Publications by authors named "Kenkichi Baba"

51 Publications

Removal of melatonin receptor type 1 signalling induces dyslipidaemia and hormonal changes in mice subjected to environmental circadian disruption.

Endocrinol Diabetes Metab 2021 01 10;4(1):e00171. Epub 2020 Sep 10.

Circadian Rhythms and Sleep Disorders Program Neuroscience Institute Atlanta GA USA.

Background: Melatonin is a hormone secreted by the pineal gland in a circadian rhythmic manner with peak synthesis at night. Melatonin signalling was suggested to play a critical role in metabolism during the circadian disruption.

Methods: Melatonin-proficient (C3H-f or WT) and melatonin receptor type 1 knockout (MT KO) male and female mice were phase-advanced (6 hours) once a week for 6 weeks. Every week, we measured weight, food intake and basal glucose levels. At the end of the experiment, we sacrificed the animals and measured the blood's plasma for lipids profile (total lipids, phospholipids, triglycerides and total cholesterol), metabolic hormones profiles (ghrelin, leptin, insulin, glucagon, glucagon-like-peptide and resistin) and the body composition.

Results: Environmental circadian disruption (ECD) did not produce any significant effects in C3H-f, while it increased lipids profile in MT KO with the significant increase observed in total lipids and triglycerides. For metabolic hormones profile, ECD decreased plasma ghrelin and increased plasma insulin in MT KO females. Under control condition, MT KO females have significantly different body weight, fat mass, total lipids and total cholesterol than the control C3H-f females.

Conclusion: Our data show that melatonin-proficient mice are not affected by ECD. When the MT receptors are removed, ECD induced dyslipidaemia in males and females with females experiencing the most adverse effect. Overall, our data demonstrate that MT signalling is an essential modulator of lipid and metabolic homeostasis during ECD.
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http://dx.doi.org/10.1002/edm2.171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831213PMC
January 2021

Photoreceptor Degeneration in Homozygous Male Per2 Mice During Aging.

J Biol Rhythms 2021 04 2;36(2):137-145. Epub 2020 Nov 2.

Neuroscience Institute, Department of Pharmacology & Toxicology, Morehouse School of Medicine, Atlanta, Georgia.

The Per2 mouse model developed by Takahashi laboratory is one of the most powerful models to study circadian rhythms in real time. In this study, we report that photoreceptors degenerate in male Per2 mice during aging. Young (2.5- to 5-month-old) and aged (11- to 13.5-month-old) homozygous male Per2 mice and C57BL/6J mice were used for this study. Retina structure and function were investigated via spectral domain optical coherence tomography (SD-OCT), fundus imaging, and electroretinography (ERG). Zonula occludens-1 (ZO-1) immunofluorescence was used to analyze the retinal pigment epithelium (RPE) morphology. Fundus examination revealed no difference between young Per2 and wild-type (WT) mice. However, the fundus of aged Per2 mice showed white deposits, suggestive of age-related drusen-like formation or microglia, which were absent in age-matched WT mice. No differences in retinal structure and function were observed between young Per2 and WT mice. However, with age, Per2 mice showed a significant reduction in total retinal thickness with respect to C57BL/6J mice. The reduction was mostly confined to the photoreceptor layer. Consistent with these results, we observed a significant decrease in the amplitude of a- and b-waves of the ERG in aged Per2 mice. Analysis of the RPE morphology revealed that in aged Per2 mice there was an increase in compactness and eccentricity with a decrease in solidity with respect to the values observed in WT, pointing toward signs of aging in the RPE of Per2 mice. Our data demonstrate that homozygous Per2 mice show photoreceptor degeneration during aging and a premature aging of the RPE.
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http://dx.doi.org/10.1177/0748730420965285DOI Listing
April 2021

Administration of Exogenous Melatonin Improves the Diurnal Rhythms of the Gut Microbiota in Mice Fed a High-Fat Diet.

mSystems 2020 May 19;5(3). Epub 2020 May 19.

College of Animal Science and Technology, Hunan Co-Innovation Center of Animal Production Safety, Hunan Agricultural University, Changsha, China.

Melatonin, a circadian hormone, has been reported to improve host lipid metabolism by reprogramming the gut microbiota, which also exhibits rhythmicity in a light/dark cycle. However, the effect of the administration of exogenous melatonin on the diurnal variation in the gut microbiota in mice fed a high-fat diet (HFD) is unclear. Here, we further confirmed the antiobesogenic effect of melatonin on mice fed an HFD for 2 weeks. Samples were collected every 4 h within a 24-h period, and diurnal rhythms of clock gene expression (, , , , and ) and serum lipid indexes varied with diurnal time. Notably, and triglycerides (TG) showed a marked rhythm in the control in melatonin-treated mice but not in the HFD-fed mice. The rhythmicity of these parameters was similar between the control and melatonin-treated HFD-fed mice compared with that in the HFD group, indicating an improvement caused by melatonin in the diurnal clock of host metabolism in HFD-fed mice. Moreover, 16S rRNA gene sequencing showed that most microbes exhibited daily rhythmicity, and the trends were different for different groups and at different time points. We also identified several specific microbes that correlated with the circadian clock genes and serum lipid indexes, which might indicate the potential mechanism of action of melatonin in HFD-fed mice. In addition, effects of melatonin exposure during daytime or nighttime were compared, but a nonsignificant difference was noticed in response to HFD-induced lipid dysmetabolism. Interestingly, the responses of microbiota-transplanted mice to HFD feeding also varied at different transplantation times (8:00 and 16:00) and with different microbiota donors. In summary, the daily oscillations in the expression of circadian clock genes, serum lipid indexes, and the gut microbiota appeared to be driven by short-term feeding of an HFD, while administration of exogenous melatonin improved the composition and diurnal rhythmicity of some specific gut microbiota in HFD-fed mice. The gut microbiota is strongly shaped by a high-fat diet, and obese humans and animals are characterized by low gut microbial diversity and impaired gut microbiota compositions. Comprehensive data on mammalian gut metagenomes shows gut microbiota exhibit circadian rhythms, which is disturbed by a high-fat diet. On the other hand, melatonin is a natural and ubiquitous molecule showing multiple mechanisms of regulating the circadian clock and lipid metabolism, while the role of melatonin in the regulation of the diurnal patterns of gut microbial structure and function in obese animals is not yet known. This study delineates an intricate picture of melatonin-gut microbiota circadian rhythms and may provide insight for obesity intervention.
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http://dx.doi.org/10.1128/mSystems.00002-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253360PMC
May 2020

