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Endocrinology Nov 2023Repeated or chronic stress can change the phase of peripheral circadian rhythms. Melatonin (Mel) is thought to be a circadian clock-controlled signal that might play a...
Repeated or chronic stress can change the phase of peripheral circadian rhythms. Melatonin (Mel) is thought to be a circadian clock-controlled signal that might play a role in synchronizing peripheral rhythms, in addition to its direct suppressing effects on the stress axis. In this study we test whether Mel can reduce the social-defeat stress-induced phase shifts in peripheral rhythms, either by modulating circadian phase or by modulating the stress axis. Two experiments were performed with male Mel-deficient C57BL/6J mice carrying the circadian reporter gene construct (PER2::LUC). In the first experiment, mice received night-restricted (ZT11-21) Mel in their drinking water, resulting in physiological levels of plasma Mel peaking in the early dark phase. This treatment facilitated re-entrainment of the activity rhythm to a shifted light-dark cycle, but did not prevent the stress-induced (ZT21-22) reduction of activity during stress days. Also, this treatment did not attenuate the phase-delaying effects of stress in peripheral clocks in the pituitary, lung, and kidney. In a second experiment, pituitary, lung, and kidney collected from naive mice (ZT22-23), were treated with Mel, dexamethasone (Dex), or a combination of the two. Dex application affected PER2 rhythms in the pituitary, kidney, and lung by changing period, phase, or both. Administering Mel did not influence PER2 rhythms nor did it alleviate Dex-induced delays in PER2 rhythms in those tissues. We conclude that exogenous Mel is insufficient to affect peripheral PER2 rhythms and reduce stress effects on locomotor activity and phase changes in peripheral tissues.
Topics: Mice; Male; Animals; Melatonin; Light; Suprachiasmatic Nucleus; Mice, Inbred C57BL; Circadian Rhythm; Circadian Clocks
PubMed: 38128120
DOI: 10.1210/endocr/bqad183 -
Frontiers in Physiology 2023Emerging evidence has highlighted that the gut microbiota plays a critical role in the regulation of various aspects of mammalian physiology and behavior, including...
Emerging evidence has highlighted that the gut microbiota plays a critical role in the regulation of various aspects of mammalian physiology and behavior, including circadian rhythms. Circadian rhythms are fundamental behavioral and physiological processes that are governed by circadian pacemakers in the brain. Since mice are nocturnal, voluntary wheel running activity mostly occurs at night. This nocturnal wheel-running activity is driven by the primary circadian pacemaker located in the suprachiasmatic nucleus (SCN). Food anticipatory activity (FAA) is the increased bout of locomotor activity that precedes the scheduled short duration of a daily meal. FAA is controlled by the food-entrainable oscillator (FEO) located outside of the SCN. Several studies have shown that germ-free mice and mice with gut microbiota depletion altered those circadian behavioral rhythms. Therefore, this study was designed to test if the gut microbiota is involved in voluntary wheel running activity and FAA expression. To deplete gut microbiota, C57BL/6J wildtype mice were administered an antibiotic cocktail via their drinking water throughout the experiment. The effect of antibiotic cocktail treatment on wheel running activity rhythm in both female and male mice was not detectable with the sample size in our current study. Then mice were exposed to timed restricted feeding during the day. Both female and male mice treated with antibiotics exhibited normal FAA which was comparable with the FAA observed in the control group. Those results suggest that gut microbiota depletion has minimum effect on both circadian behavioral rhythms controlled by the SCN and FEO respectively. Our result contradicts recently published studies that reported significantly higher FAA levels in germ-free mice compared to their control counterparts and gut microbiota depletion significantly reduced voluntary activity by 50%.
