Differential arousal regulation by prokineticin 2 signaling in the nocturnal mouse and the diurnal monkey
© The Author(s). 2016
Received: 7 June 2016
Accepted: 26 July 2016
Published: 18 August 2016
The temporal organization of activity/rest or sleep/wake rhythms for mammals is regulated by the interaction of light/dark cycle and circadian clocks. The neural and molecular mechanisms that confine the active phase to either day or night period for the diurnal and the nocturnal mammals are unclear. Here we report that prokineticin 2, previously shown as a circadian clock output molecule, is expressed in the intrinsically photosensitive retinal ganglion cells, and the expression of prokineticin 2 in the intrinsically photosensitive retinal ganglion cells is oscillatory in a clock-dependent manner. We further show that the prokineticin 2 signaling is required for the activity and arousal suppression by light in the mouse. Between the nocturnal mouse and the diurnal monkey, a signaling receptor for prokineticin 2 is differentially expressed in the retinorecipient suprachiasmatic nucleus and the superior colliculus, brain projection targets of the intrinsically photosensitive retinal ganglion cells. Blockade with a selective antagonist reveals the respectively inhibitory and stimulatory effect of prokineticin 2 signaling on the arousal levels for the nocturnal mouse and the diurnal monkey. Thus, the mammalian diurnality or nocturnality is likely determined by the differential signaling of prokineticin 2 from the intrinsically photosensitive retinal ganglion cells onto their retinorecipient brain targets.
The temporal organization of activity/rest or sleep/wake rhythms for mammals is regulated by the interaction of light/dark cycle and circadian clocks. Several lines of evidence indicate that the known master circadian clock, suprachiasmatic (SCN), operates quite similarly in nocturnal and diurnal mammals. The oscillations of clockwork genes, such as Bmal1, Per1, and Per2, are in the same phase in the SCN, regardless whether the mammals are diurnal or nocturnal [1, 2]. The firing rate and the glucose utilization of SCN neurons are also in the same phase for both the nocturnal and the diurnal mammals [3, 4]. The same phase oscillation has also been shown for the two SCN output molecules, vasopressin and prokineticin 2 (PK2) [5–7]. Therefore, the divergent mechanisms that confine the active phase to either day or night period for the diurnal and the nocturnal mammals have been postulated to lie downstream of the SCN clock [4, 8, 9]. However, no such divergent mechanism has been identified.
Besides modulating the activity/rest or the sleep/wake rhythms indirectly via its ability to phase shift and entrain the SCN circadian clock to the ambient light–dark cycle, light also exerts a direct effect on the activity or arousal levels. In the nocturnal animals, light strongly suppresses activity and induces sleep (photosomnolence) [10, 11]. In the diurnal mammals, such as monkeys and humans, light produces opposite effects of inducing the arousal or increasing the activity levels [12–14]. For the nocturnal animals, the direct light effect of activity suppression is commonly referred to as masking [10, 11, 15]. Light-induced activity suppression and circadian clock entrainment appears to utilize the identical photic input pathways from the retina. Both classical (rod/cone) photoreceptors and intrinsically photosensitive retinal ganglion cells (ipRGC), the retinal ganglion cells that express melanopsin (OPN4), participate in the masking and the circadian clock entrainment, as well as other non-image-forming visual responses such as the pupillary reflex [11, 16–19]. Masking is attenuated in Opn4-deficient mice , and is essentially abolished in the mice deficient in both Opn4 and rod photoreceptors . Masking and circadian clock entrainment to light/dark cycle is completely abolished in the mice lacking the ipRGC generated by genetic or chemical ablation [21–25]. Thus, the ipRGC are the only channels that relay the photic information to brains for the masking and the circadian clock entrainment. The neural pathway of mediating the light masking downstream of the ipRGC is thought to act through the retinohypothalamic tract (RHT) projection to the SCN [9, 11], the same neural pathway that mediates the phase shifting and the entrainment of the SCN clock. The light masking was abolished with complete transection of RHT . SCN lesion together with the loss of RHT eliminates the circadian rhythmicity as well as the light masking . Transplantation of embryonic SCN to arrhythmic adults restores some locomotor rhythmicity without restoring the masking effect . Thus, the ipRGC-SCN neural pathway appears to be critical for the light masking in the nocturnal animals.
