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Journal of Biological Rhythms Apr 2024It has been 50 years since the suprachiasmatic nucleus (SCN) was first identified as the central circadian clock and 25 years since the last overview of developments... (Review)
Review
It has been 50 years since the suprachiasmatic nucleus (SCN) was first identified as the central circadian clock and 25 years since the last overview of developments in the field was published in the . Here, we explore new mechanisms and concepts that have emerged in the subsequent 25 years. Since 1997, methodological developments, such as luminescent and fluorescent reporter techniques, have revealed intricate relationships between cellular and network-level mechanisms. In particular, specific neuropeptides such as arginine vasopressin, vasoactive intestinal peptide, and gastrin-releasing peptide have been identified as key players in the synchronization of cellular circadian rhythms within the SCN. The discovery of multiple oscillators governing behavioral and physiological rhythms has significantly advanced our understanding of the circadian clock. The interaction between neurons and glial cells has been found to play a crucial role in regulating these circadian rhythms within the SCN. Furthermore, the properties of the SCN network vary across ontogenetic stages. The application of cell type-specific genetic manipulations has revealed components of the functional input-output system of the SCN and their correlation with physiological functions. This review concludes with the high-risk effort of identifying open questions and challenges that lie ahead.
Topics: Circadian Rhythm; Neuropeptides; Suprachiasmatic Nucleus; Vasoactive Intestinal Peptide; Gastrin-Releasing Peptide
PubMed: 38366616
DOI: 10.1177/07487304231225706 -
International Journal of Molecular... Feb 2024Prostaglandins are bioactive compounds, and the activation of their receptors affects the expression of clock genes. However, the prostaglandin F receptor () has no...
Prostaglandins are bioactive compounds, and the activation of their receptors affects the expression of clock genes. However, the prostaglandin F receptor () has no known relationship with biological rhythms. Here, we first measured the locomotor period lengths of (B6.129-) mice and found that they were longer under constant dark conditions (DD) than those of wild-type (C57BL/6J) mice. We then investigated the clock gene patterns within the suprachiasmatic nucleus in mice under DD and observed a decrease in the expression of the clock gene cryptochrome 1 (), which is related to the circadian cycle. Moreover, the expression of , , and () mRNA were significantly altered in the mouse liver in mice under DD. In the wild-type mouse, the plasma prostaglandin F (PGF) levels showed a circadian rhythm under a 12 h cycle of light-dark conditions. In addition, in vitro experiments showed that the addition of PTGFR agonists altered the amplitude of ::luc activity, and this alteration differed with the timing of the agonist addition. These results lead us to hypothesize that the plasma rhythm of PGF is important for driving clock genes, thus suggesting the involvement of PGF- and -targeting drugs in the biological clock cycle.
Topics: Mice; Animals; Dinoprost; Mice, Inbred C57BL; Circadian Rhythm; Biological Clocks; Suprachiasmatic Nucleus; Gene Expression; Cryptochromes
PubMed: 38339119
DOI: 10.3390/ijms25031841 -
Frontiers in Physiology 2023Light-sensitive neurons are located in the ventral and central core of the suprachiasmatic nucleus (SCN), whereas stably oscillating clock neurons are found mainly in...