Dopamine 2 Receptor Signaling Controls the Daily Burst in Phagocytic Activity in the Mouse Retinal Pigment Epithelium.

Invest Ophthalmol Vis Sci 2020 05;61(5):10

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Purpose: A burst in phagocytosis of spent photoreceptor outer fragments by RPE is a rhythmic process occurring 1 to 2 hours after the onset of light. This phenomenon is considered crucial for the health of the photoreceptors and RPE. We have recently reported that dopamine, via dopamine 2 receptor (D2R), shifts the circadian rhythm in the RPE.

Methods: Here, we first investigated the impact of the removal of D2R on the daily peak of phagocytosis by RPE and then we analyzed the function and morphology of retina and RPE in the absence of D2R.

Results: D2R knockout (KO) mice do not show a daily burst of phagocytic activity after the onset of light. RNA sequencing revealed a total of 394 differentially expressed genes (DEGs) between ZT 23 and ZT 1 in the control mice, whereas in D2R KO mice, we detected 1054 DEGs. Pathway analysis of the gene expression data implicated integrin signaling to be one of the upregulated pathways in control but not in D2R KO mice. Consistent with the gene expression data, phosphorylation of focal adhesion kinase (FAK) did not increase significantly in KO mice at ZT 1. No difference in retinal thickness, visual function, or morphology of RPE cells was observed between wild-type (WT) and D2R KO mice at the age of 3 and 12 months.

Conclusions: Our data suggest that removal of D2R prevents the burst of phagocytosis and a related increase in the phosphorylation of FAK after light onset. The pathway analysis points toward a putative role of D2R in controlling integrin signaling, which is known to play an important role in the control of the daily burst of phagocytosis by the RPE. Our data also indicate that the absence of the burst of phagocytic activity in the early morning does not produce any apparent deleterious effect on the retina or RPE up to 1 year of age.
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http://dx.doi.org/10.1167/iovs.61.5.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405625PMC
May 2020

Melatonin receptor heterodimerization in a photoreceptor-like cell line endogenously expressing melatonin receptors.

Mol Vis 2019 2;25:791-799. Epub 2019 Dec 2.

Department of Pharmacology and Toxicology and Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA.

Purpose: Melatonin signaling plays an important role in the modulation of retinal physiology and photoreceptor viability during aging. In this study, we investigated whether 661W cells-a photoreceptor-like cell that endogenously expresses melatonin receptor type 1 (MT) and melatonin receptor type 2 (MT) receptors-represent a useful model for studying the biology of heterodimerization and signaling of MT receptors.

Methods: 661W cells were cultured, and MT/MT heterodimerization in 661W cells was assessed with proximity ligation assay. MT was removed from the 661W cells using the MT-CRISPR/Cas9 system. Melatonin receptor signaling was investigated by measuring cAMP levels and activation of the AKT-FoxO1 pathway.

Results: The results demonstrated that heterodimerization of MT and MT receptors occurs in 661W cells. The pathways activated by MT/MT heterodimer (MT) in 661W cells are similar to those previously reported in mouse photoreceptors. Disruption of the heterodimer formation by genetically ablating MT from 661W cells abolished the activation of melatonin signaling in these cells.

Conclusions: The data indicated that in 661W cells, MT and MT receptors are functional only when they are associated in a heteromeric complex, as occurs in mouse photoreceptors. 661W cells represent a useful model for studying the mechanism underlying MT/MT heterodimerization.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887793PMC
June 2020

Retinal Circadian Clocks are Major Players in the Modulation of Retinal Functions and Photoreceptor Viability.

Yale J Biol Med 2019 06 27;92(2):233-240. Epub 2019 Jun 27.

Department of Pharmacology & Toxicology and Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA.

Circadian rhythms control many biochemical and physiological functions within the body of an organism. These circadian rhythms are generated by a molecular clock that is located in almost every cell of the body. Accumulating data indicate that dysfunction of the circadian clock negatively affects the health status of the tissue in which the circadian clock has been disabled. The eye also contains a complex circadian system that regulates many important functions such as the processing of light information, the release of neurotransmitters, and phagocytic activity by the retinal pigment epithelium, to name just a few. Emerging experimental evidence indicates that dysfunction of the circadian clock within the retina has severe consequence for retinal function and photoreceptor viability. The aim of this review is to provide the reader with a summary of current knowledge about the eye circadian system and what effects emerge with a disruption of this system.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585523PMC
June 2019

Removing melatonin receptor type 1 signaling leads to selective leptin resistance in the arcuate nucleus.

J Pineal Res 2019 Sep 29;67(2):e12580. Epub 2019 Apr 29.

Department of Pharmacology and Toxicology and Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia.