In the current study, we show the oscillatory expression of PK2, previously demonstrated as a critical SCN output signal, in the ipRGC in a clock-dependent manner. We further show that PK2 signaling is required for the sustained light-induced activity suppression and sleep induction in mice. Blockade with PK2 antagonist demonstrated the opposite effects of the PK2 signaling on the arousal levels in the nocturnal mouse and the diurnal monkey. Together with the observed differential expression of a PK2 signaling receptor in the retinorecipient brain targets of the ipRGC between the nocturnal mouse and the diurnal monkey, the mammalian diurnal/nocturnal determination lies among the ipRGC-brain pathways, upstream of the SCN clock.
PK2 signaling is required for the sustained light-induced suppression of the locomotor activity and the arousal in mice
Clock-dependent oscillatory expression of PK2 in the intrinsically photosensitive retinal ganglion cells (ipRGC)
Differential expression of PK2 receptor in the brain targets of the intrinsically photosensitive retinal ganglion cells between the nocturnal mouse and the diurnal monkey
Opposite effects of PK2 blockade on the arousal levels in the nocturnal mouse and the diurnal monkey
The PK2 signaling of the ipRGC likely regulates the arousal levels via impinging on the brain targets of the ipRGC, particularly the SCN and the SC. The differential expression of the PK2 receptor (PKR2) in the retinorecipient compartment of the SCN and the retinorecipient superficial layer of the SC may then underlie the opposite effects of light on the arousal levels between the nocturnal mouse and the diurnal monkey. In the mouse brain, PKR2 is robustly expressed in the retinorecipient SCN, but absent in the SC, and the PK2 signaling of the ipRGC thus funnels through arousal-inhibitory ipRGC-SCN pathway in the nocturnal mouse. In contrast, PKR2 is not expressed in the retinorecipient ventral SCN of the monkey brain, but strongly expressed in the retinorecipient superficial layer of the SC, and thus the ipRGC-SC pathway dominates in the diurnal monkey.
The PK2 signaling of the ipRGC-SC pathway is likely to be stimulatory for the arousal levels. SC has previously been indicated as a critical nucleus for the light-induced arousal or other higher brain functions, such as attention, that are closely tied with increased arousal [42–45]. In the monkeys, bilateral lesions of the SC have been found to drastically affect the arousal levels, including response to light . Lesion studies in rats have revealed that the SC is required for EEG desynchronization (arousal) in response to light flashes . This rat lesion study suggests that the ipRGC-SC pathway may be stimulatory for the arousal levels for the nocturnal animals, at least briefly in response to light flashes. Over a longer duration, light is inhibitory for the arousal levels of the nocturnal animals as the inhibitory ipRGC-SCN pathway dominates. In diurnal mammals such as monkeys, SC may mediate the light-driven arousal via the ascending projections to cortices that are routed through the lateral posterior/Pulvinar complex of the thalamus [46, 47]. The lateral posterior/Pulvinar complex of the thalamus is known to play a critical role for higher function such as attention . In this regard, wakefulness may be viewed as low level attention. It is well known that, compared to the nocturnal animals, the overall size of the SC, the lateral posterior/Pulvinar complex of the thalamus, and the associated cortices are all significantly enlarged and expanded in the diurnal mammalian species, such as the primates [49, 50]. As the mammalian species are believed to start being nocturnal , diurnality of the mammals may evolve via the expansion of the arousal-stimulatory ipRGC-SC pathway and the simultaneous diminishment of the arousal-inhibitory ipRGC-SCN pathway. Our model (Fig. 10) indicates that the nocturnal/diurnal determination of arousal levels lies in the upstream of the SCN circadian clock, and divergent signaling downstream of the SCN clock may not be necessary. The melatonin rhythms, known to lie downstream of