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Zoological Science Feb 2024Melatonin (-acetyl-5-methoxytryptamine) is an indolamine that is synthesized from tryptophan in the pineal glands of vertebrates through four enzymatic reactions....
Melatonin (-acetyl-5-methoxytryptamine) is an indolamine that is synthesized from tryptophan in the pineal glands of vertebrates through four enzymatic reactions. Melatonin is a quite unique bioactive substance, characterized by a combination of both receptor-mediated and receptor-independent actions, which promote the diverse effects of melatonin. One of the main functions of melatonin, via its membrane receptors, is to regulate the circadian or seasonal rhythm. In mammals, light information, which controls melatonin synthesis, is received in the eye, and transmitted to the pineal gland, via the suprachiasmatic nucleus, where the central clock is located. Alternatively, in many vertebrates other than mammals, the pineal gland cells, which are involved in melatonin synthesis and secretion and in the circadian clock, directly receive light. Recently, it has been reported that melatonin possesses several metabolic functions, which involve bone and glucose, in addition to regulating the circadian rhythm. Melatonin improves bone strength by inhibiting osteoclast activity. It is also known to maintain brain activity during sleep by increasing glucose uptake at night, in an insulin-independent manner. Moreover, as a non-receptor-mediated action, melatonin has antioxidant properties. Melatonin has been proven to be a potent free radical scavenger and a broad-spectrum antioxidant, even protecting organisms against radiation from space. Melatonin is a ubiquitously distributed molecule and is found in bacteria, unicellular organisms, fungi, and plants. It is hypothesized that melatonin initially functioned as an antioxidant, then, in vertebrates, it combined this role with the ability to regulate rhythm and metabolism, via its receptors.
Topics: Animals; Melatonin; Antioxidants; Vertebrates; Circadian Clocks; Mammals
PubMed: 38587523
DOI: 10.2108/zs230057 -
IScience Apr 2024Individuals within the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD) often experience disruptive mental behaviors and sleep-wake...
Individuals within the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD) often experience disruptive mental behaviors and sleep-wake disturbances. The hallmark of ALS/FTD is the pathological involvement of TAR DNA-binding protein 43 (TDP-43). Understanding the role of TDP-43 in the circadian clock holds promise for addressing these behavioral abnormalities. In this study, we unveil TDP-43 as a pivotal regulator of the circadian clock. TDP-43 knockdown induces intracellular arrhythmicity, disrupts transcriptional activation regulation, and diminishes clock genes expression. Moreover, our experiments in adult mouse reveal that TDP-43 knockdown, specifically within the suprachiasmatic nucleus (SCN), induces locomotor arrhythmia, arrhythmic c-Fos expression, and depression-like behavior. This observation offers valuable insights into the substantial impact of TDP-43 on the behavioral aberrations associated with ALS/FTD. In summary, our study illuminates the significance of TDP-43 in circadian regulation, shedding light on the circadian regulatory mechanisms that may elucidate the pathological underpinnings of ALS/FTD.
PubMed: 38585660
DOI: 10.1016/j.isci.2024.109522 -
The European Journal of Neuroscience Apr 2024Ca/calmodulin-dependent protein kinase IIα (CaMKIIα) is widely expressed in the brain and is involved in various functions, including memory formation, mood and sleep....
Ca/calmodulin-dependent protein kinase IIα (CaMKIIα) is widely expressed in the brain and is involved in various functions, including memory formation, mood and sleep. We previously reported that CaMKIIα is involved in the circadian molecular clock. Mice lacking functional CaMKIIα (K42R mice) exhibited a gradual increase in activity time (α decompression) of running-wheel (RW) activity due to a lengthened circadian period (τ) of activity offset under constant darkness (DD). In the present study, to investigate the functional roles of CaMKIIα in behavioural rhythms, we measured RW and general movements simultaneously under prolonged DD. Tau became longer as the relative intensity of behaviour activity within an activity time shifted from activity onset towards activity offset. In some K42R mice, α was gradually expanded with a marked reduction of RW activity, while general movements persisted without noticeable decline, which was followed by an abrupt shortening of α (α compression) with differential phase shifts of the activity onset and offset and recovery of RW activity. These results suggest that an internal coupling between the oscillators controlling activity onset and offset is bidirectional but with different strengths. The α compression occurred recurrently in 38% of K42R mice examined with an average interval of 37 days in association with attenuation of RW activity but never in the wild-type (WT) mice. Consistent with behavioural rhythms, the circadian period of the PER2::LUC rhythm in the cultured suprachiasmatic nucleus (SCN) slice was significantly longer in K42R than in WT. These findings are best interpreted by assuming that a loss of functional CaMKIIα attenuates the coupling between the onset and offset oscillators.