Recent studies have highlighted the involvement of melatonin in the regulation of energy homeostasis. In this study, we report that mice lacking melatonin receptor 1 (MT KO) gained more weight, had a higher cumulative food intake, and were more hyperphagic after fasting compared to controls (WT). In response to a leptin injection, MT KO mice showed a diminished reduction in body weight and food intake. To evaluate hypothalamic leptin signaling, we tested leptin-induced phosphorylation of the signal transducer and activator of transcription 3 (STAT3). Leptin failed to induce STAT3 phosphorylation in MT KO mice beyond levels observed in mice injected with phosphate-buffered saline (PBS). Furthermore, STAT3 phosphorylation within the arcuate nucleus (ARH) was decreased in MT KO mice. Leptin receptor mRNA levels in the hypothalamus of MT KO were significantly reduced (about 50%) compared to WT. This study shows that: (a) MT deficiency causes weight gain and increased food intake; (b) a lack of MT signaling induces leptin resistance; (c) leptin resistance is ARH region-specific; and (d) leptin resistance is likely due to down-regulation of the leptin receptor. Our data demonstrate that MT signaling is an important modulator of leptin signaling.
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http://dx.doi.org/10.1111/jpi.12580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687516PMC
September 2019

Removal of clock gene from the retina affects retinal development and accelerates cone photoreceptor degeneration during aging.

Proc Natl Acad Sci U S A 2018 12 29;115(51):13099-13104. Epub 2018 Nov 29.

Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA 30322-1013;

The mammalian retina contains an autonomous circadian clock system that controls many physiological functions within this tissue. Previous studies on young mice have reported that removal of the key circadian clock gene from the retina affects the circadian regulation of visual function, but does not affect photoreceptor viability. Because dysfunction in the circadian system is known to affect cell viability during aging in other systems, we compared the effect of removal from the retina on visual function, inner retinal structure, and photoreceptor viability in young (1 to 3 months) and aged (24 to 26 months) mice. We found that removal of from the retina significantly affects visual information processing in both rod and cone pathways, reduces the thickness of inner retinal nuclear and plexiform layers, accelerates the decline of visual functions during aging, and reduces the viability of cone photoreceptors. Our results thus suggest that circadian clock dysfunction, caused by genetic or other means, may contribute to the decline of visual function during development and aging.
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http://dx.doi.org/10.1073/pnas.1808137115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305005PMC
December 2018

Heteromeric MT/MT melatonin receptors modulate the scotopic electroretinogram via PKCζ in mice.

Exp Eye Res 2018 12 27;177:50-54. Epub 2018 Jul 27.

Neuroscience Institute, Department of Pharmacology and Toxicology Morehouse School of Medicine, Atlanta, GA, USA. Electronic address:

Melatonin plays an important role in the regulation of retinal functions, and previous studies have also reported that the action of melatonin on photoreceptors is mediated by melatonin receptor heterodimers. Furthermore, it has been reported that the melatonin-induced increase in the amplitude of the a- and b-wave is significantly blunted by inhibition of PKC. Previous work has also shown that PKCζ is present in the photoreceptors, thus suggesting that PCKζ may be implicated in the modulation of melatonin signaling in photoreceptors. To investigate the role PKCζ plays in the modulation of the melatonin effect on the scotopic ERG, mice were injected with melatonin and with specific inhibitors of different PKC isoforms. PKCζ knockout mice were also used in this study. PKCζ activation in photoreceptors following melatonin injection was also investigated with immunocytochemistry. Inhibition of PKCζ by PKCζ-pseudosubstrate inhibitor (20 μM) significantly reduced the melatonin-induced increase in the amplitude of the a- and b-wave. To further investigate the role of different PKCs in the modulation of the ERGs, we tested whether intra-vitreal injection of Enzastaurin (a potent inhibitor of PCKα, PKCβ, PKCγ, and PKCε) has any effect on the melatonin-induced increase in the a- and b-wave of the scotopic ERGs. Enzastaurin (100 nM) did not prevent the melatonin-induced increase in the amplitude of the a-wave, thus suggesting that PCKα, PKCβ, PKCγ, and PKCε are not involved in this phenomenon. Finally, our data indicated that, in mice lacking PKCζ, melatonin injection failed to increase the amplitude of the a- and b-waves of the scotopic ERGs. An increase in PKCζ phosphorylation in the photoreceptors was also observed by immunocytochemistry. Our data indicate that melatonin signaling does indeed use the PKCζ pathway to increase the amplitude of the a- and b-wave of the scotopic ERG.
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http://dx.doi.org/10.1016/j.exer.2018.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261696PMC
December 2018

Aging Alters Circadian Rhythms in the Mouse Eye.

J Biol Rhythms 2018 08 25;33(4):441-445. Epub 2018 Jun 25.

Department of Pharmacology & Toxicology, Morehouse School of Medicine, Atlanta, Georgia.

The eye contains a circadian system that acts independently from the master circadian clock located in the brain. This circadian system regulates important physiological functions within the eye. Emerging experimental evidence also indicates that disruption of the ocular circadian clock, or its outputs, negatively affects the overall health of the eye. Although previous studies have investigated the effect of aging on the regulation of circadian rhythms, no study has investigated the effects of aging on the circadian rhythm in the ocular system. The aim of the present study was to investigate how aging affects the circadian rhythm of PER2::LUC bioluminescence in the retina, retinal pigment epithelium (RPE), and cornea. Our data suggest that among the 3 different ocular tissues investigated, the retina appears to be the most affected by aging whereas the RPE and cornea are less affected by aging. Our data, along with studies of other organs and tissues, suggest that reduction in the amplitude of rhythms is probably the most severe effect of aging on the circadian clock.
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http://dx.doi.org/10.1177/0748730418783648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398161PMC
August 2018

The Retinal Circadian Clock and Photoreceptor Viability.

Adv Exp Med Biol 2018 ;1074:345-350

Department of Pharmacology and Toxicology Morehouse School of Medicine, Neuroscience Institute, Atlanta, GA, USA.