Light-sensitive neurons are located in the ventral and central core of the suprachiasmatic nucleus (SCN), whereas stably oscillating clock neurons are found mainly in the dorsal shell. Signals between the SCN core and shell are believed to play an important role in light entrainment. Core neurons express vasoactive intestinal polypeptide (VIP), gastrin-releasing peptide (GRP), and Neuroglobin (Ngb), whereas the shell neurons express vasopressin (AVP), prokineticin 2, and the VIP type 2 (VPAC2) receptor. In rodents, light has a phase-shifting capacity at night, which induces rapid and transient expression of the EGR1 and FOS in the SCN. The present study used immunohistochemical staining of FOS, EGR1, and phenotypical markers of SCN neurons (VIP, AVP, Ngb) to identify subtypes/populations of light-responsive neurons at early night. Double immunohistochemistry and cell counting were used to evaluate the number of SCN neurons expressing FOS and EGR1 in the SCN. The number of neurons expressing either EGR1 or FOS was higher than the total number of neurons co-storing EGR1 and FOS. Of the total number of light-responsive cells, 42% expressed only EGR1, 43% expressed only FOS, and 15% expressed both EGR1 and FOS. Light-responsive VIP neurons represented only 31% of all VIP neurons, and EGR1 represents the largest group of light-responsive VIP neurons (18%). VIP neurons expressing only FOS represented 1% of the total light-responsive VIP neurons. 81% of the Ngb neurons in the mouse SCN were light-responsive, and of these neurons expressing only EGR1 after light stimulation represented 44%, whereas 24% expressed FOS. Although most light-responsive neurons are found in the core of the SCN, 29% of the AVP neurons in the shell were light-responsive, of which 8% expressed EGR1, 10% expressed FOS, and 11% co-expressed both EGR1 and FOS after light stimulation. Our analysis revealed cell-specific differences in light responsiveness between different peptidergic and Ngb-expressing neurons in different compartments of the mouse SCN, indicating that light activates diverse neuronal networks in the SCN, some of which participate in photoentrainment.
PubMed: 38317846
DOI: 10.3389/fphys.2023.1321007 -
Neurobiology of Disease Mar 2024The most prominent symptom of Alzheimer's disease (AD) is cognitive decline; however, sleep and other circadian disruptions are also common in AD patients. Sleep...
The amyloid precursor protein intracellular domain induces sleep disruptions and its nuclear localization fluctuates in circadian pacemaker neurons in Drosophila and mice.
The most prominent symptom of Alzheimer's disease (AD) is cognitive decline; however, sleep and other circadian disruptions are also common in AD patients. Sleep disruptions have been connected with memory problems and therefore the changes in sleep patterns observed in AD patients may also actively contribute to cognitive decline. However, the underlying molecular mechanisms that connect sleep disruptions and AD are unclear. A characteristic feature of AD is the formation of plaques consisting of Amyloid-β (Aβ) peptides generated by cleavage of the Amyloid Precursor Protein (APP). Besides Aβ, APP cleavage generates several other fragments, including the APP intracellular domain (AICD) that has been linked to transcriptional regulation and neuronal homeostasis. Here we show that overexpression of the AICD reduces the early evening expression of two core clock genes and disrupts the sleep pattern in flies. Analyzing the subcellular localization of the AICD in pacemaker neurons, we found that the AICD levels in the nucleus are low during daytime but increase at night. While this pattern of nuclear AICD persisted with age, the nighttime levels were higher in aged flies. Increasing the cleavage of the fly APP protein also disrupted AICD nuclear localization. Lastly, we show that the day/nighttime nuclear pattern of the AICD is also detectable in neurons in the suprachiasmatic nucleus of mice and that it also changes with age. Together, these data suggest that AD-associated changes in APP processing and the subsequent changes in AICD levels may cause sleep disruptions in AD.