PubMed: 38571281
DOI: 10.1111/ejn.16316 -
Archives of Women's Mental Health Apr 2024Biological factors and mechanisms that drive higher prevalence of insomnia in females are poorly understood. This study focused on the neurological consequences of...
PURPOSE
Biological factors and mechanisms that drive higher prevalence of insomnia in females are poorly understood. This study focused on the neurological consequences of X-chromosome functional imbalances between sexes.
METHODS
Benefited from publicly available large-scale genetic, transcriptional and epigenomic data, we curated and contrasted different gene lists: (1) X-liked genes, including assignments for X-chromosome inactivation patterns and disease associations; (2) sleep-associated genes; (3) gene expression markers for the suprachiasmatic nucleus.
RESULTS
We show that X-linked markers for the suprachiasmatic nucleus are significantly enriched for clinically relevant genes in the context of rare genetic syndromes and brain waves modulation.
CONCLUSION
Considering female-specific patterns on brain transcriptional programs becomes essential when designing health care strategies for mental and sleep illnesses with sex bias in prevalence.
PubMed: 38563984
DOI: 10.1007/s00737-024-01452-2 -
Antioxidants (Basel, Switzerland) Mar 2024Visible light refers to the frequencies within the electromagnetic spectrum that humans can see, encompassing radiation with wavelengths falling between 380 nm to 760... (Review)
Review
Visible light refers to the frequencies within the electromagnetic spectrum that humans can see, encompassing radiation with wavelengths falling between 380 nm to 760 nm. The energy of a single photon increases with its frequency. In the retina, photoreceptor cells contain light-sensitive pigments that absorb light and convert it into electrical stimuli through a process known as phototransduction. However, since the absorption spectrum of photoreceptors closely aligns with blue light (ranging from 400 to 500 nm), exposure to high light intensities or continuous illumination can result in oxidative stress within these cells, leading to a loss of their functionality. Apart from photoreceptor cells, the retina also houses photosensitive ganglion cells, known as intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells relay information to the suprachiasmatic nucleus in the brain, playing a crucial role in modulating melatonin secretion, which in turn helps in synchronizing the body's circadian rhythms and responses to seasonal changes. Both, ipRGCs and skin possess a peak sensitivity to blue wavelengths, rendering them particularly susceptible to the effects of excessive blue light exposure. This study delves into the consequences of excessive illumination and/or prolonged exposure to blue light on retinal function and explores its implications for human health.
PubMed: 38539895
DOI: 10.3390/antiox13030362 -
Cell Reports Mar 2024Plasticity in daily timing of activity has been observed in many species, yet the underlying mechanisms driving nocturnality and diurnality are unknown. By regulating...
Plasticity in daily timing of activity has been observed in many species, yet the underlying mechanisms driving nocturnality and diurnality are unknown. By regulating how much wheel-running activity will be rewarded with a food pellet, we can manipulate energy balance and switch mice to be nocturnal or diurnal. Here, we present the rhythmic transcriptome of 21 tissues, including 17 brain regions, sampled every 4 h over a 24-h period from nocturnal and diurnal male CBA/CaJ mice. Rhythmic gene expression across tissues comprised different sets of genes with minimal overlap between nocturnal and diurnal mice. We show that non-clock genes in the suprachiasmatic nucleus (SCN) change, and the habenula was most affected. Our results indicate that adaptive flexibility in daily timing of behavior is supported by gene expression dynamics in many tissues and brain regions, especially in the habenula, which suggests a crucial role for the observed nocturnal-diurnal switch.
Topics: Mice; Male; Animals; Circadian Rhythm; Transcriptome; Mice, Inbred CBA; Brain; Suprachiasmatic Nucleus
PubMed: 38508192
DOI: 10.1016/j.celrep.2024.113951 -
Proceedings of the National Academy of... Mar 2024We show that nocturnal aversive stimuli presented to mice while they are eating and drinking outside of their safe nest can entrain circadian behaviors, leading to a...
We show that nocturnal aversive stimuli presented to mice while they are eating and drinking outside of their safe nest can entrain circadian behaviors, leading to a shift toward daytime activity. We also show that the canonical molecular circadian clock is necessary for fear entrainment and that an intact molecular clockwork in the suprachiasmatic nucleus, the site of the central circadian pacemaker, is necessary but not sufficient to sustain fear entrainment of circadian rhythms. Our results demonstrate that entrainment of a circadian clock by cyclic fearful stimuli can lead to severely mistimed circadian behavior that persists even after the aversive stimulus is removed. Together, our findings support the interpretation that circadian and sleep symptoms associated with fear and anxiety disorders are, in part, the output of a fear-entrained clock, and provide a mechanistic insight into this clock.
Topics: Mice; Animals; Circadian Clocks; Suprachiasmatic Nucleus; Circadian Rhythm; Fear
PubMed: 38502706
DOI: 10.1073/pnas.2316841121 -
Physiology & Behavior May 2024Melatonin is a neurohormone synthesized by the pineal gland to regulate the circadian rhythms and has proven to be effective in treating drug addiction and dependence....
