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Cell Reports May 2024The suprachiasmatic nucleus (SCN) encodes time of day through changes in daily firing; however, the molecular mechanisms by which the SCN times behavior are not fully...
The suprachiasmatic nucleus (SCN) encodes time of day through changes in daily firing; however, the molecular mechanisms by which the SCN times behavior are not fully understood. To identify factors that could encode day/night differences in activity, we combine patch-clamp recordings and single-cell sequencing of individual SCN neurons in mice. We identify PiT2, a phosphate transporter, as being upregulated in a population of VipNms SCN neurons at night. Although nocturnal and typically showing a peak of activity at lights off, mice lacking PiT2 (PiT2) do not reach the activity level seen in wild-type mice during the light/dark transition. PiT2 loss leads to increased SCN neuronal firing and broad changes in SCN protein phosphorylation. PiT2 mice display a deficit in seasonal entrainment when moving from a simulated short summer to longer winter nights. This suggests that PiT2 is responsible for timing activity and is a driver of SCN plasticity allowing seasonal entrainment.
Topics: Animals; Suprachiasmatic Nucleus; Mice; Neurons; Locomotion; Mice, Inbred C57BL; Vasoactive Intestinal Peptide; Male; Circadian Rhythm; Photoperiod; Mice, Knockout; Sodium-Phosphate Cotransporter Proteins, Type III; Phosphate Transport Proteins
PubMed: 38735047
DOI: 10.1016/j.celrep.2024.114220 -
International Journal of Molecular... Apr 2024Long-term spaceflight is known to induce disruptions in circadian rhythms, which are driven by a central pacemaker located in the suprachiasmatic nucleus (SCN) of the...
Long-term spaceflight is known to induce disruptions in circadian rhythms, which are driven by a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus, but the underlying molecular mechanisms remain unclear. Here, we developed a rat model that simulated microgravity and isolation environments through tail suspension and isolation (TSI). We found that the TSI environment imposed circadian disruptions to the core body temperature, heart rate, and locomotor-activity rhythms of rats, especially in the amplitude of these rhythms. In TSI model rats' SCNs, the core circadian gene NR1D1 showed higher protein but not mRNA levels along with decreased BMAL1 levels, which indicated that NR1D1 could be regulated through post-translational regulation. The autophagosome marker LC3 could directly bind to NR1D1 via the LC3-interacting region (LIR) motifs and induce the degradation of NR1D1 in a mitophagy-dependent manner. Defects in mitophagy led to the reversal of NR1D1 degradation, thereby suppressing the expression of BMAL1. Mitophagy deficiency and subsequent mitochondrial dysfunction were observed in the SCN of TSI models. Urolithin A (UA), a mitophagy activator, demonstrated an ability to enhance the amplitude of core body temperature, heart rate, and locomotor-activity rhythms by prompting mitophagy induction to degrade NR1D1. Cumulatively, our results demonstrate that mitophagy exerts circadian control by regulating NR1D1 degradation, revealing mitophagy as a potential target for long-term spaceflight as well as diseases with SCN circadian disruption.
Topics: Animals; Mitophagy; Rats; Circadian Rhythm; Male; ARNTL Transcription Factors; Nuclear Receptor Subfamily 1, Group D, Member 1; Weightlessness Simulation; Suprachiasmatic Nucleus; Microtubule-Associated Proteins; Body Temperature; Heart Rate; Rats, Sprague-Dawley; Proteolysis
PubMed: 38732079
DOI: 10.3390/ijms25094853 -
Frontiers in Neuroscience 2024
PubMed: 38707592
DOI: 10.3389/fnins.2024.1371195 -
Journal of Advanced Research Apr 2024Melatonin is mainly secreted by the pineal gland during darkness and regulates biological rhythms through its receptors in the suprachiasmatic nucleus of the... (Review)
Review
BACKGROUND
Melatonin is mainly secreted by the pineal gland during darkness and regulates biological rhythms through its receptors in the suprachiasmatic nucleus of the hypothalamus. In addition, it also plays a role in the reproductive system by affecting the function of the hypothalamic-pituitary-gonadal axis, and by acting as a free radical scavenger thus contributing to the maintenance of the optimal physiological state of the gonads. Besides, melatonin can freely cross the placenta to influence fetal development. However, there is still a lack of overall understanding of the role of melatonin in the reproductive cycle of female mammals.
