Parkinson's disease (PD) evolves over an extended and variable period in humans; years prior to the onset of classical motor symptoms, sleep and biological rhythm disorders develop, significantly impacting the quality-of-life of patients. Circadian-rhythm disorders are accompanied by mild cognitive deficits that progressively worsen with disease progression and can constitute a severe burden for patients at later stages. The gold-standard 6-methyl-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) macaque model of PD recapitulates the progression of motor and nonmotor symptoms over contracted periods of time. Here, this multidisciplinary/multiparametric study follows, in five animals, the steady progression of motor and nonmotor symptoms and describes their reversal following grafts of neural precursors in diverse functional domains of the basal ganglia. Results show unprecedented recovery from cognitive symptoms in addition to a strong clinical motor recuperation. Both motor and cognitive recovery and partial circadian rhythm recovery correlate with the degree of graft integration, and in a subset of animals, with in vivo levels of striatal dopaminergic innervation and function. The present study provides empirical evidence that integration of neural precursors following transplantation efficiently restores function at multiple levels in parkinsonian nonhuman primates and, given interindividuality of disease progression and recovery, underlines the importance of longitudinal multidisciplinary assessments in view of clinical translation.

Cognitive deficits as well as disorders of sleep and biological rhythms constitute non-motor symptoms that significantly impact quality of life in Parkinson’s disease patients. Few studies have evaluated the impact of cell replacement therapy on such non-motor symptoms. Here we used a multidisciplinary approach to assess the therapeutic potential of bilateral grafts of neural stem cells in a macaque model of Parkinson’s disease on both motor and non-motor markers of functional recovery. Grafts led to varying degrees of functional recovery while sham experiments did not. We show unprecedented recovery from cognitive symptoms in addition to a clear clinical motor recuperation. Motor and cognitive recovery but not circadian rhythm recovery correlated with the degree of graft integration into the host environment and with in-vivo levels of striatal dopaminergic transporters and function. This study provides empirical evidence that neural stem cells transplantation efficiently restore function at multiple levels in Parkinsonian non-human primates. We demonstrate the promising potential of multiple-sites neural stem cells grafts for Parkinson’s disease but furthermore underline the crucial importance of such multidisciplinary approaches for an effective clinical translation.

Successful antidepressant (AD) treatments are still difficult to achieve. Recently, bright light stimulation (BLS) was shown effective in non-seasonal depression but its mode of action remains elusive. We demonstrate here, using a new mouse model of depression resistant to ADs including ketamine, that chemogenetic activation of lateral habenula (LHb) astroglia prevented the potentiating effect of BLS on the AD response. Additionally, the beneficial action of BLS was associated with upregulation of a specific part of the prefrontal cortex opioid system. These results show that improved behavioral outcome produced by BLS requires habenular astroglia and endogenous opioids as crucial buffer systems.

While rods, cones, and intrinsically photosensitive melanopsin-containing ganglion cells (ipRGCs) all drive light entrainment of the master circadian pacemaker of the suprachiasmatic nucleus, recent studies have proposed that entrainment of the mouse retinal clock is exclusively mediated by a UV-sensitive photopigment, neuropsin (OPN5). Here, we report that the retinal circadian clock can be phase shifted by short duration and relatively low-irradiance monochromatic light in the visible part of the spectrum, up to 520 nm. Phase shifts exhibit a classical photon dose-response curve. Comparing the response of mouse models that specifically lack middle-wavelength (MW) cones, melanopsin, and/or rods, we found that only the absence of rods prevented light-induced phase shifts of the retinal clock, whereas light-induced phase shifts of locomotor activity are normal. In a "rod-only" mouse model, phase shifting response of the retinal clock to light is conserved. At shorter UV wavelengths, our results also reveal additional recruitment of short-wavelength (SW) cones and/or OPN5. These findings suggest a primary role of rod photoreceptors in the light response of the retinal clock in mammals.

Diurnal gene expression patterns underlie time-of-the-day-specific functional specialization of tissues. However, available circadian gene expression atlases of a few organs are largely from nocturnal vertebrates. We report the diurnal transcriptome of 64 tissues, including 22 brain regions, sampled every 2 hours over 24 hours, from the primate Papio anubis (baboon). Genomic transcription was highly rhythmic, with up to 81.7% of protein-coding genes showing daily rhythms in expression. In addition to tissue-specific gene expression, the rhythmic transcriptome imparts another layer of functional specialization. Most ubiquitously expressed genes that participate in essential cellular functions exhibit rhythmic expression in a tissue-specific manner. The peak phases of rhythmic gene expression clustered around dawn and dusk, with a "quiescent period" during early night. Our findings also unveil a different temporal organization of central and peripheral tissues between diurnal and nocturnal animals.