Topics: Animals; Humans; Aged; Amyloid beta-Protein Precursor; Drosophila; Central Pattern Generators; Alzheimer Disease; Amyloid beta-Peptides; Sleep
PubMed: 38309627
DOI: 10.1016/j.nbd.2024.106429 -
Frontiers in Psychology 2023The evaluation of pupillary light reflex (PLR) by chromatic pupillometry may provide a unique insight into specific photoreceptor functions. Chromatic pupillometry... (Review)
Review
The evaluation of pupillary light reflex (PLR) by chromatic pupillometry may provide a unique insight into specific photoreceptor functions. Chromatic pupillometry refers to evaluating PLR to different wavelengths and intensities of light in order to differentiate outer/inner retinal photoreceptor contributions to the PLR. Different protocols have been tested and are now established to assess PLR contribution mediated by melanopsin retinal ganglion cells (mRGCs). These intrinsically photosensitive photoreceptors modulate the non-image-forming functions of the eye, which are mainly the circadian photoentrainment and PLR, via projections to the hypothalamic suprachiasmatic and olivary pretectal nucleus, respectively. In this context, chromatic pupillometry has been used as an alternative and non-invasive tool to evaluate the mRGC system in several clinical settings, including hereditary optic neuropathies, glaucoma, and neurodegenerative disorders such as Parkinson's disease (PD), idiopathic/isolated rapid eye movement sleep behavior disorder (iRBD), and Alzheimer's disease (AD). The purpose of this article is to review the key steps of chromatic pupillometry protocols for studying mRGC-system functionality and provide the main findings of this technique in the research setting on neurodegeneration. mRGC-dependent pupillary responses are short-wavelength sensitive, have a higher threshold of activation, and are much slower and sustained compared with rod- and cone-mediated responses, driving the tonic component of the PLR during exposure to high-irradiance and continuous light stimulus. Thus, mRGCs contribute mainly to the tonic component of the post-illumination pupil response (PIPR) to bright blue light flash that persists after light stimulation is switched off. Given the role of mRGCs in circadian photoentrainment, the use of chromatic pupillometry to perform a functional evaluation of mRGcs may be proposed as an early biomarker of mRGC-dysfunction in neurodegenerative disorders characterized by circadian and/or sleep dysfunction such as AD, PD, and its prodromal phase iRBD. The evaluation by chromatic pupillometry of mRGC-system functionality may lay the groundwork for a new, easily accessible biomarker that can be exploited also as the starting point for future longitudinal cohort studies aimed at stratifying the risk of conversion in these disorders.
PubMed: 38259552
DOI: 10.3389/fpsyg.2023.1295129 -
Frontiers in Neuroanatomy 2023The catecholaminergic component of the brain-pituitary-gonadal axis, which mediates the influence of external and internal stimuli on the central nervous system and...
Ontogenetic changes in the tyrosine hydroxylase immunoreactive preoptic area in the small-spotted catshark (L., 1758) females: catecholaminergic involvement in sexual maturation.
INTRODUCTION
The catecholaminergic component of the brain-pituitary-gonadal axis, which mediates the influence of external and internal stimuli on the central nervous system and gonad development in vertebrates, is largely unexplored in Chondrichthyes. We considered (L., 1758) females as a model for this vertebrate's class, to assess the involvement of the catecholaminergic system of the brain in its reproduction. Along the reproductive cycle, we characterized and evaluated differences in somata morphometry and the number of putative catecholaminergic neurons in two brain nuclei: the periventricular preoptic nucleus, hypothesized to be a positive control for ovarian development, and the suprachiasmatic nucleus, examined as a negative control.
MATERIALS AND METHODS
16 wild females were sampled and grouped in maturity stages (immature, maturing, mature, and mature egg-laying). The ovary was histologically processed for the qualitative description of maturity stages. Anti-tyrosine hydroxylase immunofluorescence was performed on the diencephalic brain sections. The immunoreactive somata were investigated for morphometry and counted using the optical fractionator method, throughout the confocal microscopy.
RESULTS AND DISCUSSIONS
Qualitative and quantitative research confirmed two separate populations of immunoreactive neurons. The modifications detected in the preoptic nucleus revealed that somata were more numerous, significantly smaller in size, and more excitable during the maturing phase but decreased, becoming slightly bigger and less excitable in the egg-laying stage. This may indicate that the catecholaminergic preoptic nucleus is involved in the control of reproduction, regulating both the onset of puberty and the imminent spawning. In contrast, somata in the suprachiasmatic nucleus grew in size and underwent turnover in morphometry, increasing the total number from the immature-virgin to maturing stage, with similar values in the more advanced maturity stages. These changes were not linked to a reproductive role. These findings provide new valuable information on Chondrichthyes, suggesting the existence of an additional brain system implicated in the integration of internal and environmental cues for reproduction.
PubMed: 38239387
DOI: 10.3389/fnana.2023.1301651 -
Neural Regeneration Research Sep 2024Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer's disease. A predominant function of the retina is circadian synchronization, carrying...
Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer's disease. A predominant function of the retina is circadian synchronization, carrying information to the brain through the retinohypothalamic tract, which projects to the suprachiasmatic nucleus. Notably, Alzheimer's disease hallmarks, including amyloid-β, are present in the retinas of Alzheimer's disease patients, followed/associated by structural and functional disturbances. However, the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in Alzheimer's disease is not fully understood, although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.
PubMed: 38227523
DOI: 10.4103/1673-5374.390962 -
IScience Jan 2024The biological rhythms governed by negative feedback loops have undergone extensive investigation. However, developing reliable and versatile warning signals to predict...
The biological rhythms governed by negative feedback loops have undergone extensive investigation. However, developing reliable and versatile warning signals to predict periodic fluctuations in physiological processes and behaviors associated with these rhythms remains a challenge. Here, we monitored the heart rate and tracked ovulation dates of 91 fertile women. The finding strongly links the velocity (derivative) of heart rate with ovulation in menstrual cycles, providing a predictive warning signal. Similarly, an analysis of calcium signaling in the suprachiasmatic nucleus (SCN) of mice reveals that the maximum velocity of rising calcium signal aligns with locomotor activity offsets. To demonstrate the generality of derivative-transitions link, numerical simulations using a negative feedback loop model were conducted. Statistical analysis indicated that over 90% of the oscillations exhibited a correlation between maximum velocity and transition points. Consequently, the maximum velocity derived from oscillatory curves holds significant potential as an early warning signal for critical transitions.
PubMed: 38226166
DOI: 10.1016/j.isci.2023.108716 -
Biology of Sex Differences Jan 2024Patients with anorexia nervosa (AN) often present sleep disorders and circadian hormonal dysregulation. The role of the microbiota-gut-brain axis in the regulation of...
RATIONALE
Patients with anorexia nervosa (AN) often present sleep disorders and circadian hormonal dysregulation. The role of the microbiota-gut-brain axis in the regulation of feeding behavior has emerged during the last decades but its relationships with the circadian rhythm remains poorly documented. Thus, we aimed to characterize the circadian clock genes expression in peripheral and central tissues in the activity-based anorexia mouse model (ABA), as well as the dynamics of the gut-microbiota composition.
METHODS
From day 1 to day 17, male and female C57Bl/6 mice were submitted or not to the ABA protocol (ABA and control (CT) groups), which combines a progressive limited access to food and a free access to a running wheel. At day 17, fasted CT and ABA mice were euthanized after either resting (EoR) or activity (EoA) phase (n = 10-12 per group). Circadian clock genes expression was assessed by RT-qPCR on peripheral (liver, colon and ileum) and central (hypothalamic suprachiasmatic nucleus or SCN) tissues. Cecal bacterial taxa abundances were evaluated by qPCR. Data were compared by two-way ANOVA followed by post-tests.
RESULTS
ABA mice exhibited a lower food intake, a body weight loss and an increase of diurnal physical activity that differ according with the sex. Interestingly, in the SCN, only ABA female mice exhibited altered circadian clock genes expression (Bmal1, Per1, Per2, Cry1, Cry2). In the intestinal tract, modification of clock genes expression was also more marked in females compared to males. For instance, in the ileum, female mice showed alteration of Bmal1, Clock, Per1, Per2, Cry1, Cry2 and Rev-erbα mRNA levels, while only Per2 and Cry1 mRNAs were affected by ABA model in males. By contrast, in the liver, clock genes expression was more markedly affected in males compared to females in response to ABA. Finally, circadian variations of gut-bacteria abundances were observed in both male and female mice and sex-dependent alteration were observed in response to the ABA model.
CONCLUSIONS
This study shows that alteration of circadian clock genes expression at both peripheral and central levels occurs in response to the ABA model. In addition, our data underline that circadian variations of the gut-microbiota composition are sex-dependent.
Topics: Animals; Female; Male; Mice; Anorexia; ARNTL Transcription Factors; Circadian Rhythm; Gene Expression; Microbiota; RNA, Messenger; CLOCK Proteins
PubMed: 38217033
DOI: 10.1186/s13293-023-00576-x