the SCN clock, will operate in the same phase of the SCN clocks and thus no difference will be exhibited in the nocturnal and diurnal mammals. Our model also argues against the previously presumed central role of SCN as the master clock for diurnal mammals, such as monkeys, at least for the regulation of arousal levels under light and dark conditions. Although the supporting evidence for the SCN as the master circadian clock is overwhelmingly strong for the nocturnal mammals, such claim has actually limited supporting evidence in the case of the diurnal animals . The well cited work of increased sleep by the SCN lesion in squirrel monkeys , interpreted as the arousal-promoting of the SCN for the diurnal animals, could be due to the concurrent lesions to the retinohypothalamic tract, which would damage projections to both SCN and SC. Under light and dark condition, it is likely that the ipRGC play central roles for the regulation of arousal levels regardless whether the mammals are diurnal or nocturnal. In nocturnal mammals, ipRGC and SCN act in sequential neural projections (and with the similar oscillatory phase) to regulate arousal levels, thus nocturnal activity patterns are displayed. In diurnal mammals, the arousal-stimulatory ipRGC-SC projections overcome the diminished arousal-inhibitory ipRGC-SCN projections, and thus diurnal activity patterns are exhibited
PK2−/− mice and their littermate wild type controls in mixed genetic background were generated as described [29, 31]. Bmal1−/− mice were produced by crossing from heterozygous mice that were procured from Jackson laboratory. Mice were fed at libo and housed at regular light/dark cycle, with lights (~150 lux white light) on at 7:00 a.m. (Zeitgeber Time ZT0, light period ZT0-ZT12) and lights off at 7:00 p.m. (ZT12, dark period ZT12-ZT0). All animal procedures were approved by appropriate institutional animal use committee.
Measurement and analysis of the locomotor activity in mice
Monitoring of the locomotor activity was carried out as described . Briefly, mice were individually housed with cages equipped with infrared beams for the monitoring of the locomotor activity (AccuScan Instrument Inc. Columbus, OH). Mice were housed at regular 12 h Light (~150 lux white light): 12 h Dark cycle. The locomotor activities were recorded as counts per 10-min interval and were analyzed in 30 or 60 min pins. Light pulses or dim light at the indicated intensities were administered.
Measurement and analysis of the arousal level in mice
Electrodes for recording the electroencephalographic (EEG) and electromyogram (EMG) signals were implanted as described [29, 31]. The mice were connected to a swivel system of tether/commutator system (Plastics One, Roanoke, VA) for the collection of the EEG/EMG signals. The EEG/EMG signals were amplified using a Grass Model 78 (Grass Instruments, West Warwick, RI) and filtered (EEG: 0.3–100 Hz, EMG: 30–300 Hz) before being digitized at a sampling rate of 128 Hz, stored on a computer. After sleep data were collected, EEG/EMG records were scored with SleepSign software sleep scoring system (Kissei Comtec America, Irvine, CA) as described . Mice were housed at a regular 12 h light/12 h dark cycle. Light pulses or dim light at the indicated intensities were administered.
In situ hybridization
Procedures for In situ hybridization were carried out similarly as described [6, 7]. Tissue sections were cut at −20 °C, and then fixed with 4 % paraformaldehyde, followed by three washes of 0.1 M phosphate buffer, air-dried, and stored at −20 °C until use. For In situ hybridization, sections were dried at room temperature, followed by pretreatment of proteinase K (1 μg/ml). Sections were then air-dried and hybridized with S -labelled riboprobes by incubation at 60 °C for 18 h. After hybridization, tissue sections were treated with RNAase (20 μg/ml) (Sigma-Aldrich, St. Louis, MO), decreasing salinity washes and high stringency (68 °C) wash. After dehydration and air-drying, tissue sections were exposed to Kodak Biomax film. Images were captured with image analysis system (MCID, Imaging Research, Ontario, Canada).