Current antidepressant pharmacotherapy remains unsatisfactory because of its limited adherence and partial therapeutic efficacy. Accordingly, there is a crucial need of validated animal models that fully reflect the nature of the disease and do not only separate facets of the disorder. We read with great interest the recent publication of Mul et al. (2016) reporting that, although the 5 d forced swimming stress model (5D-FSSM) of depression effectively increased floating behavior for 4 weeks, other depressive-like indexes, such as the sucrose preference test, were unaltered. Hence, they conclude that the 5D-FSSM model lacks “construct or face validity to model human depression.” As these data clearly contrast with those from previous published studies (Sun et al., 2011; Serchov et al., 2015), an obvious question is …

Les cellules ganglionnaires à mélanopsine (ipRGC), avec les cônes et bâtonnets, forment un réseau rétinien de photoréception sous-tendant l’effet non visuel (NV) de la lumière. L’objectif de notre travail est de déterminer la contribution individuelle de ces substrats neuronaux dans les réponses du cerveau NV. Notre stratégie expérimentale repose sur les propriétés spectrales, spatiales différentes des cônes et ipRGCs. Vingt-huit sujets (within-subject design) ont été exposés consécutivement à 4 stimuli lumineux de 50 min chacun, de 19–23 h. Le stimulus fut composé d’une lumière blanche centrale (20°, 7000 lux, LBC) focalisée sur la fovéa (cônes), et d’une lumière en périphérie (20–220°, 300 lux) enrichie en bleu (BE) afin d’activer les ipRGCs, ou rouge (RE) afin de limiter cette activation. L’EEG, le reflexe pupillaire (PLR), les performances cognitives et visuelles ont été mesurées pendant l’exposition. Nos résultats préliminaires ne montrent pas de différence entre RE vs BE dans la dynamique de l’activité bêta (13,5–32 Hz) et ondes lentes (1–7 Hz). Les performances cognitives sont similaires. L’allumage différée de la LBC provoque une constriction supplémentaire de la pupille (+10 %, p < 0,05) dans les 2 conditions. La vision n’a pas été affectée. Nos résultats suggèrent que la dynamique/sensibilité à la lumière varie pour chaque réponse NV. Le PLR reçoit un message photoreceptif impliquant les ipRGC et cônes. De manière surprenante, un stimulus lumineux présenté dans le champ visuel périphérique, et de faible intensité (300 lux), peut recruter les ipRGC et activer les fonctions NV.

Purpose: Diabetic retinopathy is one of the most common consequences of diabetes that affects millions of working-age adults worldwide and leads to progressive degeneration of the retina, visual loss, and blindness. Diabetes is associated with circadian disruption of the central and peripheral circadian clocks, but the mechanisms responsible for such alterations are unknown. Using a streptozotocin (STZ)-induced model of diabetes, we investigated whether diabetes alters 1) the circadian regulation of clock genes in the retina and in the central clocks, 2) the light response of clock genes in the retina, and/or 3) light-driven retinal dopamine (DA), a major output marker of the retinal clock.Methods: To quantify circadian expression of clock and clock-controlled genes, retinas and suprachiasmatic nucleus (SCN) from the same animals were collected every 4 h in circadian conditions, 12 weeks post-diabetes. Induction of Per1, Per2, and c-fos mRNAs was quantified in the retina after the administration of a pulse of monochromatic light (480 nm, 1.17x10(14) photons/cm(2)/s, 15 min) at circadian time 16. Gene expression was assessed with real-time reverse transcription PCR (RT-PCR). Pooled retinas from the control and STZ-diabetic mice were collected 2 h after light ON and light OFF (Zeitgeber time (ZT)2 and ZT14), and DA and its metabolite were analyzed with high-performance liquid chromatography (HPLC).Results: We found variable effects of diabetes on the expression of clock genes in the retina and only slight differences in phase and/or amplitude in the SCN. c-fos and Per1 induction by a 480 nm light pulse was abolished in diabetic animals at 12 weeks post-induction of diabetes in comparison with the control mice, suggesting a deficit in light-induced neuronal activation of the retinal clock. Finally, we quantified a 56% reduction in the total number of tyrosine hydroxylase (TH) immunopositive cells, associated with a decrease in DA levels during the subjective day (ZT2).Conclusions: These findings demonstrate that diabetes affects the molecular machinery and the light response of the retinal clock and alters the light-driven retinal DA level.