PubMed: 38107475
DOI: 10.3389/fphys.2023.1299474 -
Schizophrenia Research Feb 2024A molecular clock in the suprachiasmatic nucleus of the anterior hypothalamus, which is entrained by the dark-light cycle and controls the sleep-wake cycle, regulates... (Review)
Review
A molecular clock in the suprachiasmatic nucleus of the anterior hypothalamus, which is entrained by the dark-light cycle and controls the sleep-wake cycle, regulates circadian rhythms. The risk of developing mental disorders, such as schizophrenia, has long been linked to sleep abnormalities. Additionally, a common aspect of mental disorders is sleep disturbance, which has a direct impact on the intensity of the symptoms and the quality of life of the patient. This relationship can be explained by gene alterations such as CLOCK in schizophrenia which are also important components of the physiological circadian rhythm. The function of dopamine and adenosine in circadian rhythm should also be noted, as these hypotheses are considered to be the most popular theories explaining schizophrenia pathogenesis. Therefore, determining the presence of a causal link between the two can be key to identifying new potential targets in schizophrenia therapy, which can open new avenues for clinical research as well as psychiatric care. We review circadian disruption in schizophrenia at the genetic, metabolic, and clinical levels. We summarize data about clock and clock-controlled genes' alterations, neurotransmitter systems' impairments, and association with chronotype in schizophrenia patients. Our findings demonstrate that in schizophrenia either homeostatic or circadian processes of sleep regulation are disturbed. Also, we found an insufficient number of studies aimed at studying the relationship between known biological phenomena of circadian disorders and clinical signs of schizophrenia.
Topics: Humans; Schizophrenia; Quality of Life; Circadian Rhythm; Sleep; Photoperiod
PubMed: 38101179
DOI: 10.1016/j.schres.2023.12.002 -
Frontiers in Neuroscience 2023Alzheimer's disease (AD) is the leading cause of dementia, with over 45 million patients worldwide, and poses significant economic and emotional burdens to both patients... (Review)
Review
Alzheimer's disease (AD) is the leading cause of dementia, with over 45 million patients worldwide, and poses significant economic and emotional burdens to both patients and caregivers, significantly raising the number of those affected. Unfortunately, much of the existing research on the disease only addresses a small subset of associated symptomologies and pathologies. In this review, we propose to target the earliest stages of the disease, when symptomology first arises. In these stages, before the onset of hallmark symptoms of AD such as cognitive impairments and memory loss, circadian and olfactory disruptions arise and are detectable. Functional similarities between circadian and olfactory systems provide a basis upon which to seek out common mechanisms in AD which may target them early on in the disease. Existing studies of interactions between these systems, while intriguing, leave open the question of the neural substrates underlying them. Potential substrates for such interactions are proposed in this review, such as indirect projections that may functionally connect the two systems and dopaminergic signaling. These substrates may have significant implications for mechanisms underlying disruptions to circadian and olfactory function in early stages of AD. In this review, we propose early detection of AD using a combination of circadian and olfactory deficits and subsequent early treatment of these deficits may provide profound benefits to both patients and caregivers. Additionally, we suggest that targeting research toward the intersection of these two systems in AD could uncover mechanisms underlying the broader set of symptoms and pathologies that currently elude researchers.
PubMed: 38094003
DOI: 10.3389/fnins.2023.1295998 -
IScience Dec 2023Does the circadian clock keep running under such hypothermic states as daily torpor and hibernation? This fundamental question has been a research subject for decades...
Does the circadian clock keep running under such hypothermic states as daily torpor and hibernation? This fundamental question has been a research subject for decades but has remained unsettled. We addressed this subject by monitoring the circadian rhythm of clock gene transcription and intracellular Ca in the neurons of the suprachiasmatic nucleus (SCN), master circadian clock, under a cold environment. We discovered that the transcriptional and Ca rhythms are maintained at 22°C-28°C, but suspended at 15°C, accompanied by a large Ca increase. Rewarming instantly resets the Ca rhythms, while transcriptional rhythms reach a stable phase after the transient state and recover their phase relationship with the Ca rhythm. We conclude that SCN neurons remain functional under moderate hypothermia but stop ticking in deep hypothermia and that the rhythms reset after rewarming. These data also indicate that stable Ca oscillation precedes clock gene transcriptional rhythms in SCN neurons.
