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Frontiers in Endocrinology 2023The suprachiasmatic nucleus (SCN) within the hypothalamus is a key brain structure required to relay light information to the body and synchronize cell and tissue level...
The transcription factor VAX1 in VIP neurons of the suprachiasmatic nucleus impacts circadian rhythm generation, depressive-like behavior, and the reproductive axis in a sex-specific manner in mice.
BACKGROUND
The suprachiasmatic nucleus (SCN) within the hypothalamus is a key brain structure required to relay light information to the body and synchronize cell and tissue level rhythms and hormone release. Specific subpopulations of SCN neurons, defined by their peptide expression, regulate defined SCN output. Here we focus on the vasoactive intestinal peptide (VIP) expressing neurons of the SCN. SCN VIP neurons are known to regulate circadian rhythms and reproductive function.
METHODS
To specifically study SCN VIP neurons, we generated a novel knock out mouse line by conditionally deleting the SCN enriched transcription factor, Ventral Anterior Homeobox 1 (Vax1), in VIP neurons (Vax1; Vax1:Vip).
RESULTS
We found that Vax1 females presented with lengthened estrous cycles, reduced circulating estrogen, and increased depressive-like behavior. Further, Vax1 males and females presented with a shortened circadian period in locomotor activity and SCN circadian period. On a molecular level, the shortening of the SCN period was driven, at least partially, by a direct regulatory role of VAX1 on the circadian clock genes and . Interestingly, Vax1 females presented with increased expression of arginine vasopressin () in the paraventricular nucleus, which resulted in increased circulating corticosterone. SCN VIP and AVP neurons regulate the reproductive gonadotropin-releasing hormone (GnRH) and kisspeptin neurons. To determine how the reproductive neuroendocrine network was impacted in Vax1 mice, we assessed GnRH sensitivity to a kisspeptin challenge . We found that GnRH neurons in Vax1 females, but not males, had an increased sensitivity to kisspeptin, leading to increased luteinizing hormone release. Interestingly, Vax1 males showed a small, but significant increase in total sperm and a modest delay in pubertal onset. Both male and female Vax1 mice were fertile and generated litters comparable in size and frequency to controls.
CONCLUSION
Together, these data identify VAX1 in SCN VIP neurons as a neurological overlap between circadian timekeeping, female reproduction, and depressive-like symptoms in mice, and provide novel insight into the role of SCN VIP neurons.
Topics: Male; Female; Animals; Mice; Transcription Factors; Vasoactive Intestinal Peptide; Kisspeptins; Semen; Suprachiasmatic Nucleus; Reproduction; Neurons; Circadian Rhythm; Gonadotropin-Releasing Hormone; Neuropeptides; Homeodomain Proteins
PubMed: 38205198
DOI: 10.3389/fendo.2023.1269672 -
Molecular Neurodegeneration Jan 2024Tauopathies, a group of neurodegenerative diseases that includes Alzheimer's disease, commonly lead to disturbances in sleep-wake patterns and circadian rhythm... (Review)
Review
Tauopathies, a group of neurodegenerative diseases that includes Alzheimer's disease, commonly lead to disturbances in sleep-wake patterns and circadian rhythm disorders. The circadian rhythm, a recurring 24-hour cycle governing human biological activity, is regulated by the hypothalamic suprachiasmatic nucleus (SCN) and endogenous transcriptional-translational feedback loops. Surprisingly, little attention has been given to investigating tauopathy-driven neuropathology in the SCN and the repercussions of SCN and circadian gene dysfunction in the human brain affected by tauopathies. This review aims to provide an overview of the current literature on the vulnerability of the SCN in tauopathies in humans. Emphasis is placed on elucidating the neuronal and glial changes contributing to the widespread disruption of the molecular circadian clock. Furthermore, this review identifies areas of knowledge requiring further investigation.
