological functions, displays a daily rhythm. This daily rhythmicity is controlled by the circadian timing system of which the central master... (Review)
Review
Feeding, like many other biological functions, displays a daily rhythm. This daily rhythmicity is controlled by the circadian timing system of which the central master clock is located in the hypothalamic suprachiasmatic nucleus (SCN). Other brain areas and tissues throughout the body also display rhythmic functions and contain the molecular clock mechanism known as peripheral oscillators. To generate the daily feeding rhythm, the SCN signals to different hypothalamic areas with the lateral hypothalamus, paraventricular nucleus and arcuate nucleus being the most prominent. With respect to the rewarding aspects of feeding behavior, the dopaminergic system is also under circadian influence. However the SCN projects only indirectly to the different reward regions, such as the ventral tegmental area where dopamine neurons are located. In addition, high palatable, high caloric diets have the potential to disturb the normal daily rhythms of physiology and have been shown to alter for example meal patterns. Around a meal several hormones and peptides are released that are also under circadian influence. For example, the release of postprandial insulin and glucagon-like peptide following a meal depend on the time of the day. Finally, we review the effect of deletion of different clock genes on feeding behavior. The most prominent effect on feeding behavior has been observed in Clock mutants, whereas deletion of Bmal1 and Per1/2 only disrupts the day-night rhythm, but not overall intake. Data presented here focus on the rodent literature as only limited data are available on the mechanisms underlying daily rhythms in human eating behavior.
Topics: Animals; Feeding Behavior; Circadian Rhythm; Humans; Suprachiasmatic Nucleus
PubMed: 38795953
DOI: 10.1016/j.neuropharm.2024.110007 -
Chrono-Endocrinology in Clinical Practice: A Journey from Pathophysiological to Therapeutic Aspects.Life (Basel, Switzerland) Apr 2024This review was aimed at collecting the knowledge on the pathophysiological and clinical aspects of endocrine rhythms and their implications in clinical practice,... (Review)
Review
This review was aimed at collecting the knowledge on the pathophysiological and clinical aspects of endocrine rhythms and their implications in clinical practice, derived from the published literature and from some personal experiences on this topic. We chose to review, according to the PRISMA guidelines, the results of original and observational studies, reviews, meta-analyses and case reports published up to March 2024. Thus, after summarizing the general aspects of biological rhythms, we will describe the characteristics of several endocrine rhythms and the consequences of their disruption, paying particular attention to the implications in clinical practice. Rhythmic endocrine secretions, like other physiological rhythms, are genetically determined and regulated by a central hypothalamic CLOCK located in the suprachiasmatic nucleus, which links the timing of the rhythms to independent clocks, in a hierarchical organization for the regulation of physiology and behavior. However, some environmental factors, such as daily cycles of light/darkness, sleep/wake, and timing of food intake, may influence the rhythm characteristics. Endocrine rhythms are involved in important physiological processes and their disruption may cause several disorders and also cancer. Thus, it is very important to prevent disruptions of endocrine rhythms and to restore a previously altered rhythm by an early corrective chronotherapy.
PubMed: 38792568
DOI: 10.3390/life14050546