Circadian rhythms are present in most living organisms, and these rhythms are not just a consequence of the day/night fluctuation, but rather they are generated by endogenous biological clocks with a periodicity of about 24 h. In mammals, the master pacemaker of circadian rhythms is localized in the suprachiasmatic nuclei (SCN) of the hypothalamus. The SCN controls circadian rhythms in peripheral organs. The retina also contains circadian clocks which regulate many aspects of retinal physiology, independently of the SCN. Emerging experimental evidence indicates that the retinal circadian clocks also affect ocular health, and a few studies have now demonstrated that disruption of retinal clocks may contribute to the development of retinal diseases. Our study indicates that in mice lacking the clock gene Bmal1, photoreceptor viability during aging is significantly reduced. Bmal1 knockout mice at 8-9 months of age have 20-30% less nuclei in the outer nuclear layer. No differences were observed in the other retinal layers. Our study suggests that the retinal circadian clock is an important modulator of photoreceptor health.
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http://dx.doi.org/10.1007/978-3-319-75402-4_42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003627PMC
May 2019

Tumoricidal effect and pain relief after concurrent therapy by strontium-89 chloride and zoledronic acid for bone metastases.

Hell J Nucl Med 2018 Jan-Apr;21(1):15-23. Epub 2018 Mar 20.

Department of General Diagnosis and Treatment, Fukuoka Kieikai Hospital, Chihaya 5-11-5, Higashiku, Fukuoka City, Fukuoka, 813-0044, Japan.

Objective: The purpose of this study was to investigate the palliative and tumoricidal effects of concurrent therapy of strontium-89 chloride (SrCl) and zoledronic acid (ZA) for painful bone metastases.

Subjects And Methods: Fifty-one patients with painful bone metastases prostate cancer (n=17), lung cancer (n=13), breast cancer (n=12), other cancers (n=9) were treated. Bone metastases was confirmed in all patients by technetium-99m hydroxymethylene diphosphonate (Tc-HMDP) bone scintigraphy. The numeric rating scale (NRS) and performance status (PS) were used to assess the degree of pain and patients' physical condition. The extent of bone metastases was assessed with imaging modalities including CT, MRI and/or Tc bone scintigraphy before treatment and 2 or 3 months after.

Results: The pain relief response of SrCl with ZA for bone metastases was 94% (48/51) from 1 to 3 months after treatment. The tumoricidal effect of concurrent therapy by SrCl with ZA for painful bone metastases was 8/22 as shown by imaging modalities and the rate of non-progressive disease (non-PD) was 19/22. Pain due to bone metastases assessed with the NRS was significantly improved (P<0.001) in many types of primary cancer, including prostate, breast and lung cancers.

Conclusion: Concurrent therapy of SrCl with ZA may offer not only pain relief, but also a tumoricidal effect for painful bone metastases.
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http://dx.doi.org/10.1967/s002449910702DOI Listing
June 2018

Melatonin partially protects 661W cells from HO-induced death by inhibiting Fas/FasL-caspase-3.

Mol Vis 2017 3;23:844-852. Epub 2017 Dec 3.

Department of Pharmacology and Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA.

Purpose: Previous studies have shown that melatonin (MEL) signaling is involved in the modulation of photoreceptor viability during aging. Recent work by our laboratory suggested that MEL may protect cones by modulating the Fas/FasL-caspase-3 pathway. In this study, we first investigated the presence of MEL receptors (MT and MT) in 661W cells, then whether MEL can prevent HO-induced cell death, and last, through which pathway MEL confers protection.

Methods: The mRNA and proteins of the MEL receptors were detected with quantitative PCR (q-PCR) and immunocytochemistry, respectively. To test the protective effect of MEL, 661W cells were treated with HO for 2 h in the presence or absence of MEL, a MEL agonist, and an antagonist. To study the pathways involved in HO-mediated cell death, a Fas/FasL antagonist was used before the exposure to HO. Finally, Fas/FasL and caspase-3 mRNA was analyzed with q-PCR and immunocytochemistry in cells treated with HO and/or MEL. Cell viability was analyzed by using Trypan Blue.

Results: Both MEL receptors (MT and MT) were detected at the mRNA and protein levels in 661W cells. MEL partially prevented HO-mediated cell death (20-25%). This effect was replicated with IIK7 (a melatonin receptor agonist) when used at a concentration of 1 µM. Preincubation with luzindole (a melatonin receptor antagonist) blocked MEL protection. Kp7-6, an antagonist of Fas/FasL, blocked cell death caused by HO similarly to what was observed for MEL. and expression was increased in cells treated with HO, and this effect was prevented by MEL. Finally, MEL treatment partially prevented the activation of caused by HO.

Conclusions: The results demonstrate that MEL receptors are present and functional in 661W cells. MEL can prevent photoreceptor cell death induced by HO via the inhibition of the proapoptotic pathway Fas/FasL-caspase-3.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723148PMC
May 2018

Nocturnal activation of melatonin receptor type 1 signaling modulates diurnal insulin sensitivity via regulation of PI3K activity.

J Pineal Res 2018 Apr 9;64(3). Epub 2018 Jan 9.

Circadian Rhythms and Sleep Disorders Program, Neuroscience Institute, Atlanta, GA, USA.