Topics: Animals; Humans; Neuroglia; Tauopathies; Suprachiasmatic Nucleus; Alzheimer Disease; Models, Animal
PubMed: 38195580
DOI: 10.1186/s13024-023-00695-4 -
Frontiers in Neuroscience 2023The suprachiasmatic nucleus (SCN) of the hypothalamus is the master circadian clock in mammals. SCN neurons exhibit circadian Ca rhythms in the cytosol, which is thought...
The suprachiasmatic nucleus (SCN) of the hypothalamus is the master circadian clock in mammals. SCN neurons exhibit circadian Ca rhythms in the cytosol, which is thought to act as a messenger linking the transcriptional/translational feedback loop (TTFL) and physiological activities. Transcriptional regulation occurs in the nucleus in the TTFL model, and Ca-dependent kinase regulates the clock gene transcription. However, the Ca regulatory mechanisms between cytosol and nucleus as well as the ionic origin of Ca rhythms remain unclear. In the present study, we monitored circadian-timescale Ca dynamics in the nucleus and cytosol of SCN neurons at the single-cell and network levels. We observed robust nuclear Ca rhythm in the same phase as the cytosolic rhythm in single SCN neurons and entire regions. Neuronal firing inhibition reduced the amplitude of both nuclear and cytosolic Ca rhythms, whereas blocking of Ca release from the endoplasmic reticulum (ER) via ryanodine and inositol 1,4,5-trisphosphate (IP) receptors had a minor effect on either Ca rhythms. We conclude that the in-phasic circadian Ca rhythms in the cytosol and nucleus are mainly driven by Ca influx from the extracellular space, likely through the nuclear pore. It also raises the possibility that nuclear Ca rhythms directly regulate transcription
PubMed: 38178840
DOI: 10.3389/fnins.2023.1323565 -
Diabetes & Metabolism Journal Jan 2024Novel strategies are required to reduce the risk of developing diabetes and/or clinical outcomes and complications of diabetes. In this regard, the role of the circadian... (Review)
Review
Novel strategies are required to reduce the risk of developing diabetes and/or clinical outcomes and complications of diabetes. In this regard, the role of the circadian system may be a potential candidate for the prevention of diabetes. We reviewed evidence from animal, clinical, and epidemiological studies linking the circadian system to various aspects of the pathophysiology and clinical outcomes of diabetes. The circadian clock governs genetic, metabolic, hormonal, and behavioral signals in anticipation of cyclic 24-hour events through interactions between a "central clock" in the suprachiasmatic nucleus and "peripheral clocks" in the whole body. Currently, circadian rhythmicity in humans can be subjectively or objectively assessed by measuring melatonin and glucocorticoid levels, core body temperature, peripheral blood, oral mucosa, hair follicles, rest-activity cycles, sleep diaries, and circadian chronotypes. In this review, we summarized various circadian misalignments, such as altered light-dark, sleep-wake, rest-activity, fasting-feeding, shift work, evening chronotype, and social jetlag, as well as mutations in clock genes that could contribute to the development of diabetes and poor glycemic status in patients with diabetes. Targeting critical components of the circadian system could deliver potential candidates for the treatment and prevention of type 2 diabetes mellitus in the future.
Topics: Animals; Humans; Diabetes Mellitus, Type 2; Circadian Rhythm; Circadian Clocks; Melatonin; Sleep
PubMed: 38173377
DOI: 10.4093/dmj.2023.0193 -
International Journal of Biological... 2024Rhythmicity of the circadian system is a 24-hour period, driven by transcription-translation feedback loops of circadian clock genes. The central circadian pacemaker in... (Review)
Review
Rhythmicity of the circadian system is a 24-hour period, driven by transcription-translation feedback loops of circadian clock genes. The central circadian pacemaker in mammals is located in the hypothalamic suprachiasmatic nucleus (SCN), which controls peripheral circadian clocks. In general, most physiological processes are regulated by the circadian system, which is modulated by environmental cues such as exposure to light and/or dark, temperature, and the timing of sleep/wake and food intake. The chronic circadian disruption caused by shift work, jetlag, and/or irregular sleep-wake cycles has long-term health consequences. Its dysregulation contributes to the risk of psychiatric disorders, sleep abnormalities, hypothyroidism and hyperthyroidism, cancer, and obesity. A number of neurological conditions may be worsened by changes in the circadian clock via the SCN pacemaker. For stroke, different physiological activities such as sleep/wake cycles are disrupted due to alterations in circadian rhythms. Moreover, the immunological processes that affect the evolution and recovery processes of stroke are regulated by the circadian clock or core-clock genes. Thus, disrupted circadian rhythms may increase the severity and consequences of stroke, while readjustment of circadian clock machinery may accelerate recovery from stroke. In this manuscript, we discuss the relationship between stroke and circadian rhythms, particularly on stroke development and its recovery process. We focus on immunological and/or molecular processes linking stroke and the circadian system and suggest the circadian rhythm as a target for designing effective therapeutic strategies in stroke.