PURPOSE:Although several methods have been proposed to evaluate lens transmittance, to date there is no consensual in vivo approach in clinical practice. The aim of this study was to compare ocular lens density and transmittance measurements obtained by an improved psychophysical scotopic heterochromatic flicker photometry (sHFP) technique to the results obtained by three other measures: a psychophysical threshold technique, a Scheimpflug imaging technique, and a clinical assessment using a validated subjective scale.METHODS:Forty-three subjects (18 young, 9 middle aged, and 16 older) were included in the study. Individual lens densities were measured and transmittance curves were derived from sHFP indexes. Ocular lens densities were compared across methods by using linear regression analysis.RESULTS:The four approaches showed a quadratic increase in lens opacification with age. The sHFP technique revealed that transmittance decreased with age over the entire visual spectrum. This decrease was particularly pronounced between young and older participants in the short (53.03% decrease in the 400-500 nm range) wavelength regions of the light spectrum. Lens density derived from sHFP highly correlated with the values obtained with the other approaches. Compared to other objective measures, sHFP also showed the lowest variability and the best fit with a quadratic trend (r2 = 0.71) of lens density increase as a function of age.CONCLUSIONS:The sHFP technique offers a practical, reliable, and accurate method to measure lens density in vivo and predict lens transmittance over the visible spectrum. An accurate quantification of lens transmittance should be obtained in clinical practice, but also in research in visual and nonvisual photoreception.

Disturbances of the daily sleep/wake cycle are common non-motor symptoms of Parkinson's disease (PD). However, the impact of dopamine (DA) depletion on circadian rhythms in PD patients or non-human primate (NHP) models of the disorder have not been investigated. We evaluated alterations of circadian rhythms in NHP following MPTP lesion of the dopaminergic nigro-striatal system. DA degeneration was assessed by in vivo PET ([(11)C]-PE2I) and post-mortem TH and DAT quantification. In a light∶dark cycle, control and MPTP-treated NHP both exhibit rest-wake locomotor rhythms, although DA-depleted NHP show reduced amplitude, decreased stability and increased fragmentation. In all animals, 6-sulphatoxymelatonin peaks at night and cortisol in early morning. When the circadian system is challenged by exposure to constant light, controls retain locomotor rest-wake and hormonal rhythms that free-run with stable phase relationships whereas in the DA-depleted NHP, locomotor rhythms are severely disturbed or completely abolished. The amplitude and phase relations of hormonal rhythms nevertheless remain unaltered. Use of a light-dark masking paradigm shows that expression of daily rest-wake activity in MPTP monkeys requires the stimulatory and inhibitory effects of light and darkness. These results suggest that following DA lesion, the central clock in the SCN remains intact but, in the absence of environmental timing cues, is unable to drive downstream rhythmic processes of striatal clock gene and dopaminergic functions that control locomotor output. These findings suggest that the circadian component of the sleep-wake disturbances in PD is more profoundly affected than previously assumed.