Recent genetic studies have highlighted the potential involvement of melatonin receptor 1 (MT ) and melatonin receptor 2 (MT ) in the pathogenesis of type 2 diabetes. Here, we report that mice lacking MT (MT KO) tend to accumulate more fat mass than WT mice and exhibit marked systemic insulin resistance. Additional experiments revealed that the main insulin signaling pathway affected by the loss of MT was the activation of phosphatidylinositol-3-kinase (PI3K). Transcripts of both catalytic and regulatory subunits of PI3K were strongly downregulated within MT KO mice. Moreover, the suppression of nocturnal melatonin levels within WT mice, by exposing mice to constant light, resulted in impaired PI3K activity and insulin resistance during the day, similar to what was observed in MT KO mice. Inversely, administration of melatonin to WT mice exposed to constant light was sufficient and necessary to restore insulin-mediated PI3K activity and insulin sensitivity. Hence, our data demonstrate that the activation of MT signaling at night modulates insulin sensitivity during the day via the regulation of the PI3K transcription and activity. Lastly, we provide evidence that decreased expression of MTNR1A (MT ) in the liver of diabetic individuals is associated with poorly controlled diabetes.
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http://dx.doi.org/10.1111/jpi.12462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843510PMC
April 2018

Gnaz couples the circadian and dopaminergic system to G protein-mediated signaling in mouse photoreceptors.

PLoS One 2017 31;12(10):e0187411. Epub 2017 Oct 31.

Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

The mammalian retina harbors a circadian clockwork that regulates vision and promotes healthiness of retinal neurons, mainly through directing the rhythmic release of the neurohormones dopamine-acting on dopamine D4 receptors-and melatonin-acting on MT1 and MT2 receptors. The gene Gnaz-a unique Gi/o subfamily member-was seen in the present study to be expressed in photoreceptors where its protein product Gαz shows a daily rhythm in its subcellular localization. Apart from subcellular localization, Gnaz displays a daily rhythm in expression-with peak values at night-in preparations of the whole retina, microdissected photoreceptors and photoreceptor-related pinealocytes. In retina, Gnaz rhythmicity was observed to persist under constant darkness and to be abolished in retina deficient for Clock or dopamine D4 receptors. Furthermore, circadian regulation of Gnaz was disturbed in the db/db mouse, a model of diabetic retinopathy. The data of the present study suggest that Gnaz links the circadian clockwork-via dopamine acting on D4 receptors-to G protein-mediated signaling in intact but not diabetic retina.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187411PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663513PMC
November 2017

Dopamine 2 Receptor Activation Entrains Circadian Clocks in Mouse Retinal Pigment Epithelium.

Sci Rep 2017 07 11;7(1):5103. Epub 2017 Jul 11.

Circadian Rhythms and Sleep Disorders Program, Neuroscience Institute, and Department of Pharmacology & Toxicology, Morehouse School of Medicine, Atlanta, GA, 30310, USA.

Many of the physiological, cellular, and molecular rhythms that are present within the eye are under the control of circadian clocks. Experimental evidence suggests that the retinal circadian clock, or its output signals (e.g., dopamine and melatonin), may contribute to eye disease and pathology. We recently developed a retinal pigment ephithelium (RPE)-choroid preparation to monitor the circadian clock using PERIOD2 (PER2)::LUC knock-in mouse. In this study we report that dopamine, but not melatonin, is responsible for entrainment of the PER2::LUC bioluminescence rhythm in mouse RPE-choroid. Dopamine induced phase-advances of the PER2::LUC bioluminescence rhythm during the subjective day and phase-delays in the late subjective night. We found that dopamine acts exclusively through Dopamine 2 Receptors to entrain the circadian rhythm in PER2::LUC bioluminescence. Finallly, we found that DA-induced expression of core circadian clock genes Period1 and Period2 accompanied both phase advances and phase delays of the RPE-choroid clock, thus suggesting that - as in other tissues - the rapid induction of these circadian clock genes drives the resetting process. Since the RPE cells persist for the entire lifespan of an organism, we believe that RPE-choroid preparation may represent a new and unique tool to study the effects of circadian disruption during aging.
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http://dx.doi.org/10.1038/s41598-017-05394-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505969PMC
July 2017

Circadian and Dopaminergic Regulation of Fatty Acid Oxidation Pathway Genes in Retina and Photoreceptor Cells.

PLoS One 2016 11;11(10):e0164665. Epub 2016 Oct 11.

Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

The energy metabolism of the retina might comply with daily changes in energy demand and is impaired in diabetic retinopathy-one of the most common causes of blindness in Europe and the USA. The aim of this study was to investigate putative adaptation of energy metabolism in healthy and diabetic retina. Hence expression analysis of metabolic pathway genes was performed using quantitative polymerase chain reaction, semi-quantitative western blot and immunohistochemistry. Transcriptional profiling of key enzymes of energy metabolism identified transcripts of mitochondrial fatty acid β-oxidation enzymes, i.e. carnitine palmitoyltransferase-1α (Cpt-1α) and medium chain acyl-CoA dehydrogenase (Acadm) to display daily rhythms with peak values during daytime in preparations of the whole retina and microdissected photoreceptors. The cycling of both enzymes persisted in constant darkness, was dampened in mice deficient for dopamine D4 (D4) receptors and was altered in db/db mice-a model of diabetic retinopathy. The data of the present study are consistent with circadian clock-dependent and dopaminergic regulation of fatty acid oxidation in retina and its putative disturbance in diabetic retina.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164665PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058478PMC
May 2017

Melatonin Signaling Controls the Daily Rhythm in Blood Glucose Levels Independent of Peripheral Clocks.

PLoS One 2016 29;11(1):e0148214. Epub 2016 Jan 29.

Neuroscience Institute and Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.

Melatonin is rhythmically secreted by both the pineal gland and retina in a circadian fashion, with its peak synthesis occurring during the night. Once synthesized, melatonin exerts its effects by binding to two specific G-protein coupled receptors-melatonin receptor type 1(MT1) and melatonin receptor type 2(MT2). Recent studies suggest the involvement of MT1 and MT2 in the regulation of glucose homeostasis; however the ability of melatonin signaling to impart timing cues on glucose metabolism remains poorly understood. Here we report that the removal of MT1 or MT2 in mice abolishes the daily rhythm in blood glucose levels. Interestingly, removal of melatonin receptors produced small effects on the rhythmic expression patterns of clock genes within skeletal muscle, liver, and adipose tissue. Taken together, our data suggest that the loss of the daily rhythm in blood glucose observed in MT1(-/-) and MT2(-/-) mice does not occur as a consequence of 'disrupted' clocks within insulin sensitive tissues. Finally our results highlight a diurnal contribution of melatonin receptor signaling in the daily regulation of blood glucose levels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148214PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732609PMC
July 2016

Pgc-1α and Nr4a1 Are Target Genes of Circadian Melatonin and Dopamine Release in Murine Retina.

