bims-ciryme 2021-02-07 papers

Proc Natl Acad Sci U S A. 2021 Feb 09. pii: e2010168118. [Epub ahead of print]118(6):

GABA from vasopressin neurons regulates the time at which suprachiasmatic nucleus molecular clocks enable circadian behavior.

Takashi Maejima, Yusuke Tsuno, Shota Miyazaki, Yousuke Tsuneoka, Emi Hasegawa, Md Tarikul Islam, Ryosuke Enoki, Takahiro J Nakamura, Michihiro Mieda.

The suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals, is a network structure composed of multiple types of γ-aminobutyric acid (GABA)-ergic neurons and glial cells. However, the roles of GABA-mediated signaling in the SCN network remain controversial. Here, we report noticeable impairment of the circadian rhythm in mice with a specific deletion of the vesicular GABA transporter in arginine vasopressin (AVP)-producing neurons. These mice showed disturbed diurnal rhythms of GABAA receptor-mediated synaptic transmission in SCN neurons and marked lengthening of the activity time in circadian behavioral rhythms due to the extended interval between morning and evening locomotor activities. Synchrony of molecular circadian oscillations among SCN neurons did not significantly change, whereas the phase relationships between SCN molecular clocks and circadian morning/evening locomotor activities were altered significantly, as revealed by PER2::LUC imaging of SCN explants and in vivo recording of intracellular Ca2+ in SCN AVP neurons. In contrast, daily neuronal activity in SCN neurons in vivo clearly showed a bimodal pattern that correlated with dissociated morning/evening locomotor activities. Therefore, GABAergic transmission from AVP neurons regulates the timing of SCN neuronal firing to temporally restrict circadian behavior to appropriate time windows in SCN molecular clocks.

Keywords: GABA; arginine vasopressin; circadian rhythm; suprachiasmatic nucleus

DOI: https://doi.org/10.1073/pnas.2010168118

FASEB J. 2021 Feb;35(2): e21342

Two-meal caloric restriction induces 12-hour rhythms and improves glucose homeostasis.

Nikkhil Velingkaar, Volha Mezhnina, Allan Poe, Roman V Kondratov.

Glucose metabolism is tightly regulated and disrupting glucose homeostasis is a hallmark of many diseases. Caloric restriction (CR), periodic fasting, and circadian rhythms are interlinked with glucose metabolism. Here, we directly investigated if CR depends on periodic fasting and circadian rhythms to improve glucose metabolism. CR was implemented as two-meals per day (2M-CR), provided at 12-hour intervals, and compared with one meal per day CR, mealtime (MT), and ad libitum (AL) feeding. The 2M-CR impacted the circadian rhythms in blood glucose, metabolic signaling, circadian clock, and glucose metabolism gene expression. 2M-CR significantly reduced around the clock blood glucose and improved glucose tolerance. Twenty-four-hour rhythms in mTOR signaling and gene expression observed under AL, MT, and CR, became 12-hour rhythms in 2M-CR. The 12-hour rhythms in behavior, gene expression, and signaling persisted in fasted mice, implicating some internal regulation. The study highlights that the reduction in caloric intake rather than meal frequency and duration of fasting is essential for metabolic reprograming and improvement in glucose metabolism and provides evidence on food-entrained molecular pacemaker, which can be uncoupled from the light-entrained circadian clock and rhythms.

Keywords: 12-hour rhythms; aging; circadian rhythms; diet; gene expression; glucose homeostasis; metabolism

DOI: https://doi.org/10.1096/fj.202002470R

Clocks Sleep. 2021 Jan 26. 3(1): 87-97

General Anaesthesia Shifts the Murine Circadian Clock in a Time-Dependant Fashion.

Nicola M Ludin, Alma Orts-Sebastian, James F Cheeseman, Janelle Chong, Alan F Merry, David Cumin, Shin Yamazaki, Matthew D M Pawley, Guy R Warman.