Melatonin is a neurohormone synthesized by the pineal gland to regulate the circadian rhythms and has proven to be effective in treating drug addiction and dependence. However, the effects of melatonin to modulate the drug-seeking behavior of fentanyl and its underlying molecular mechanism is elusive. This study was designed to investigate the effects of melatonin on fentanyl - induced behavioral sensitization and circadian rhythm disorders in mice. The accompanying changes in the expression of Brain and Muscle Arnt-Like (BMAL1), tyrosine hydroxylase (TH), and monoamine oxidase A (MAO-A) in relevant brain regions including the suprachiasmatic nucleus (SCN), nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus (Hip) were investigated by western blot assays to dissect the mechanism by which melatonin modulates fentanyl - induced behavioral sensitization and circadian rhythm disorders. The present study suggest that fentanyl (0.05, 0.1 and 0.2 mg/kg) could induce behavioral sensitization and melatonin (30.0 mg/kg) could attenuate the behavioral sensitization and circadian rhythm disorders in mice. Fentanyl treatment reduced the expression of BMAL1 and MAO-A and increased that of TH in relevant brain regions. Furthermore, melatonin treatment could reverse the expression levels of BMAL1, MAO-A, and TH. In conclusion, our study demonstrate for the first time that melatonin has therapeutic potential for fentanyl addiction.
Topics: Mice; Animals; Melatonin; ARNTL Transcription Factors; Fentanyl; Suprachiasmatic Nucleus; Circadian Rhythm; Chronobiology Disorders; Monoamine Oxidase
PubMed: 38492912
DOI: 10.1016/j.physbeh.2024.114523 -
The Journal of Neuroscience : the... May 2024Sleep is regulated by homeostatic sleep drive and the circadian clock. While tremendous progress has been made in elucidating the molecular components of the core...
Sleep is regulated by homeostatic sleep drive and the circadian clock. While tremendous progress has been made in elucidating the molecular components of the core circadian oscillator, the output mechanisms by which this robust oscillator generates rhythmic sleep behavior remain poorly understood. At the cellular level, growing evidence suggests that subcircuits in the master circadian pacemaker suprachiasmatic nucleus (SCN) in mammals and in the clock network in regulate distinct aspects of sleep. Thus, to identify novel molecules regulating the circadian timing of sleep, we conducted a large-scale screen of mouse SCN-enriched genes in Here, we show that Tob (Transducer of ERB-B2) regulates the timing of sleep onset at night in female fruit flies. Knockdown of Tob pan-neuronally, either constitutively or conditionally, advances sleep onset at night. We show that Tob is specifically required in "evening neurons" (the LNds and the fifth s-LNv) of the clock network for proper timing of sleep onset. Tob levels cycle in a clock-dependent manner in these neurons. Silencing of these "evening" clock neurons results in an advanced sleep onset at night, similar to that seen with Tob knockdown. Finally, sharp intracellular recordings demonstrate that the amplitude and kinetics of LNd postsynaptic potentials (PSPs) cycle between day and night, and this cycling is attenuated with Tob knockdown in these cells. Our data suggest that Tob acts as a clock output molecule in a subset of clock neurons to potentiate their activity in the evening and enable the proper timing of sleep onset at night.
Topics: Animals; Female; Animals, Genetically Modified; Circadian Rhythm; Drosophila; Drosophila Proteins; Neurons; Sleep; Suprachiasmatic Nucleus
PubMed: 38485259
DOI: 10.1523/JNEUROSCI.0389-23.2024 -
Cell Death Discovery Mar 2024The disruption of circadian rhythms caused by long-term shift work can cause metabolic diseases such as obesity. Early growth response 3 (EGR3) is a member of early...
The disruption of circadian rhythms caused by long-term shift work can cause metabolic diseases such as obesity. Early growth response 3 (EGR3) is a member of early growth response (EGR) family, which is involved in several cellular responses, had been reported as a circadian rhythm gene in suprachiasmatic nucleus. In this research, EGR3 was found to be widely expressed in the different tissue of human and mice, and downregulated in adipose tissue of obese subjects and high-fat diet mice. Moreover, EGR3 was found negatively regulated by cortisol. In addition, EGR3 is a key negative modulator of hADSCs and 3T3-L1 adipogenesis via regulating HDAC6, which is a downstream target gene of EGR3 and a negative regulator of adipogenesis and lipogenesis. These findings may explain how circadian rhythm disorder induced by shift works can cause obesity. Our study revealed a potential therapeutic target to alleviate metabolic disorders in shift workers and may provide better health guidance to shift workers.
PubMed: 38467615
DOI: 10.1038/s41420-024-01904-9