PubMed: 38077129
DOI: 10.1016/j.isci.2023.108390 -
Cells Nov 2023Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays a pivotal role in various physiological processes. Its release is finely orchestrated... (Review)
Review
Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays a pivotal role in various physiological processes. Its release is finely orchestrated by the suprachiasmatic nucleus, governing the circadian rhythm and activating the intricate hypothalamic-pituitary-adrenal (HPA) axis, a vital neuroendocrine system responsible for stress response and maintaining homeostasis. Disruptions in cortisol regulation due to chronic stress, disease, and aging have profound implications for multiple bodily systems. Animal models have been instrumental in elucidating these complex cortisol dynamics during stress, shedding light on the interplay between physiological, neuroendocrine, and immune factors in the stress response. These models have also revealed the impact of various stressors, including social hierarchies, highlighting the role of social factors in cortisol regulation. Moreover, chronic stress is closely linked to the progression of neurodegenerative diseases, like Alzheimer's and Parkinson's, driven by excessive cortisol production and HPA axis dysregulation, along with neuroinflammation in the central nervous system. The relationship between cortisol dysregulation and major depressive disorder is complex, characterized by HPA axis hyperactivity and chronic inflammation. Lastly, chronic pain is associated with abnormal cortisol patterns that heighten pain sensitivity and susceptibility. Understanding these multifaceted mechanisms and their effects is essential, as they offer insights into potential interventions to mitigate the detrimental consequences of chronic stress and cortisol dysregulation in these conditions.
Topics: Animals; Hydrocortisone; Depressive Disorder, Major; Neurodegenerative Diseases; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System
PubMed: 38067154
DOI: 10.3390/cells12232726 -
PLoS Biology Dec 2023Visual system function depends upon the elaboration of precise connections between retinal ganglion cell (RGC) axons and their central targets in the brain. Though some...
Visual system function depends upon the elaboration of precise connections between retinal ganglion cell (RGC) axons and their central targets in the brain. Though some progress has been made in defining the molecules that regulate RGC connectivity required for the assembly and function of image-forming circuitry, surprisingly little is known about factors required for intrinsically photosensitive RGCs (ipRGCs) to target a principal component of the non-image-forming circuitry: the suprachiasmatic nucleus (SCN). Furthermore, the molecules required for forming circuits critical for circadian behaviors within the SCN are not known. We observe here that the adhesion molecule teneurin-3 (Tenm3) is highly expressed in vasoactive intestinal peptide (VIP) neurons located in the core region of the SCN. Since Tenm3 is required for other aspects of mammalian visual system development, we investigate roles for Tenm3 in regulating ipRGC-SCN connectivity and function. Our results show that Tenm3 negatively regulates association between VIP and arginine vasopressin (AVP) neurons within the SCN and is essential for M1 ipRGC axon innervation to the SCN. Specifically, in Tenm3-/- mice, we find a reduction in ventro-medial innervation to the SCN. Despite this reduction, Tenm3-/- mice have higher sensitivity to light and faster re-entrainment to phase advances, probably due to the increased association between VIP and AVP neurons. These data show that Tenm3 plays key roles in elaborating non-image-forming visual system circuitry and that it influences murine responses to phase-advancing light stimuli.
Topics: Animals; Mice; Axons; Circadian Rhythm; Mammals; Retinal Ganglion Cells; Suprachiasmatic Nucleus; Vasoactive Intestinal Peptide
PubMed: 38048352
DOI: 10.1371/journal.pbio.3002412 -
Proceedings of the National Academy of... Dec 2023The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of a central circadian clock that orchestrates overt rhythms of physiology and behavior. Circadian...
The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of a central circadian clock that orchestrates overt rhythms of physiology and behavior. Circadian timekeeping requires intercellular communication among SCN neurons, and multiple signaling pathways contribute to SCN network coupling. Gamma-aminobutyric acid (GABA) is produced by virtually all SCN neurons, and previous work demonstrates that this transmitter regulates coupling in the adult SCN but is not essential for the nucleus to sustain overt circadian rhythms. Here, we show that the deletion of the gene that codes for the GABA vesicular transporter from neuromedin-S (NMS) neurons-a subset of neurons critical for SCN function-causes arrhythmia of locomotor activity and sleep. Further, NMS- deletion impairs intrinsic clock gene rhythms in SCN explants cultured ex vivo. Although vasoactive intestinal polypeptide (VIP) is critical for SCN function, deletion from VIP-expressing neurons did not lead to circadian arrhythmia in locomotor activity rhythms. Likewise, adult SCN-specific deletion of led to mild impairment of behavioral rhythms. Our results suggest that while the removal of GABA release from the adult SCN does not affect the pacemaker's ability to sustain overt circadian rhythms, its removal from a critical subset of neurons within the SCN throughout development removes the nucleus ability to sustain circadian rhythms. Our findings support a model in which SCN GABA release is critical for the developmental establishment of intercellular network properties that define the SCN as a central pacemaker.