Event Abstract Back to Event Prior light history impacts on higher order cognitive brain function Sarah L. Chellappa1, Julien Q. Ly1, Christelle Meyer1, Evelyn Balteau1, Christian Delgueldre1, Andre Luxen1, Christophe Phillips1, Howard Cooper2 and Gilles Vandewalle1* 1 University of Liège, Cyclotron Research Center, Belgium 2 INSERM Stem Cell and Brain Research Institute, Department of Chronobiology, France Light powerfully modulates human alertness and cognition, presumably through intrinsically-photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin. In humans, evidence for melanopsin involvement in light-driven cognitive stimulation remains indirect, due to the difficulty to selectively isolate its contribution. Therefore, a role for melanopsin in human cognitive function remains to be established. Recent data suggest that melanopsin has dual-state properties, such that its light sensitivity is modulated by prior light exposure. Accordingly, prior exposure to 590nm, 515nm and 480nm monochromatic light would lead to higher, medium or lower subsequent melanopsin sensitivity, respectively. Here we tested whether light history modulates the subsequent impact of light on cognitive brain function, and if this modulation is compatible with melanopsin dual-state properties. Sixteen participants underwent 3 identical and consecutive fMRI sessions during which they were exposed to a monochromatic green test-light (515nm), while performing a simple auditory detection task (0-back task) and a more difficult auditory working memory task (3-back task). Seventy minutes before each session, participants were exposed to 10min of orange (589nm), green (515nm) or blue (461nm) monochromatic light. Prior exposure to orange, as compared to blue light, increased executive responses bilaterally in the dorsolateral prefrontal cortex, in the right ventrolateral prefrontal cortex, and in the pulvinar. Furthermore, prior exposure to green, as compared to blue light, increased executive responses in the left ventrolateral prefrontal cortex. Remaining comparisons (orange>green; green>orange; blue>orange; blue>green) had no significant prefrontal responses. This wavelength-dependent impact of prior light exposure is consistent with recent theories of light-driven melanopsin dual states. Our results emphasize the key role of light for cognitive brain responses and are, to date, the strongest evidence in favor of a cognitive role for melanopsin. Ultimately, this photopigment may confer a form of “photic memory” to human cognitive brain function. Acknowledgements FNRS (Belgium), FMRE, University of Liège (ULg), Financial support: FNRS (Belgium), FMRE, University of Liège (ULg), Agence National de Recherche, France. Keywords: Melanopsin, Cognition, Light, fMRI, non-image-forming, Executive Function Conference: Belgian Brain Council 2014 MODULATING THE BRAIN: FACTS, FICTION, FUTURE, Ghent, Belgium, 4 Oct - 4 Oct, 2014. Presentation Type: Poster Presentation Topic: Basic Neuroscience Citation: Chellappa SL, Ly JQ, Meyer C, Balteau E, Delgueldre C, Luxen A, Phillips C, Cooper H and Vandewalle G (2014). Prior light history impacts on higher order cognitive brain function. Conference Abstract: Belgian Brain Council 2014 MODULATING THE BRAIN: FACTS, FICTION, FUTURE. doi: 10.3389/conf.fnhum.2014.214.00039 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Jun 2014; Published Online: 30 Jun 2014. * Correspondence: Dr. Gilles Vandewalle, University of Liège, Cyclotron Research Center, Liège, 4000, Belgium, gilles.vandewalle@uliege.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Sarah L Chellappa Julien Q Ly Christelle Meyer Evelyn Balteau Christian Delgueldre Andre Luxen Christophe Phillips Howard Cooper Gilles Vandewalle Google Sarah L Chellappa Julien Q Ly Christelle Meyer Evelyn Balteau Christian Delgueldre Andre Luxen Christophe Phillips Howard Cooper Gilles Vandewalle Google Scholar Sarah L Chellappa Julien Q Ly Christelle Meyer Evelyn Balteau Christian Delgueldre Andre Luxen Christophe Phillips Howard Cooper Gilles Vandewalle PubMed Sarah L Chellappa Julien Q Ly Christelle Meyer Evelyn Balteau Christian Delgueldre Andre Luxen Christophe Phillips Howard Cooper Gilles Vandewalle Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The delayed appearance of motor symptoms in PD poses a crucial challenge for early detection of the disease. We measured the binding potential of the selective dopamine active transporter (DAT) radiotracer [(11)C]PE2I in MPTP-treated macaque monkeys, thus establishing a detailed profile of the nigrostriatal DA status following MPTP intoxication and its relation to induced motor and non-motor symptoms. Clinical score and cognitive performance were followed throughout the study. We measured longitudinally in vivo the non-displaceable binding potential to DAT in premotor, motor-recovered (i.e. both non-symptomatic) and symptomatic MPTP-treated monkeys. Results show an unexpected and pronounced dissociation between clinical scores and [(11)C]PE2I-BP(ND) during the premotor phase i.e. DAT binding in the striatum of premotor animals was increased around 20%. Importantly, this broad increase of DAT binding in the caudate, ventral striatum and anterior putamen was accompanied by i) deteriorated cognitive performance, showing a likely causal role of the observed hyperdopaminergic state (Cools, 2011; Cools and D'Esposito, 2011) and ii) an asymmetric decrease of DAT binding at a focal point of the posterior putamen, suggesting that increased DAT is one of the earliest, intrinsic compensatory mechanisms. Following spontaneous recovery from motor deficits, DAT binding was greatly reduced as recently shown in-vivo with other radiotracers (Blesa et al., 2010, 2012). Finally, high clinical scores were correlated to considerably low levels of DAT only after the induction of a stable parkinsonian state. We additionally show that the only striatal region which was significantly correlated to the degree of motor impairments is the ventral striatum. Further research on this period should allow better understanding of DA compensation at premature stages of PD and potentially identify new diagnosis and therapeutic index.

