Circadian Rhythms in the Neuronal Network Timing the Luteinizing Hormone Surge

For 3.5 billion years before electric light was invented in 1879, life on Earth evolved under the pattern of light during the day and darkness during the night. Through evolution, nearly all organisms internalized the temporal rhythm of Earth’s 24-hour rotation and evolved self-sustaining biological clocks with a ~24-hour rhythm. These internal rhythms are called circadian rhythms, and the molecular constituents that generate them are called molecular circadian clocks. Alignment of molecular clocks with the environmental light-dark rhythms optimizes physiology and behavior. This is particularly true for reproductive function, in which seasonal breeders use day-length information to time yearly changes in fertility. However, it is becoming increasingly clear that light-induced disruption of circadian rhythms can negatively impact fertility in non-seasonal breeders as well. In particular, the luteinizing hormone surge promoting ovulation, is sensitive to circadian disruption. In this review, we will summarize our current understanding of the neuronal networks that underlie circadian rhythms and the luteinizing hormone surge.

SOX2 Regulates Neuronal Differentiation of the Suprachiasmatic Nucleus

In mammals, the hypothalamic suprachiasmatic nucleus (SCN) functions as the central circadian pacemaker, orchestrating behavioral and physiological rhythms in alignment to the environmental light/dark cycle. The neurons that comprise the SCN are anatomically and functionally heterogeneous, but despite their physiological importance, little is known about the pathways that guide their specification and differentiation. Here, we report that the stem/progenitor cell transcription factor, Sex determining region Y-box 2 (Sox2), is required in the embryonic SCN to control the expression of SCN-enriched neuropeptides and transcription factors. Ablation of Sox2 in the developing SCN leads to downregulation of circadian neuropeptides as early as embryonic day (E) 15.5, followed by a decrease in the expression of two transcription factors involved in SCN development, Lhx1 and Six6, in neonates. Thymidine analog-retention assays revealed that Sox2 deficiency contributed to reduced survival of SCN neurons during the postnatal period of cell clearance, but did not affect progenitor cell proliferation or SCN specification. Our results identify SOX2 as an essential transcription factor for the proper differentiation and survival of neurons within the developing SCN.

PHASE: A MATLAB Based Program for the Analysis of Drosophila Phase, Activity, and Sleep under Entrainment

The problem of entrainment is central to circadian biology. In this regard, Drosophila has been an important model system. Owing to the simplicity of its nervous system and the availability of powerful genetic tools, the system has shed significant light on the molecular and neural underpinnings of entrainment. However, much remains to be learned regarding the molecular and physiological mechanisms underlying this important phenomenon. Under cyclic light/dark conditions, Drosophila melanogaster displays crepuscular patterns of locomotor activity with one peak anticipating dawn and the other anticipating dusk. These peaks are characterized through an estimation of their phase relative to the environmental light cycle and the extent of their anticipation of light transitions. In Drosophila chronobiology, estimations of phases are often subjective, and anticipation indices vary significantly between studies. Though there is increasing interest in building flexible analysis software tools in the field, none incorporates objective measures of Drosophila activity peaks in combination with the analysis of fly activity/sleep in the same program. To this end, we have developed PHASE, a MATLAB-based program that is simple and easy to use and (i) supports the visualization and analysis of activity and sleep under entrainment, (ii) allows analysis of both activity and sleep parameters within user-defined windows within a diurnal cycle, (iii) uses a smoothing filter for the objective identification of peaks of activity (and therefore can be used to quantitatively characterize them), and (iv) offers a series of analyses for the assessment of behavioral anticipation of environmental transitions.

Cross-Sensor Nighttime Lights Image Calibration for DMSP/OLS and SNPP/VIIRS with Residual U-Net

Remote sensing of nighttime lights (NTL) is widely used in socio-economic studies of economic growth, urbanization, stability of power grid, environmental light pollution, pandemics and military conflicts. Currently, NTL data are collected with two sensors: (1) Operational Line-scan System (OLS) onboard the satellites from the Defense Meteorology Satellite Program (DMSP) and (2) Visible Infrared Imaging Radiometer Suite (VIIRS) onboard the Suomi NPP (SNPP) and NOAA-20 satellites from the Joint Polar Satellite System (JPSS). However, the nighttime images acquired by these two sensors are incompatible in spatial resolution and dynamic range. To address this problem, we propose a method for the cross-sensor calibration with residual U-net convolutional neural network (CNN). The CNN produces DMSP-like NTL composites from the VIIRS annual NTL composites. The pixel radiances predicted from VIIRS are highly correlated with NTL observed with OLS (0.96 < R2 < 0.99). The method can be used to extend long-term series of annual NTL after the end of DMSP mission or to cross-calibrate same year NTL from different satellites to study diurnal variations.