Following general anaesthesia (GA), patients frequently experience sleep disruption and fatigue, which has been hypothesized to result at least in part by GA affecting the circadian clock. Here, we provide the first comprehensive time-dependent analysis of the effects of the commonly administered inhalational anaesthetic, isoflurane, on the murine circadian clock, by analysing its effects on (a) behavioural locomotor rhythms and (b) PER2::LUC expression in the suprachiasmatic nuclei (SCN) of the mouse brain. Behavioural phase shifts elicited by exposure of mice (n = 80) to six hours of GA (2% isoflurane) were determined by recording wheel-running rhythms in constant conditions (DD). Phase shifts in PER2::LUC expression were determined by recording bioluminescence in organotypic SCN slices (n = 38) prior to and following GA exposure (2% isoflurane). Full phase response curves for the effects of GA on behaviour and PER2::LUC rhythms were constructed, which show that the effects of GA are highly time-dependent. Shifts in SCN PER2 expression were much larger than those of behaviour (c. 0.7 h behaviour vs. 7.5 h PER2::LUC). We discuss the implications of this work for understanding how GA affects the clock, and how it may inform the development of chronotherapeutic strategies to reduce GA-induced phase-shifting in patients.

Keywords: PERIOD2::LUC; circadian clock; clock gene; general anaesthesia; phase response curve

DOI: https://doi.org/10.3390/clockssleep3010006

Elife. 2021 Feb 02. pii: e63671. [Epub ahead of print]10

Leptin-receptor neurons in the dorsomedial hypothalamus regulate diurnal patterns of feeding, locomotion, and metabolism.

Chelsea L Faber, Jennifer D Deem, Bao Anh Phan, Tammy P Doan, Kayoko Ogimoto, Zaman Mirzadeh, Michael W Schwartz, Gregory J Morton.

Animal behavior and metabolism are tightly coordinated with sleep-wake cycles governed by the brain in harmony with environmental light:dark cycles. Within the brain, the dorsomedial hypothalamic nucleus (DMH) has been implicated in the integrative control of feeding, energy homeostasis, and circadian rhythms,1 but the underlying cell types are unknown. Here, we identify a role for DMH leptin receptor-expressing neurons (DMHLepR) in this integrative control. Using a viral approach, we show that silencing neurotransmission in DMHLepR neurons in adult mice not only increases body weight and adiposity, but also phase-advances diurnal rhythms of feeding and metabolism into the light-cycle and abolishes the normal increase in dark-cycle locomotor activity (LMA) characteristic of nocturnal rodents. Finally, DMHLepR-silenced mice fail to entrain to a restrictive change in food availability. Together, these findings identify DMHLepR neurons as critical determinants of the daily time of feeding and associated metabolic rhythms.

Keywords: mouse; neuroscience

DOI: https://doi.org/10.7554/eLife.63671

Nat Commun. 2021 01 27. 12(1): 617

A circadian clock regulates efflux by the blood-brain barrier in mice and human cells.

Shirley L Zhang, Nicholas F Lahens, Zhifeng Yue, Denice M Arnold, Peter P Pakstis, Jessica E Schwarz, Amita Sehgal.

The blood-brain barrier (BBB) is critical for neural function. We report here circadian regulation of the BBB in mammals. Efflux of xenobiotics by the BBB oscillates in mice, with highest levels during the active phase and lowest during the resting phase. This oscillation is abrogated in circadian clock mutants. To elucidate mechanisms of circadian regulation, we profiled the transcriptome of brain endothelial cells; interestingly, we detected limited circadian regulation of transcription, with no evident oscillations in efflux transporters. We recapitulated the cycling of xenobiotic efflux using a human microvascular endothelial cell line to find that the molecular clock drives cycling of intracellular magnesium through transcriptional regulation of TRPM7, which appears to contribute to the rhythm in efflux. Our findings suggest that considering circadian regulation may be important when therapeutically targeting efflux transporter substrates to the CNS.

DOI: https://doi.org/10.1038/s41467-020-20795-9