bims-ciryme 2021-04-04 papers

Front Neurosci. 2021 ;15 642745

Biological Timing and Neurodevelopmental Disorders: A Role for Circadian Dysfunction in Autism Spectrum Disorders.

Ethan Lorsung, Ramanujam Karthikeyan, Ruifeng Cao.

Autism spectrum disorders (ASDs) are a spectrum of neurodevelopmental disorders characterized by impaired social interaction and communication, as well as stereotyped and repetitive behaviors. ASDs affect nearly 2% of the United States child population and the worldwide prevalence has dramatically increased in recent years. The etiology is not clear but ASD is thought to be caused by a combination of intrinsic and extrinsic factors. Circadian rhythms are the ∼24 h rhythms driven by the endogenous biological clock, and they are found in a variety of physiological processes. Growing evidence from basic and clinical studies suggest that the dysfunction of the circadian timing system may be associated with ASD and its pathogenesis. Here we review the findings that link circadian dysfunctions to ASD in both experimental and clinical studies. We first introduce the organization of the circadian system and ASD. Next, we review physiological indicators of circadian rhythms that are found disrupted in ASD individuals, including sleep-wake cycles, melatonin, cortisol, and serotonin. Finally, we review evidence in epidemiology, human genetics, and biochemistry that indicates underlying associations between circadian regulation and the pathogenesis of ASD. In conclusion, we propose that understanding the functional importance of the circadian clock in normal and aberrant neurodevelopmental processes may provide a novel perspective to tackle ASD, and clinical treatments for ASD individuals should comprise an integrative approach considering the dynamics of daily rhythms in physical, mental, and social processes.

Keywords: autism spectrum disorders; circadian rhythms; clock genes; cortisol; mTOR; melatonin; serotonin; sleep

DOI: https://doi.org/10.3389/fnins.2021.642745

Bio Protoc. 2021 Mar 05. 11(5): e3944

Generation of Mouse Primary Hypothalamic Neuronal Cultures for Circadian Bioluminescence Assays.

Cosima X Schmidt, Anthony H Tsang, Henrik Oster.

An endogenous circadian clock system enables organisms to adapt to time-of-day dependent environmental changes. In consequence, most physiological processes exhibit daily rhythms of, e.g., energy metabolism, immune function, sleep, or hormone production. Hypothalamic circadian clocks have been identified to play a particular role in coordinating many of these processes. Primary neuronal cultures are widely used as a physiologically relevant model to study molecular events within neurons. However, as circadian rhythms include dynamic molecular changes over longer timescales that vary between individual cells, longitudinal measurement methods are essential to investigate the regulation of circadian clocks of hypothalamic neurons. Here we provide a protocol for generating primary hypothalamic neuronal cultures expressing a circadian luciferase reporter. Such reporter cells can be used to longitudinally monitor cellular circadian rhythms at high temporal resolution by performing bioluminescence measurements.

Keywords: Bmal1; Circadian clocks; Circadian rhythms; Luciferase reporter; Primary hypothalamic neurons

DOI: https://doi.org/10.21769/BioProtoc.3944

PLoS Comput Biol. 2021 Mar 31. 17(3): e1008514

Modeling the circadian regulation of the immune system: Sexually dimorphic effects of shift work.

Stéphanie M C Abo, Anita T Layton.

The circadian clock exerts significance influence on the immune system and disruption of circadian rhythms has been linked to inflammatory pathologies. Shift workers often experience circadian misalignment as their irregular work schedules disrupt the natural light-dark cycle, which in turn can cause serious health problems associated with alterations in genetic expressions of clock genes. In particular, shift work is associated with impairment in immune function, and those alterations are sex-specific. The goal of this study is to better understand the mechanisms that explain the weakened immune system in shift workers. To achieve that goal, we have constructed a mathematical model of the mammalian pulmonary circadian clock coupled to an acute inflammation model in the male and female rats. Shift work was simulated by an 8h-phase advance of the circadian system with sex-specific modulation of clock genes. The model reproduces the clock gene expression in the lung and the immune response to various doses of lipopolysaccharide (LPS). Under normal conditions, our model predicts that a host is more sensitive to LPS at circadian time (CT) CT12 versus CT0 due to a dynamic change of Interleukin 10 (IL-10), an anti-inflammatory cytokine. We identify REV-ERB as a key modulator of IL-10 activity throughout the circadian day. The model also predicts a reversal of the times of lowest and highest sensitivity to LPS, with males and females exhibiting an exaggerated response to LPS at CT0, which is countered by a blunted immune response at CT12. Overall, females produce fewer pro-inflammatory cytokines than males, but the extent of sequelae experienced by males and females varies across the circadian day. This model can serve as an essential component in an integrative model that will yield mechanistic understanding of how shift work-mediated circadian disruptions affect the inflammatory and other physiological responses.

DOI: https://doi.org/10.1371/journal.pcbi.1008514

Nat Aging. 2021 Jan;1(1): 73-86

Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice.

Protein restricted (PR) diets promote health and longevity in many species. While the precise components of a PR diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of PR can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse models, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in lifespan and a reduction in frailty in male, but not female, wild-type mice when fed lifelong. Our results demonstrate that restricting dietary BCAAs can increase healthspan and longevity in mice, and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging.

Keywords: branched-chain amino acids; healthspan; lifespan; mTOR; mTORC1; progeria; protein restriction; rapamycin

DOI: https://doi.org/10.1038/s43587-020-00006-2

Integr Comp Biol. 2021 Mar 31. pii: icab017. [Epub ahead of print]

Light at Night and Disrupted Circadian Rhythms Alter Physiology and Behavior.

Jacob R Bumgarner, Randy J Nelson.

Life on earth has evolved during the past several billion years under relatively bright days and dark nights. Virtually, all organisms on the planet display an internal representation of the solar days in the form of circadian rhythms driven by biological clocks. Nearly every aspect of physiology and behavior is mediated by these internal clocks. The widespread adoption of electric lights during the past century has exposed animals, including humans, to significant light at night for the first time in our evolutionary history. Importantly, endogenous circadian clocks depend on light for synchronization with the external daily environment. Thus, light at night can derange temporal adaptations. Indeed, disruption of natural light-dark cycles results in several physiological and behavioral changes. In this review, we highlight recent evidence demonstrating how light at night exposure can have serious implications for adaptive physiology and behavior, including immune, endocrine, and metabolic function, as well as reproductive, foraging, and migratory behavior. Lastly, strategies to mitigate the consequences of light at night on behavior and physiology will be considered.

DOI: https://doi.org/10.1093/icb/icab017