Invest Ophthalmol Vis Sci 2015 Sep;56(10):6084-94

Institute of Functional and Clinical Anatomy University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Purpose: The neurohormones melatonin and dopamine mediate clock-dependent/circadian regulation of inner retinal neurons and photoreceptor cells and in this way promote their functional adaptation to time of day and their survival. To fulfill this function they act on melatonin receptor type 1 (MT1 receptors) and dopamine D4 receptors (D4 receptors), respectively. The aim of the present study was to screen transcriptional regulators important for retinal physiology and/or pathology (Dbp, Egr-1, Fos, Nr1d1, Nr2e3, Nr4a1, Pgc-1α, Rorβ) for circadian regulation and dependence on melatonin signaling/MT1 receptors or dopamine signaling/D4 receptors.

Methods: This was done by gene profiling using quantitative polymerase chain reaction in mice deficient in MT1 or D4 receptors.

Results: The data obtained determined Pgc-1α and Nr4a1 as transcriptional targets of circadian melatonin and dopamine signaling, respectively.

Conclusions: The results suggest that Pgc-1α and Nr4a1 represent candidate genes for linking circadian neurohormone release with functional adaptation and healthiness of retina and photoreceptor cells.
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http://dx.doi.org/10.1167/iovs.15-17503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585341PMC
September 2015

Melatonin Entrains PER2::LUC Bioluminescence Circadian Rhythm in the Mouse Cornea.

Invest Ophthalmol Vis Sci 2015 Jul;56(8):4753-8

Purpose: Previous studies have reported the presence of a circadian rhythm in PERIOD2::LUCIFERASE (PER2::LUC) bioluminescence in mouse photoreceptors, retina, RPE, and cornea. Melatonin (MLT) modulates many physiological functions in the eye and it is believed to be one of the key circadian signals within the eye. The aim of the present study was to investigate the regulation of the PER2::LUC circadian rhythm in mouse cornea and to determine the role played by MLT.

Methods: Corneas were obtained from PER2::LUC mice and cultured to measure bioluminescence rhythmicity in isolated tissue using a Lumicycle or CCD camera. To determine the time-dependent resetting of the corneal circadian clocks in response to MLT or IIK7 (a melatonin type 2 receptor, MT2, agonist) was added to the cultured corneas at different times of the day. We also defined the location of the MT2 receptor within different corneal layers using immunohistochemistry.

Results: A long-lasting bioluminescence rhythm was recorded from cultured PER2::LUC cornea and PER2::LUC signal was localized to the corneal epithelium and endothelium. MLT administration in the early night delayed the cornea rhythm, whereas administration of MLT at late night to early morning advanced the cornea rhythm. Treatment with IIK7 mimicked the MLT phase-shifting effect. Consistent with these results, MT2 immunoreactivity was localized to the corneal epithelium and endothelium.

Conclusions: Our work demonstrates that MLT entrains the PER2::LUC bioluminescence rhythm in the cornea. Our data indicate that the cornea may represent a model to study the molecular mechanisms by which MLT affects the circadian clock.
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http://dx.doi.org/10.1167/iovs.15-17124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516012PMC
July 2015

Shell neurons of the master circadian clock coordinate the phase of tissue clocks throughout the brain and body.

BMC Biol 2015 Jun 23;13:43. Epub 2015 Jun 23.

Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA, 30310, USA.

Background: Daily rhythms in mammals are programmed by a master clock in the suprachiasmatic nucleus (SCN). The SCN contains two main compartments (shell and core), but the role of each region in system-level coordination remains ill defined. Herein, we use a functional assay to investigate how downstream tissues interpret region-specific outputs by using in vivo exposure to long day photoperiods to temporally dissociate the SCN. We then analyze resulting changes in the rhythms of clocks located throughout the brain and body to examine whether they maintain phase synchrony with the SCN shell or core.

Results: Nearly all of the 17 tissues examined in the brain and body maintain phase synchrony with the SCN shell, but not the SCN core, which indicates that downstream oscillators are set by cues controlled specifically by the SCN shell. Interestingly, we also found that SCN dissociation diminished the amplitude of rhythms in core clock gene and protein expression in brain tissues by 50-75 %, which suggests that light-driven changes in the functional organization of the SCN markedly influence the strength of rhythms in downstream tissues.

Conclusions: Overall, our results reveal that body clocks receive time-of-day cues specifically from the SCN shell, which may be an adaptive design principle that serves to maintain system-level phase relationships in a changing environment. Further, we demonstrate that lighting conditions alter the amplitude of the molecular clock in downstream tissues, which uncovers a new form of plasticity that may contribute to seasonal changes in physiology and behavior.
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http://dx.doi.org/10.1186/s12915-015-0157-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489020PMC
June 2015

Melatonin signaling modulates clock genes expression in the mouse retina.

PLoS One 2014 9;9(9):e106819. Epub 2014 Sep 9.

Neuroscience Institute and Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.