Immunohistochemistry was performed according to previous publications [53, 54]. Retinal sections were mounted onto coated glass slides. Sections were rehydrated in PBS for 20 min then immersed in a blocking buffer containing 2 % BSA, 0.5 % Tween-20 and 0.05 % Triton-X 100 for 1 h. Primary antibody for PK2 (Hamster monoclonal, 1:200, Roche Inc.) or OPN4 (Affinity purified rabbit polyclonal, 1:200, Millipore Inc.) was added to the sections overnight at 4 °C. Slides were washed with PBS containing 0.5 % Tween-20 five times for 5 min each. Anti-rabbit or anti-hamster secondary antibodies (Alexa Fluor 488 or 555 1:2000; Invitrogen Inc.) were then applied, followed by incubation with 10 μg/ml Hoechst 33342 (Invitrogen Inc) for 5 min at room temperature to stain the nucleus. Sections were viewed under a Nikon inverted fluorescence microscope (Model TE-2000U; Nikon Inc, Tokyo, Japan). Images were captured with a SPOT digital camera (Diagnostic Instruments, Inc, Sterling Heights, MI). Immunofluorescence intensity was quantified with Image J. For DAB (3,3′-diaminobenzidine) immunostaining, sections were incubated with anti-PK2 antibody (Hamster monoclonal, 1:500 dilution) antibody, followed by incubation with biotinylated anti-hamster secondary antibody. Color development of DAB immunostaining was carried out with the standard ABC method .
Pharmacological experiments of examining the effect of a PK2 antagonist on the activity or arousal levels in the mice and the monkeys
A PK2 antagonist (PKR#7) was prepared similarly as described . PKR#7 (40 mg/kg) was administered to the mice intraperitoneally at ZT6. PKR#7 (10 mg/kg) was administered to the monkeys intramuscularly at ZT10. For the pharmacological experiments, animals were treated with either the vehicle or antagonist and then crossed over with the opposite treatments 1 week later to form paired controls.
Sleep and activity data of the PK2 antagonist or control-treated mice were acquired and analyzed as described for the PK2−/− mice. For the sleep studies of the monkeys, young adult monkeys (Macaca fascicularis) were housed under standard light (white light ~250 lux) and dark cycle. The measurement and analysis of the arousal levels in the monkey were carried out as follows. A wearable wireless sleep tracker, similar to described previously for human subjects [56–59] and for non-human primates , was used. This wireless system enabled remote monitoring of the sleep/wake status of the monkeys for an ambulatory setting for a long time with minimal disturbing of the monkeys. The sleep data obtained from the wireless sleep tracker were verified with with concurrent recording of infrared video camera. The sleep data of the sleep trackers were retrieved daily with mobile phones that were seated about ten meters away from the animal cages, without physical contact with the monkeys. Previous studies have shown excellent agreement of sleep data obtained by the sleep tracker, video camera and classical sleep/wake data obtained by the EEG/EMG method [56, 59, 61].
To reduce the impact of data variations due to ultradian rhythms, the measurements of mouse locomotor activity and EEG/EMG were performed two times that were separated by 3 or 4 days, and the average values of these two measurements were used in statistical analyses. Statistical analyses were performed with 1 or 2 ways ANOVA by using GraphPad Prism Software Version 5.0 (San Diego, CA), followed by appropriate post tests.
EEG, electroencephalography; EMG: electromyogram; ipRGC, intrinsically photosensitive retinal ganglion cells; LD, light/dark cycle; OPN4, melanopsin; PK2, prokineticin 2; RHT, retinohypothalamic tract; SC, superior colliculus; SCN, suprachiasmatic nucleus; ZT, Zeitgeber Time.
We thank Jincheng Huang and Andy Le for their technical helps.
This research project was supported in part by grants from NIH to QYZ.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article.
QYZ, conceived the project, designed the research, synthesized the antagonist, performed some of the mouse behavioral experiments and wrote the manuscript; KJB, carried out the in situ hybridization experiments; MLN and AGK, performed the immunohistochemistry experiments; YQ and YM performed the monkey sleep experiment; YS and XX, implanted the electrodes for the mouse sleep studies; XL performed some of mouse behavioral experiments and processed retinal tissues. All authors read and approved the final manuscript.
A provisional patent application has been filed, in part based on some of the findings described in the article.
Consent for publication
Ethics approval and consent to participate
The Animal Care and Use Committee of University of California, Irvine and Kunming University of Science and Technology approved all experimental protocols.
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