AIM OF REVIEW
Here we focus the role of melatonin in female reproduction from follicular development to delivery as well as the relationship between melatonin and lactation. We further summarize the potential role of melatonin in the treatment of preeclampsia, polycystic ovary syndrome, endometriosis, and ovarian aging.
KEY SCIENTIFIC CONCEPTS OF REVIEW
Understanding the physiological role of melatonin in female reproductive processes will contribute to the advancement of human fertility and reproductive medicine research.
PubMed: 38692429
DOI: 10.1016/j.jare.2024.04.025 -
The Journal of Reproduction and... Apr 2024Understanding of central nervous system mechanisms underlying age-related infertility remains limited. Fibril α-synuclein, distinct from its monomeric form, is...
Understanding of central nervous system mechanisms underlying age-related infertility remains limited. Fibril α-synuclein, distinct from its monomeric form, is implicated in age-related diseases. Notably, fibril α-synuclein spreads among neurons, similar to prions, from damaged old neurons in cortex and hippocampus to healthy neurons. However, less is known whether α-synuclein propagates into oxytocin neurons, which play crucial roles in reproduction. We compared α-synuclein expression in the oxytocin neurons in suprachiasmatic nucleus (SCN), supraoptic nucleus (SON), paraventricular hypothalamic nucleus (PVN), and posterior pituitary (PP) gland of healthy heifers and aged cows to determine its role in age-related infertility. We analyzed mRNA and protein expression, along with Congo red histochemistry and fluorescent immunohistochemistry for oxytocin and α-synuclein, followed by confocal microscopy with Congo red staining. Both mRNA and protein expressions of α-synuclein were confirmed in the bovine cortex, hippocampus, SCN, SON, PVN, and PP tissues. Significant differences in α-synuclein mRNA expressions were observed in the cortex and hippocampus between young heifers and old cows. Western blots showed five bands of α-synuclein, probably reflecting monomers, dimers, and oligomers, in the cortex, hippocampus, SCN, SON, PVN, and PP tissues, and there were significant differences in some bands between the young heifers and old cows. Bright-field and polarized light microscopy did not detect obvious amyloid deposition in the aged hypothalami; however, higher-sensitive confocal microscopy unveiled strong positive signals for Congo red and α-synuclein in oxytocin neurons in the aged hypothalami. α-synuclein was expressed in oxytocin neurons, and some differences were observed between young and old hypothalami.
PubMed: 38684411
DOI: 10.1262/jrd.2024-020 -
Journal of Cellular and Molecular... May 2024TRP channels, are non-specific cationic channels that are involved in multiple physiological processes that include salivation, cellular secretions, memory extinction... (Review)
Review
TRP channels, are non-specific cationic channels that are involved in multiple physiological processes that include salivation, cellular secretions, memory extinction and consolidation, temperature, pain, store-operated calcium entry, thermosensation and functionality of the nervous system. Here we choose to look at the evidence that decisively shows how TRP channels modulate human neuron plasticity as it relates to the molecular neurobiology of sleep/circadian rhythm. There are numerous model organisms of sleep and circadian rhythm that are the results of the absence or genetic manipulation of the non-specific cationic TRP channels. Drosophila and mice that have had their TRP channels genetically ablated or manipulated show strong evidence of changes in sleep duration, sleep activity, circadian rhythm and response to temperature, noxious odours and pattern of activity during both sleep and wakefulness along with cardiovascular and respiratory function during sleep. Indeed the role of TRP channels in regulating sleep and circadian rhythm is very interesting considering the parallel roles of TRP channels in thermoregulation and thermal response with concomitant responses in growth and degradation of neurites, peripheral nerves and neuronal brain networks. TRP channels provide evidence of an ability to create, regulate and modify our sleep and circadian rhythm in a wide array of physiological and pathophysiological conditions. In the current review, we summarize previous results and novel recent advances in the understanding of calcium ion entry via TRP channels in different sleep and circadian rhythm conditions. We discuss the role of TRP channels in sleep and circadian disorders.
Topics: Circadian Rhythm; Animals; Humans; Sleep; Transient Receptor Potential Channels
PubMed: 38676362
DOI: 10.1111/jcmm.18274 -
Frontiers in Cellular Neuroscience 2024Vasoactive intestinal peptide (VIP) is an important component of the suprachiasmatic nucleus (SCN) which relays circadian information to neuronal populations, including...