Previous studies have shown that retinal melatonin plays an important role in the regulation of retinal daily and circadian rhythms. Melatonin exerts its influence by binding to G-protein coupled receptors named melatonin receptor type 1 and type 2 and both receptors are present in the mouse retina. Earlier studies have shown that clock genes are rhythmically expressed in the mouse retina and melatonin signaling may be implicated in the modulation of clock gene expression in this tissue. In this study we determined the daily and circadian expression patterns of Per1, Per2, Bmal1, Dbp, Nampt and c-fos in the retina and in the photoreceptor layer (using laser capture microdissection) in C3H-f+/+ and in melatonin receptors of knockout (MT1 and MT2) of the same genetic background using real-time quantitative RT-PCR. Our data indicated that clock and clock-controlled genes are rhythmically expressed in the retina and in the photoreceptor layer. Removal of melatonin signaling significantly affected the pattern of expression in the retina whereas in the photoreceptor layer only the Bmal1 circadian pattern of expression was affected by melatonin signaling removal. In conclusion, our data further support the notion that melatonin signaling may be important for the regulation of clock gene expression in the inner or ganglion cells layer, but not in photoreceptors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106819PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159264PMC
May 2015

Heteromeric MT1/MT2 melatonin receptors modulate photoreceptor function.

Sci Signal 2013 Oct 8;6(296):ra89. Epub 2013 Oct 8.

1Neuroscience Institute and Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, GA 30310, USA.

The formation of G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) heteromers enables signaling diversification and holds great promise for improved drug selectivity. Most studies of these oligomerization events have been conducted in heterologous expression systems, and in vivo validation is lacking in most cases, thus questioning the physiological significance of GPCR heteromerization. The melatonin receptors MT1 and MT2 exist as homomers and heteromers when expressed in cultured cells. We showed that melatonin MT1/MT2 heteromers mediated the effect of melatonin on the light sensitivity of rod photoreceptors in mice. This effect of melatonin involved activation of the heteromer-specific phospholipase C and protein kinase C (PLC/PKC) pathway and was abolished in MT1(-/-) or MT2(-/-) mice, as well as in mice overexpressing a nonfunctional MT2 mutant that interfered with the formation of functional MT1/MT2 heteromers in photoreceptor cells. Not only does this study establish an essential role of melatonin receptor heteromers in retinal function, it also provides in vivo support for the physiological importance of GPCR heteromerization. Thus, the MT1/MT2 heteromer complex may provide a specific pharmacological target to improve photoreceptor function.
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http://dx.doi.org/10.1126/scisignal.2004302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867265PMC
October 2013

Melatonin: an underappreciated player in retinal physiology and pathophysiology.

Exp Eye Res 2012 Oct 31;103:82-9. Epub 2012 Aug 31.

Circadian Rhythms and Sleep Disorders Program, Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA.

In the vertebrate retina, melatonin is synthesized by the photoreceptors with high levels of melatonin at night and lower levels during the day. Melatonin exerts its influence by interacting with a family of G-protein-coupled receptors that are negatively coupled with adenylyl cyclase. Melatonin receptors belonging to the subtypes MT(1) and MT(2) have been identified in the mammalian retina. MT(1) and MT(2) receptors are found in all layers of the neural retina and in the retinal pigmented epithelium. Melatonin in the eye is believed to be involved in the modulation of many important retinal functions; it can modulate the electroretinogram (ERG), and administration of exogenous melatonin increases light-induced photoreceptor degeneration. Melatonin may also have protective effects on retinal pigment epithelial cells, photoreceptors and ganglion cells. A series of studies have implicated melatonin in the pathogenesis of age-related macular degeneration, and melatonin administration may represent a useful approach to prevent and treat glaucoma. Melatonin is used by millions of people around the world to retard aging, improve sleep performance, mitigate jet lag symptoms, and treat depression. Administration of exogenous melatonin at night may also be beneficial for ocular health, but additional investigation is needed to establish its potential.
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http://dx.doi.org/10.1016/j.exer.2012.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462291PMC
October 2012

Age-related changes in the daily rhythm of photoreceptor functioning and circuitry in a melatonin-proficient mouse strain.

PLoS One 2012 22;7(5):e37799. Epub 2012 May 22.

Circadian Rhythms and Sleep Disorders Program, Neuroscience Institute, Department of Anatomy and Neurobiology, Morehouse School of Medicine, CNR, Pisa, Italy.

Retinal melatonin is involved in the modulation of many important retinal functions. Our previous studies have shown that the viability of photoreceptors and ganglion cells is reduced during aging in mice that lack melatonin receptor type 1. This demonstrates that melatonin signaling is important for the survival of retinal neurons. In the present study, we investigate the effects of aging on photoreceptor physiology and retinal organization in CH3-f+/+ mice, a melatonin proficient mouse strain. Our data indicate that the amplitude of the a and b waves of the scotopic and photopic electroretinogram decreases with age. Moreover, the daily rhythm in the amplitude of the a- and b-waves is lost during the aging process. Similarly, the scotopic threshold response is significantly affected by aging, but only when it is measured during the night. Interestingly, the changes observed in the ERGs are not paralleled by relevant changes in retinal morphological features, and administration of exogenous melatonin does not affect the ERGs in C3H-f(+/+) at 12 months of age. This suggests that the responsiveness of the photoreceptors to exogenous melatonin is reduced during aging.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0037799PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358282PMC
December 2012

GPR179 is required for depolarizing bipolar cell function and is mutated in autosomal-recessive complete congenital stationary night blindness.

Am J Hum Genet 2012 Feb;90(2):331-9

Cole Eye Institute, Cleveland Clinic, OH 44195, USA.