Neuroinflammation as a Therapeutic Target in Retinitis Pigmentosa and Quercetin as Its Potential Modulator

The retina is a multilayer neuronal tissue located in the back of the eye that transduces the environmental light into a neural impulse. Many eye diseases caused by endogenous or exogenous harm lead to retina degeneration with neuroinflammation being a major hallmark of these pathologies. One of the most prevalent retinopathies is retinitis pigmentosa (RP), a clinically and genetically heterogeneous hereditary disorder that causes a decline in vision and eventually blindness. Most RP cases are related to mutations in the rod visual receptor, rhodopsin. The mutant protein triggers inflammatory reactions resulting in the activation of microglia to clear degenerating photoreceptor cells. However, sustained insult caused by the abnormal genetic background exacerbates the inflammatory response and increases oxidative stress in the retina, leading to a decline in rod photoreceptors followed by cone photoreceptors. Thus, inhibition of inflammation in RP has received attention and has been explored as a potential therapeutic strategy. However, pharmacological modulation of the retinal inflammatory response in combination with rhodopsin small molecule chaperones would likely be a more advantageous therapeutic approach to combat RP. Flavonoids, which exhibit antioxidant and anti-inflammatory properties, and modulate the stability and folding of rod opsin, could be a valid option in developing treatment strategies against RP.

Central Nervous System Associated With Light Perception and Physiological Responses of Birds

Environmental light that animal receives (i.e., photoperiod and light intensity) has recently been shown that it affects avian central nervous system for the physiological responses to the environment by up or downregulation of dopamine and serotonin activities, and this, in turn, affects the reproductive function and stress-related behavior of birds. In this study, the author speculated on the intriguing possibility that one of the proposed avian deep-brain photoreceptors (DBPs), i.e., melanopsin (Opn4), may play roles in the dual sensory-neurosecretory cells in the hypothalamus, midbrain, and brain stem for the behavior and physiological responses of birds by light. Specifically, the author has shown that the direct light perception of premammillary nucleus dopamine-melatonin (PMM DA-Mel) neurons is associated with the reproductive activation in birds. Although further research is required to establish the functional role of Opn4 in the ventral tegmental area (VTA), dorsal raphe nucleus, and caudal raphe nucleus in the light perception and physiological responses of birds, it is an exciting prospect because the previous results in birds support this hypothesis that Opn4 in the midbrain DA and serotonin neurons may play significant roles on the light-induced welfare of birds.

Maternal Environmental Light Conditions Affect the Morphological Allometry and Dispersal Potential of Acer palmatum Samaras

Seed dispersal plays critical roles in determining species survival and community structures. Since the dispersal is biologically under maternal control, it is hypothesized that intraspecific variation of dispersal potential and associated traits of seeds (diaspores) should be influenced by maternal habitat quality. We tested this hypothesis by examining the effects of maternal environmental light condition on morphological traits and descending performance of nearly 1800 wind-dispersed samaras collected from maple species Acer palmatum. Results showed that samaras produced by trees from shaded microhabitats had greater dispersal potential, in terms of slower terminal velocity of descent, than those produced in open microhabitats. This advantage was largely attributed to morphological plasticity. On average, samaras produced in shaded microhabitats, as compared to those produced in open habitats, had lower wing loading by only reducing weight but not area. In allometric details, in the large size range, samaras from shaded microhabitats had larger areas than those from open microhabitats; in the small size range, samaras from shaded microhabitats had wider wings. These findings suggest that greater dispersal potential of samaras in response to stressful maternal light environment reflected an active maternal control through the morphological allometry of samaras.

Reduced plasticity in coupling strength in the SCN clock in aging as revealed by Kuramoto modelling

The mammalian circadian clock is located in the suprachiasmatic nucleus (SCN) and consist of a network of coupled neurons, which are entrained to the environmental light-dark cycle. The phase coherence of the neurons is plastic and driven by the length of the day. With aging the capacity to behaviorally adapt to changes in the light regime reduces. The mechanisms underlying photoperiodic adaptation are largely unknown, but are important to unravel for the development of novel interventions to improve the quality of life of the elderly. We analyzed the neuronal synchronization of PER2::LUC protein expression in the SCN of young and old mice entrained to either long or short photoperiod and used the synchronization levels as input for a two-community noisy Kuramoto model. With the Kuramoto model we estimated the coupling strength between and within neuronal subpopulations. The model revealed that the coupling strength between and within subpopulations contributes to photoperiod induced changes in the phase relationship among neurons. We found that the SCN of young mice adapts in coupling strength over a large range, with low coupling strength in long photoperiod and higher coupling strength in short photoperiod. In aged mice we also found low coupling strength in long photoperiod, but strongly reduced capacity to reach high coupling strength in short photoperiod. The inability to respond with an increase in coupling strength shows that manipulation of photoperiod is not a suitable strategy to enhance clock function with aging. We conclude that the inability of aged mice to reach high coupling strength makes aged mice less capable to seasonal adaptation than young mice.

Circadian Clock-Controlled Checkpoints in the Pathogenesis of Complex Disease

The circadian clock coordinates physiology, metabolism, and behavior with the 24-h cycles of environmental light. Fundamental mechanisms of how the circadian clock regulates organ physiology and metabolism have been elucidated at a rapid speed in the past two decades. Here we review circadian networks in more than six organ systems associated with complex disease, which cluster around metabolic disorders, and seek to propose critical regulatory molecules controlled by the circadian clock (named clock-controlled checkpoints) in the pathogenesis of complex disease. These include clock-controlled checkpoints such as circadian nuclear receptors in liver and muscle tissues, chemokines and adhesion molecules in the vasculature. Although the progress is encouraging, many gaps in the mechanisms remain unaddressed. Future studies should focus on devising time-dependent strategies for drug delivery and engagement in well-characterized organs such as the liver, and elucidating fundamental circadian biology in so far less characterized organ systems, including the heart, blood, peripheral neurons, and reproductive systems.