Vasoactive intestinal peptide (VIP) is an important component of the suprachiasmatic nucleus (SCN) which relays circadian information to neuronal populations, including GnRH neurons. Human and animal studies have shown an impact of disrupted daily rhythms (chronic shift work, temporal food restriction, clock gene disruption) on both male and female reproduction and fertility. To date, how VIP modulates GnRH neurons remains unknown. Calcium imaging and electrophysiology on primary GnRH neurons in explants and adult mouse brain slice, respectively, were used to address this question. We found VIP excites GnRH neurons via the VIP receptor, VPAC2. The downstream signaling pathway uses both Gs protein/adenylyl cyclase/protein kinase A (PKA) and phospholipase C/phosphatidylinositol 4,5-bisphosphate (PIP) depletion. Furthermore, we identified a UCL2077-sensitive target, likely contributing to the slow afterhyperpolarization current (I), as the PKA and PIP depletion target, and the KCa3.1 channel as a specific target. Thus, VIP/VPAC2 provides an example of Gs protein-coupled receptor-triggered excitation in GnRH neurons, modulating GnRH neurons likely via the slow I. The possible identification of KCa3.1 in the GnRH neuron slow I may provide a new therapeutical target for fertility treatments.
PubMed: 38633445
DOI: 10.3389/fncel.2024.1354095 -
Proceedings of the National Academy of... Apr 2024Circadian regulation and temperature dependency are important orchestrators of molecular pathways. How the integration between these two drivers is achieved, is not...
Circadian regulation and temperature dependency are important orchestrators of molecular pathways. How the integration between these two drivers is achieved, is not understood. We monitored circadian- and temperature-dependent effects on transcription dynamics of cold-response protein RNA Binding Motif 3 (Rbm3). Temperature changes in the mammalian master circadian pacemaker, the suprachiasmatic nucleus (SCN), induced Rbm3 transcription and regulated its circadian periodicity, whereas the core clock gene Per2 was unaffected. Rbm3 induction depended on a full Brain And Muscle ARNT-Like Protein 1 (Bmal1) complement: reduced Bmal1 erased Rbm3 responses and weakened SCN circuit resilience to temperature changes. By focusing on circadian and temperature dependency, we highlight weakened transmission between core clock and downstream pathways as a potential route for reduced circadian resilience.
Topics: Animals; Circadian Rhythm; Temperature; Period Circadian Proteins; ARNTL Transcription Factors; RNA; Suprachiasmatic Nucleus; Mammals
PubMed: 38625943
DOI: 10.1073/pnas.2316646121 -
Frontiers in Neural Circuits 2024Animals need sleep, and the suprachiasmatic nucleus, the center of the circadian rhythm, plays an important role in determining the timing of sleep. The main input to... (Review)
Review
Animals need sleep, and the suprachiasmatic nucleus, the center of the circadian rhythm, plays an important role in determining the timing of sleep. The main input to the suprachiasmatic nucleus is the retinohypothalamic tract, with additional inputs from the intergeniculate leaflet pathway, the serotonergic afferent from the raphe, and other hypothalamic regions. Within the suprachiasmatic nucleus, two of the major subtypes are vasoactive intestinal polypeptide (VIP)-positive neurons and arginine-vasopressin (AVP)-positive neurons. VIP neurons are important for light entrainment and synchronization of suprachiasmatic nucleus neurons, whereas AVP neurons are important for circadian period determination. Output targets of the suprachiasmatic nucleus include the hypothalamus (subparaventricular zone, paraventricular hypothalamic nucleus, preoptic area, and medial hypothalamus), the thalamus (paraventricular thalamic nuclei), and lateral septum. The suprachiasmatic nucleus also sends information through several brain regions to the pineal gland. The olfactory bulb is thought to be able to generate a circadian rhythm without the suprachiasmatic nucleus. Some reports indicate that circadian rhythms of the olfactory bulb and olfactory cortex exist in the absence of the suprachiasmatic nucleus, but another report claims the influence of the suprachiasmatic nucleus. The regulation of circadian rhythms by sensory inputs other than light stimuli, including olfaction, has not been well studied and further progress is expected.
Topics: Animals; Suprachiasmatic Nucleus; Hypothalamus; Circadian Rhythm; Vasoactive Intestinal Peptide; Sleep; Arginine Vasopressin
PubMed: 38590628
DOI: 10.3389/fncir.2024.1385908 -
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