Topics: Humans; Circadian Rhythm; Neurons; Circadian Clocks; Vasoactive Intestinal Peptide; Suprachiasmatic Nucleus; gamma-Aminobutyric Acid; Arrhythmias, Cardiac
PubMed: 38019855
DOI: 10.1073/pnas.2314857120 -
Genes Nov 2023Knowledge of circadian rhythm clock gene expression outside the suprachiasmatic nucleus is increasing. The purpose of this study was to determine whether expression of...
Knowledge of circadian rhythm clock gene expression outside the suprachiasmatic nucleus is increasing. The purpose of this study was to determine whether expression of circadian clock genes differed within or among the bovine stress axis tissues (e.g., amygdala, hypothalamus, pituitary, adrenal cortex, and adrenal medulla). Tissues were obtained at an abattoir from eight mature nonpregnant Brahman cows that had been maintained in the same pasture and nutritional conditions. Sample tissues were stored in RNase-free sterile cryovials at -80 °C until the total RNA was extracted, quantified, assessed, and sequenced (NovaSeq 6000 system; paired-end 150 bp cycles). The trimmed reads were then mapped to a () reference genome (Umd3.1). Further analysis used the edgeR package. Raw gene count tables were read into RStudio, and low-expression genes were filtered out using the criteria of three minimum reads per gene in at least five samples. Normalization factors were then calculated using the trimmed mean of M values method to produce normalized gene counts within each sample tissue. The normalized gene counts important for a circadian rhythm were analyzed within and between each tissue of the stress axis using the GLM and CORR procedures of the Statistical Analysis System (SAS). The relative expression profiles of circadian clock genes differed ( < 0.01) within each tissue, with neuronal PAS domain protein 2 () having greater expression in the amygdala ( < 0.01) and period circadian regulator () having greater expression in all other tissues ( < 0.01). The expression among tissues also differed ( < 0.01) for individual circadian clock genes, with circadian locomotor output cycles protein kaput () expression being greater within the adrenal tissues and nuclear receptor subfamily 1 group D member 1 () expression being greater within the other tissues ( < 0.01). Overall, the results indicate that within each tissue, the various circadian clock genes were differentially expressed, in addition to being differentially expressed among the stress tissues of mature Brahman cows. Future use of these findings may assist in improving livestock husbandry and welfare by understanding interactions of the environment, stress responsiveness, and peripheral circadian rhythms.
Topics: Female; Cattle; Animals; Circadian Clocks; Period Circadian Proteins; Circadian Rhythm; Hypothalamus; Adrenal Glands
PubMed: 38003025
DOI: 10.3390/genes14112082 -
Current Biology : CB Dec 2023Endotherms can survive low temperatures and food shortage by actively entering a hypometabolic state known as torpor. Although the decrease in metabolic rate and body...
Endotherms can survive low temperatures and food shortage by actively entering a hypometabolic state known as torpor. Although the decrease in metabolic rate and body temperature (Tb) during torpor is controlled by the brain, the specific neural circuits underlying these processes have not been comprehensively elucidated. In this study, we identify the neural circuits involved in torpor regulation by combining whole-brain mapping of torpor-activated neurons, cell-type-specific manipulation of neural activity, and viral tracing-based circuit mapping. We find that Trpm2-positive neurons in the preoptic area and Vgat-positive neurons in the dorsal medial hypothalamus are activated during torpor. Genetic silencing shows that the activity of either cell type is necessary to enter the torpor state. Finally, we show that these cells receive projections from the arcuate and suprachiasmatic nucleus and send projections to brain regions involved in thermoregulation. Our results demonstrate an essential role of hypothalamic neurons in the regulation of Tb and metabolic rate during torpor and identify critical nodes of the torpor regulatory network.
Topics: Hypothalamus; Torpor; Preoptic Area; Suprachiasmatic Nucleus; Brain
PubMed: 37992720
DOI: 10.1016/j.cub.2023.10.076