bims-ciryme 2020-05-17 papers

Science. 2020 May 15. 368(6492): 746-753

The malaria parasite has an intrinsic clock.

Filipa Rijo-Ferreira, Victoria A Acosta-Rodriguez, John H Abel, Izabela Kornblum, Ines Bento, Gokhul Kilaru, Elizabeth B Klerman, Maria M Mota, Joseph S Takahashi.

Malarial rhythmic fevers are the consequence of the synchronous bursting of red blood cells (RBCs) on completion of the malaria parasite asexual cell cycle. Here, we hypothesized that an intrinsic clock in the parasite Plasmodium chabaudi underlies the 24-hour-based rhythms of RBC bursting in mice. We show that parasite rhythms are flexible and lengthen to match the rhythms of hosts with long circadian periods. We also show that malaria rhythms persist even when host food intake is evenly spread across 24 hours, suggesting that host feeding cues are not required for synchrony. Moreover, we find that the parasite population remains synchronous and rhythmic even in an arrhythmic clock mutant host. Thus, we propose that parasite rhythms are generated by the parasite, possibly to anticipate its circadian environment.

DOI: https://doi.org/10.1126/science.aba2658

Sci Rep. 2020 May 14. 10(1): 7982

Bright light improves sleep in patients with Parkinson's disease: possible role of circadian restoration.

Takuyuki Endo, Ritsuko Matsumura, Isao T Tokuda, Tomoko Yoshikawa, Yasufumi Shigeyoshi, Koichi Node, Saburo Sakoda, Makoto Akashi.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Among the most common manifestations of PD are sleep problems, which are coupled with the adverse effects of dopaminergic therapies (DT). A non-pharmacological solution for these sleep problems has been sought to avoid additional pharmacological intervention. Here, we show that bright light therapy (BLT) is effective for improving sleep in Japanese PD patients receiving DT. Furthermore, experimental evaluation of peripheral clock gene expression rhythms revealed that most PD patients receiving DT who experienced improved sleep following BLT showed a circadian phase shift, indicating the existence of a correlation between circadian modulation and sleep improvement. Conversely, this result indicates that sleep problems in PD patients receiving DT may arise at least in part as a result of circadian dysfunction. Indeed, we found that chronic dopaminergic stimulation induced a rapid attenuation of autonomous oscillations of clock gene expression in ex vivo cultured mouse suprachiasmatic nucleus (SCN) at the single neuron level. In conclusion, BLT is a promising medical treatment for improving sleep in PD patients receiving DT. This BLT-induced improvement may be due to the restoration of circadian function.

DOI: https://doi.org/10.1038/s41598-020-64645-6

Elife. 2020 May 12. pii: e54090. [Epub ahead of print]9

Bmal1 integrates mitochondrial metabolism and macrophage activation.

Ryan K Alexander, Yae-Huei Liou, Nelson H Knudsen, Kyle A Starost, Chuanrui Xu, Alexander L Hyde, Sihao Liu, David Jacobi, Nan-Shih Liao, Chih-Hao Lee.

Metabolic pathways and inflammatory processes are under circadian regulation. While rhythmic immune cell recruitment is known to impact infection outcomes, whether the circadian clock modulates immunometabolism remains unclear. We find the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-g/lipopolysaccharide (M1) and tumor-conditioned medium, to maintain mitochondrial metabolism under these metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific Bmal1 knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial ROS production and Hif-1a-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, the aberrant Hif-1a activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, while administrating an SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint integrating macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1a regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.

Keywords: cell biology; mouse

DOI: https://doi.org/10.7554/eLife.54090

Trends Endocrinol Metab. 2020 Jun;pii: S1043-2760(20)30050-3. [Epub ahead of print]31(6): 459-468

Metabolic Implications of Circadian-HIF Crosstalk.

Clara B Peek.

Research over the past few decades has shed light on the mechanisms underlying the link between circadian disruption and the development of metabolic diseases such as obesity, type 2 diabetes, and cancer. However, how the clock network interacts with tissue-specificnutrient-sensing pathways during conditions of nutrient stress or pathological states remains incompletely understood. Recent work has demonstrated that the circadian clock can 'reprogram' the transcriptome to control distinct sets of genes during altered nutrient conditions, such as high fat diet, aging, and exercise. In this review, I discuss connections between circadian clock transcription factors and the oxygen- and nutrient-responsivehypoxia-inducible factor (HIF) pathway. I highlight recently uncovered mechanistic insights underlying these pathway interactions and address potential implications for the role of circadian disruption in metabolic diseases.