Topics: Animals; Humans; Circadian Clocks; Circadian Rhythm; Suprachiasmatic Nucleus; Sleep; Mammals; Stroke
PubMed: 38169640
DOI: 10.7150/ijbs.88370 -
Journal of Biomedical Research Dec 2023In mammals, the timing of physiological, biochemical and behavioral processes over a 24-h period is controlled by circadian rhythms. To entrain the master clock located...
In mammals, the timing of physiological, biochemical and behavioral processes over a 24-h period is controlled by circadian rhythms. To entrain the master clock located in the suprachiasmatic nucleus of the hypothalamus to a precise 24-h rhythm, environmental zeitgebers are used by the circadian system. This is done primarily by signals from the retina the retinohypothalamic tract, but other cues like exercise, feeding, temperature, anxiety, and social events have also been shown to act as non-photic zeitgebers. The recently identified myokine irisin is proposed to serve as an entraining non-photic signal of exercise. Irisin is a product of cleavage and modification from its precursor membrane fibronectin type Ⅲ domain-containing protein 5 (FNDC5) in response to exercise. Apart from well-known peripheral effects, such as inducing the "browning" of white adipocytes, irisin can penetrate the blood-brain barrier and display the effects on the brain. Experimental data suggest that FNDC5/irisin mediates the positive effects of physical activity on brain functions. In several brain areas, irisin induces the production of brain-derived neurotrophic factor (BDNF). In the master clock, a significant role in gating photic stimuli in the retinohypothalamic synapse for BDNF is suggested. However, the brain receptor for irisin remains unknown. In the current review, the interactions of physical activity and the irisin/BDNF axis with the circadian system are reconceptualized.
PubMed: 38164079
DOI: 10.7555/JBR.37.20230133 -
Journal of Alzheimer's Disease : JAD 2024Chronic disruption of the circadian timing system, often reflected as a loss of restful sleep, also includes myriad other pathophysiological effects.
BACKGROUND
Chronic disruption of the circadian timing system, often reflected as a loss of restful sleep, also includes myriad other pathophysiological effects.
OBJECTIVE
The current study examined how chronic circadian disruption (CD) could contribute to pathology and rate of progression in the AβPP/PS1 mouse model of Alzheimer's disease (AD).
METHODS
A chronic CD was imposed until animals reached 6 or 12 months of age in AβPP/PS1 and C57BL/6J control mice. Home cage activity was monitored for a period of 3-4 weeks prior to the endpoint along with a single timepoint measure of glucose sensitivity. To assess long term effects of CD on the AD phenotype, animals were re-entrained to a no disruption (ND) schedule just prior to the endpoint, after which a Morris water maze (MWM) was used to assess spatial learning and memory.
RESULTS
Dampening of nighttime activity levels occurred in disrupted animals, and female animals demonstrated a greater adaptability to CD. Diminished arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) levels in the suprachiasmatic nucleus (SCN) of 12-month male AβPP/PS1 exposed to the CD paradigm were observed, potentially accounting for the diminished re-entrainment response. Similarly, CD worsened performance in the MWM in 12-month male AβPP/PS1 animals, whereas no effect was seen in females.