Complete congenital stationary night blindness (cCSNB) is a clinically and genetically heterogeneous group of retinal disorders characterized by nonprogressive impairment of night vision, absence of the electroretinogram (ERG) b-wave, and variable degrees of involvement of other visual functions. We report here that mutations in GPR179, encoding an orphan G protein receptor, underlie a form of autosomal-recessive cCSNB. The Gpr179(nob5/nob5) mouse model was initially discovered by the absence of the ERG b-wave, a component that reflects depolarizing bipolar cell (DBC) function. We performed genetic mapping, followed by next-generation sequencing of the critical region and detected a large transposon-like DNA insertion in Gpr179. The involvement of GPR179 in DBC function was confirmed in zebrafish and humans. Functional knockdown of gpr179 in zebrafish led to a marked reduction in the amplitude of the ERG b-wave. Candidate gene analysis of GPR179 in DNA extracted from patients with cCSNB identified GPR179-inactivating mutations in two patients. We developed an antibody against mouse GPR179, which robustly labeled DBC dendritic terminals in wild-type mice. This labeling colocalized with the expression of GRM6 and was absent in Gpr179(nob5/nob5) mutant mice. Our results demonstrate that GPR179 plays a critical role in DBC signal transduction and expands our understanding of the mechanisms that mediate normal rod vision.
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http://dx.doi.org/10.1016/j.ajhg.2011.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276656PMC
February 2012

Relation between (99m)Tc-tetrofosmin thyroid scintigraphy and mitogen-activated protein kinase in papillary thyroid cancer patients.

Jpn J Radiol 2011 Oct 17;29(8):533-9. Epub 2011 Sep 17.

Division of Nuclear Medicine, PET Center, Department of Radiology, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.

Purpose: The aim of this study was to investigate the relation between (99m)Tc-tetrofosmin uptake and extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) expression in papillary thyroid cancer patients.

Materials And Methods: Our study population consisted of 14 patients. The histopathological findings for all patients were confirmed by surgery. Patients were administ 740 MBq of (99m)Tc-tetrofosmin. The tumor/background (T/B) ratios in regions of interest (ROIs) were measured at 10 min, 1 h, and 3 h to determine the uptake by papillary cancer. Immunohistopathological staining was performed, and the expression of phospho-ERK MAPK in papillary cancer was investigated. The relation between the expression of phospho-ERK MAPK and the T/B ratio was examined using the Mann-Whitney U-test.

Results: (99m)Tc-tetrofosmin uptake was positive in all patients. There was a statistically significant relation between the T/B ratio (at 3 h) and the expression of phospho-ERK MAPK but not with the T/B ratio at 10 min or 1 h: T/B ratio at 10 min (P = 0.32), at 1 h (P = 0.62), and at 3 h (P = 0.0072).

Conclusion: Our results suggest that the relation between (99m)Tc-tetrofosmin uptake (3 h T/B ratio) may lead us to assume cell proliferation of papillary cancer.
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http://dx.doi.org/10.1007/s11604-011-0592-8DOI Listing
October 2011

Localization of melatonin receptor 1 in mouse retina and its role in the circadian regulation of the electroretinogram and dopamine levels.

PLoS One 2011 7;6(9):e24483. Epub 2011 Sep 7.

Circadian Rhythms and Sleep Disorders Program, Neuroscience Institute and Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.

Melatonin modulates many important functions within the eye by interacting with a family of G-protein-coupled receptors that are negatively coupled with adenylate cyclase. In the mouse, Melatonin Receptors type 1 (MT(1)) mRNAs have been localized to photoreceptors, inner retinal neurons, and ganglion cells, thus suggesting that MT(1) receptors may play an important role in retinal physiology. Indeed, we have recently reported that absence of the MT(1) receptors has a dramatic effect on the regulation of the daily rhythm in visual processing, and on retinal cell viability during aging. We have also shown that removal of MT(1) receptors leads to a small (3-4 mmHg) increase in the level of the intraocular pressure during the night and to a significant loss (25-30%) in the number of cells within the retinal ganglion cell layer during aging. In the present study we investigated the cellular distribution in the C3H/f(+/+) mouse retina of MT(1) receptors using a newly developed MT(1) receptor antibody, and then we determined the role that MT(1) signaling plays in the circadian regulation of the mouse electroretinogram, and in the retinal dopaminergic system. Our data indicate that MT(1) receptor immunoreactivity is present in many retinal cell types, and in particular, on rod and cone photoreceptors and on intrinsically photosensitive ganglion cells (ipRGCs). MT(1) signaling is necessary for the circadian rhythm in the photopic ERG, but not for the circadian rhythm in the retinal dopaminergic system. Finally our data suggest that the circadian regulation of dopamine turnover does not drive the photopic ERG rhythm.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024483PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168505PMC
February 2012

N-acetylserotonin promotes hippocampal neuroprogenitor cell proliferation in sleep-deprived mice.

Proc Natl Acad Sci U S A 2011 May 9;108(21):8844-9. Epub 2011 May 9.

Department of Pathology and Laboratory Medicine and Ophthalmology and Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.

N-acetylserotonin (NAS), the immediate precursor of melatonin, the pineal gland indole, is regulated in a circadian rhythm. NAS swiftly activates TrkB in a circadian manner and exhibits antidepressant effect in a TrkB-dependent manner. Here we show that NAS regulates an early event of neurogenesis by increasing neuronal progenitor cell (NPC) proliferation. Subchronic and chronic NAS administration induces NPC proliferation in adult mice. Chronic NAS treatment triggers TrkB receptor activation and its downstream signaling in NPCs. Blockade of TrkB abolishes NAS-elicited neurogenesis in TrkBF616A knockin mice, suggesting that TrkB activation is essential for the effect of NAS-induced NPC proliferation. Moreover, NAS induces NPC proliferation in both active and sleeping phases of the mice. Strikingly, NAS significantly enhances NPC proliferation in sleep-deprived mice. Thus, our finding demonstrates a unique function of NAS in promoting robust NPC proliferation, which may contribute to hippocampal plasticity during sleeping period.
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http://dx.doi.org/10.1073/pnas.1105114108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102377PMC
May 2011