DOI: https://doi.org/10.1016/j.tem.2020.02.008

Physiol Behav. 2020 May 11. pii: S0031-9384(20)30253-5. [Epub ahead of print] 112939

Food anticipatory circadian rhythms in mice entrained to long or short day photoperiods.

Sarah C Power, Ralph E Mistlberger.

Food anticipatory activity (FAA) rhythms that emerge in nocturnal rodents fed once daily are mediated by food-entrainable circadian oscillators (FEOs) located outside of the suprachiasmatic nucleus (SCN), the site of a circadian pacemaker required for entrainment to daily light-dark (LD) cycles. Specification of the neural and molecular substrates of FEOs driving FAA is complicated by homeostatic, hedonic and environmental factors that can modulate expression of activity independent of circadian timing. Here, we examined the effect of photoperiod (duration of the daily light period) on FAA in mice fed during the last 4 h or middle 4 h of the light period for at least 5 weeks. Long photoperiods decrease SCN pacemaker amplitude, which may favor expression of FAA during the day, when the SCN normally opposes activity in nocturnal rodents. To test this prediction, in Experiment 1, mice housed with or without running discs were entrained to 24 h LD cycles with 8 h (L8) or 16 h (L16) photoperiods. When food was restricted to the last 4 h of the light period (late-day), mice housed with running discs showed more FAA in L16, whereas mice without running discs showed more FAA in L8. In Experiment 2, mice were entrained to L8 or L16 photoperiods, and the 4 h daily meal was centered in the light period (mid-day). FAA was decreased relative to late-day fed mice, but did not vary by photoperiod. In Experiment 3, mice with or without running discs were entrained to L12 or L18 photoperiods, with mealtime centered in the light period. FAA again did not differ between photoperiods. In constant dark (DD) prior to food restriction, the period (τ) of free-running rhythms was shorter in mice entrained to long days. This known after-effect of photoperiod on τ was absent in DD immediately following restricted feeding. The phase of LD entrainment, unmasked on the first day of DD with food ad-libitum, was significantly advanced in mice from the late-day feeding schedule, compared to mice from the mid-day schedules. These results indicate that FAA in mice does not vary systematically with photoperiod, possibly because daytime feeding schedules attenuate the effect of photoperiod on the mouse SCN pacemaker. FAA in the present study was more strongly influenced by running disc availability and by meal time within the light period, possibly due to effects on LD entrainment, which was phase advanced by late-day but not midday feeding.

Keywords: Circadian rhythms; Food entrainment; Food-anticipatory activity; Light-dark entrainment; Photoperiod; Running activity

DOI: https://doi.org/10.1016/j.physbeh.2020.112939

Nature. 2020 May;581(7807): 194-198

Retinal innervation tunes circuits that drive nonphotic entrainment to food.

Diego Carlos Fernandez, Ruchi Komal, Jennifer Langel, Jun Ma, Phan Q Duy, Mario A Penzo, Haiqing Zhao, Samer Hattar.

Daily changes in light and food availability are major time cues that influence circadian timing1. However, little is known about the circuits that integrate these time cues to drive a coherent circadian output1-3. Here we investigate whether retinal inputs modulate entrainment to nonphotic cues such as time-restricted feeding. Photic information is relayed to the suprachiasmatic nucleus (SCN)-the central circadian pacemaker-and the intergeniculate leaflet (IGL) through intrinsically photosensitive retinal ganglion cells (ipRGCs)4. We show that adult mice that lack ipRGCs from the early postnatal stages have impaired entrainment to time-restricted feeding, whereas ablation of ipRGCs at later stages had no effect. Innervation of ipRGCs at early postnatal stages influences IGL neurons that express neuropeptide Y (NPY) (hereafter, IGLNPY neurons), guiding the assembly of a functional IGLNPY-SCN circuit. Moreover, silencing IGLNPY neurons in adult mice mimicked the deficits that were induced by ablation of ipRGCs in the early postnatal stages, and acute inhibition of IGLNPY terminals in the SCN decreased food-anticipatory activity. Thus, innervation of ipRGCs in the early postnatal period tunes the IGLNPY-SCN circuit to allow entrainment to time-restricted feeding.

DOI: https://doi.org/10.1038/s41586-020-2204-1