CONCLUSIONS
Collectively, these findings show that exposure to chronic CD impairs circadian behavioral patterns and cognitive phenotypes of AβPP/PS1 mouse model in a sex-dependent manner.
Topics: Mice; Male; Female; Animals; Amyloid beta-Protein Precursor; Mice, Transgenic; Mice, Inbred C57BL; Alzheimer Disease; Disease Models, Animal; Presenilin-1
PubMed: 38143343
DOI: 10.3233/JAD-230089 -
International Journal of Molecular... Dec 2023The circadian rhythm is a 24 h internal clock within the body that regulates various factors, including sleep, body temperature, and hormone secretion. Circadian rhythm... (Review)
Review
The circadian rhythm is a 24 h internal clock within the body that regulates various factors, including sleep, body temperature, and hormone secretion. Circadian rhythm disruption is an important risk factor for many diseases including neurodegenerative illnesses. The central and peripheral oscillators' circadian clock network controls the circadian rhythm in mammals. The clock genes govern the central clock in the suprachiasmatic nucleus (SCN) of the brain. One function of the circadian clock is regulating lipid metabolism. However, investigations of the circadian regulation of lipid metabolism-associated apolipoprotein genes in the brain are lacking. This review summarizes the rhythmic expression of clock genes and lipid metabolism-associated apolipoprotein genes within the SCN in . Nine of the twenty apolipoprotein genes identified from searching the published database (SCNseq and CircaDB) are highly expressed in the SCN. Most apolipoprotein genes (ApoE, ApoC1, apoA1, ApoH, ApoM, and Cln) show rhythmic expression in the brain in mice and thus might be regulated by the master clock. Therefore, this review summarizes studies on lipid-associated apolipoprotein genes in the SCN and other brain locations, to understand how apolipoproteins associated with perturbed cerebral lipid metabolism cause multiple brain diseases and disorders. This review describes recent advancements in research, explores current questions, and identifies directions for future research.
Topics: Mice; Animals; Lipid Metabolism; Brain; Circadian Rhythm; Suprachiasmatic Nucleus; Circadian Clocks; Apolipoproteins; Mammals
PubMed: 38139244
DOI: 10.3390/ijms242417415 -
Scientific Reports Dec 2023Circadian (24-h) rhythms in the suprachiasmatic nucleus (SCN) are established in utero in rodents, but rhythmicity of peripheral circadian clocks appears later in...
Circadian (24-h) rhythms in the suprachiasmatic nucleus (SCN) are established in utero in rodents, but rhythmicity of peripheral circadian clocks appears later in postnatal development. Since peripheral oscillators can be influenced by maternal feeding and behavior, we investigated whether exposure to the adverse environmental conditions of limited bedding (LB) during postnatal life would alter rhythmicity in the SCN, adrenal gland and liver in neonatal (postnatal day PND10), juvenile (PND28) and adult rats. We also examined locomotor activity in adults. Limited bedding increased nursing time and slightly increased fragmentation of maternal behavior. Exposure to LB reduced the amplitude of Per2 in the SCN on PND10. Adrenal clock gene expression (Bmal1, Per2, Cry1, Rev-erbα, Dbp) and corticosterone secretion were rhythmic at all ages in NB offspring, whereas rhythmicity of Bmal1, Cry1 and corticosterone was abolished in neonatal LB pups. Circadian gene expression in the adrenal and liver was well established by PND28. In adults, liver expression of several circadian genes was increased at specific daytimes by LB and the microstructure of locomotor behavior was altered. Thus, changes in maternal care and behavior might provide important signals to the maturing peripheral oscillators and modify, in particular their output functions in the long-term.
Topics: Female; Rats; Animals; Circadian Rhythm; Corticosterone; ARNTL Transcription Factors; Circadian Clocks; Suprachiasmatic Nucleus
PubMed: 38129480
DOI: 10.1038/s41598-023-47968-y -
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