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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 -
The European Journal of Neuroscience Apr 2024The circadian clock orchestrates many physiological and behavioural rhythms in mammals with 24-h periodicity, through a hierarchical organisation, with the central clock...
The circadian clock orchestrates many physiological and behavioural rhythms in mammals with 24-h periodicity, through a hierarchical organisation, with the central clock located in the suprachiasmatic nucleus (SCN) in the hypothalamus. The circuits of the SCN generate circadian rhythms with precision, relying on intrinsic coupling mechanisms, for example, neurotransmitters like arginine vasopressin (AVP), vasoactive intestinal peptide (VIP), neuronal gamma-aminobutyric acid (GABA) signalling and astrocytes connected by gap junctions composed of connexins (Cx). In female rodents, the presence of estrogen receptors (ERs) in the dorsal SCN suggests an influence of estrogen (E2) on the circuit timekeeping that could regulate circadian rhythm and coupling. To investigate this, we used SCN explants together with hypothalamic neurons and astrocytes. First, we showed that E2 stabilised the circadian amplitude in the SCN when rAVPs (receptor-associated vasopressin peptides) were inhibited. However, the phase delay induced by VIPAC2 (VIP receptors) inhibition remained unaffected by E2. We then showed that E2 exerted its effects in the SCN via ERβ (estrogen receptor beta), resulting in increased expression of Cx36 and Cx43. Notably, specific inhibition of both connexins resulted in a significant reduction in circadian amplitude within the SCN. Remarkably, E2 restored the period with inhibited Cx36 but not with Cx43 inhibition. This implies that the network between astrocytes and neurons, responsible for coupling in the SCN, can be reinforced through E2. In conclusion, these findings provide new insights into how E2 regulates circadian rhythms ex vivo in an ERβ-dependent manner, underscoring its crucial role in fortifying the SCN's rhythm.
Topics: Animals; Female; Connexin 43; Estrogen Receptor beta; Suprachiasmatic Nucleus; Circadian Rhythm; Gap Junctions; Connexins; Vasoactive Intestinal Peptide; Estrogens; Mammals
PubMed: 38326974
DOI: 10.1111/ejn.16270 -
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 -
Chronobiology International Mar 2024Circadian rhythms play a pivotal role in governing various physiological processes, including physical performance. However, in individuals deprived of light perception,...
Circadian rhythms play a pivotal role in governing various physiological processes, including physical performance. However, in individuals deprived of light perception, such as the blind, these circadian rhythms face disruption. This study aimed to explore the influence of disturbed circadian rhythms on short-term maximal physical performance in children and adolescents with visual impairment. Forty-five volunteers participated in this study, comprising 17 blind, 13 visually impaired, and 15 sighted participants. The participants underwent a series of tests assessing maximal isometric strength performance across two days. To mitigate the influence of morning session fatigue on the evening results, each participant group performed in two separate testing sessions (. in the morning (7:00 h) and in the evening (17:00 h)) on non-consecutive days in a randomized and counterbalanced setting, with approximately 36 h of recovery time between sessions. To mitigate the impact of inter-individual differences on mean values and to account for the influence of age and sex on the studied variables, data were normalized. The outcomes revealed a significant diurnal variation in maximal isometric strength performance among sighted individuals, with peak performance observed in the evening. This pattern aligns with their well-entrained circadian rhythm. In contrast, blind and visually impaired individuals did not display significant diurnal variation, signaling disrupted circadian rhythms due to the absence of light perception. These findings emphasize the crucial consideration of circadian rhythms in assessments of physical performance, especially among participants with visual impairments.
Topics: Child; Humans; Adolescent; Circadian Rhythm; Body Temperature; Sleep Disorders, Circadian Rhythm; Fatigue; Physical Functional Performance
PubMed: 38303130
DOI: 10.1080/07420528.2024.2312814 -
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 -
Neuroreport Mar 2024Major depressive disorder (MDD) ranks among the top 10 leading causes of death. However, exercise is known to improve depressive symptoms but the mechanism responsible...
Major depressive disorder (MDD) ranks among the top 10 leading causes of death. However, exercise is known to improve depressive symptoms but the mechanism responsible is still unknown. To date, numerous studies have shown that molecular rhythms and exercise are associated with MDD. Thus, we hypothesized that exercise could affect the expression of central nervous system clock genes to improve depressive symptoms. Ninety adult male Sprague-Dawley rats (250 g) were divided into a control Normal Group, an unpredictable chronic mild stress (CMS) treated CMS Group and an Exercise Group, which was intervened by a moderate-intensity exercise training on a treadmill at 2 p.m. every day for 4 weeks after CMS treatment. The open field test, elevated plus maze and forced swim test were employed to test mood-related behaviors. The telemetry recording method recorded voluntary locomotor activity and core body temperature. Expression of core clock genes in the suprachiasmatic nucleus (SCN) was tested by qRT-PCR. Compared with the CMS Group, depressive symptoms were improved in the Exercise Group ( P < 0.05). Moreover, the periodic changes of molecular rhythms in the Exercise Group were close to those of rats in Normal Group. Next, exercise increased oscillations of expression of core clock genes in SCN after CMS treatment, and the amplitudes of core clock gene expression oscillations were negatively correlated with depressive-like behavior. Our findings suggested that exercise could change the expressions of central clock genes in MDD animals, and this effect was positively correlated with the improvement of depressive symptoms by exercise.
Topics: Rats; Male; Animals; Depression; Rats, Sprague-Dawley; Depressive Disorder, Major; Suprachiasmatic Nucleus; Exercise; Disease Models, Animal
PubMed: 38251445
DOI: 10.1097/WNR.0000000000001994 -
Life Sciences in Space Research Feb 2024The circadian clock extensively regulates physiology and behavior. In space, astronauts encounter many environmental factors that are dramatically different from those...
The circadian clock extensively regulates physiology and behavior. In space, astronauts encounter many environmental factors that are dramatically different from those on Earth; however, the effects of these factors on circadian rhythms and the mechanisms remain largely unknown. The present study aimed to investigate the changes in the mouse diurnal rhythm and gut microbiome under simulated space capsule conditions, including microgravity, noise and low atmospheric pressure (LAP). Noise and LAP were loaded in the capsule while the conditions in the animal room remained constant. The mice in the capsule showed disturbed locomotor rhythms and faster adaptation to a 6-h phase advance. RNA sequencing of hypothalamus samples containing the suprachiasmatic nucleus (SCN) revealed that microgravity simulated by hind limb unloading (HU) and exposure to noise and LAP led to decreases in the quantities of differentially expressed genes (DEGs), including circadian clock genes. Changes in the rhythmicity of genes implicated in pathways of cardiovascular deconditioning and more concentrated phases were found under HU or noise and LAP. Furthermore, 16S rRNA sequencing revealed dysbiosis in the gut microbiome, and noise and LAP may repress the temporal discrepancy in the microbiome community structure induced by microgravity. Changes in diurnal oscillations were observed in a number of gut bacteria with critical physiological consequences on metabolism and immunodefense. We also found that the superimposition of noise and LAP may repress normal changes in global gene expression and adaptation in the gut microbiome. Our data demonstrate that in addition to microgravity, exposure to noise and LAP affect the robustness of circadian rhythms and the community structure of the gut microbiome, and these factors may interfere with each other in their adaptation to respective conditions. These findings are important for furthering our understanding of the alterations in circadian rhythms in the complex environment of space.
Topics: Mice; Animals; Weightlessness; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Circadian Rhythm; Atmospheric Pressure
PubMed: 38245336
DOI: 10.1016/j.lssr.2023.09.006 -
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