Although a wide range of physiological functions regulated by dopamine (DA) display circadian variations, the role of DA in the generation and/or modulation of these rhythms is unknown. In Parkinson's disease (PD) patients, in addition to the classical motor symptoms, disturbances of the pattern of daily rest/wake cycles are common non-motor symptoms. We investigated daily and circadian rhythms of rest/activity behaviors in a transgenic MitoPark mouse model with selective inactivation of mitochondrial transcription factor A (Tfam) resulting in a slow and progressive degeneration of DA neurons in midbrain structures. Correlated with this, MitoPark mice show a gradual reduction in locomotor activity beginning at about 20 weeks of age. In a light–dark cycle, MitoPark mice exhibit a daily pattern of rest/activity rhythms that shows an age-dependent decline in both the amplitude and the stability of the rhythm, coupled with an increased fragmentation of day/night activities. When the circadian system is challenged by exposure to constant darkness or constant light conditions, control littermates retain a robust free-running circadian locomotor rhythm, whereas in MitoPark mice, locomotor rhythms are severely disturbed or completely abolished. Re-exposure to a light/dark cycle completely restores daily locomotor rhythms. MitoPark mice and control littermates express similar masking behaviors under a 1 h light/1 h dark regime, suggesting that the maintenance of a daily pattern of rest/activity in arrhythmic MitoPark mice can be attributed to the acute inhibitory and stimulatory effects of light and darkness. These results imply that, in addition to the classical motor abnormalities observed in PD, the loss of the midbrain DA neurons leads to impairments of the circadian control of rest/activity rhythms.

Light is a powerful stimulant for human alertness and cognition, presumably acting through a photoreception system that heavily relies on the photopigment melanopsin. In humans, evidence for melanopsin involvement in light-driven cognitive stimulation remains indirect, due to the difficulty to selectively isolate its contribution. Therefore, a role for melanopsin in human cognitive regulation remains to be established. Here, sixteen participants underwent consecutive and identical functional MRI recordings, during which they performed a simple auditory detection task and a more difficult auditory working memory task, while continuously exposed to the same test light (515 nm). We show that the impact of test light on executive brain responses depends on the wavelength of the light to which individuals were exposed prior to each recording. Test-light impact on executive responses in widespread prefrontal areas and in the pulvinar increased when the participants had been exposed to longer (589 nm), but not shorter (461 nm), wavelength light, more than 1 h before. This wavelength-dependent impact of prior light exposure is consistent with recent theories of the light-driven melanopsin dual states. Our results emphasize the critical role of light for cognitive brain responses and are, to date, the strongest evidence in favor of a cognitive role for melanopsin, which may confer a form of "photic memory" to human cognitive brain function.

The deterioration of sleep in the older population is a prevalent feature that contributes to a decrease in quality of life. Inappropriate entrainment of the circadian clock by light is considered to contribute to the alteration of sleep structure and circadian rhythms in the elderly. The present study investigates the effects of aging on non-visual spectral sensitivity to light and tests the hypothesis that circadian disturbances are related to a decreased light transmittance. In a within-subject design, eight aged and five young subjects were exposed at night to 60 minute monochromatic light stimulations at 9 different wavelengths (420-620 nm). Individual sensitivity spectra were derived from measures of melatonin suppression. Lens density was assessed using a validated psychophysical technique. Although lens transmittance was decreased for short wavelength light in the older participants, melatonin suppression was not reduced. Peak of non-visual sensitivity was, however, shifted to longer wavelengths in the aged participants (494 nm) compared to young (484 nm). Our results indicate that increased lens filtering does not necessarily lead to a decreased non-visual sensitivity to light. The lack of age-related decrease in non-visual sensitivity to light may involve as yet undefined adaptive mechanisms.

There is increasing evidence that melanopsin-expressing ganglion cells (ipRGCs) are altered in retinal pathologies. Using a streptozotocin-induced (STZ) model of diabetes, we investigated the impact of diabetic retinopathy on non-visual functions by analyzing ipRGCs morphology and light-induced c-Fos and Period 1-2 clock genes in the central clock (SCN). The ability of STZ-diabetic mice to entrain to light was challenged by exposure animals to 1) successive light/dark (LD) cycle of decreasing or increasing light intensities during the light phase and 2) 6-h advance of the LD cycle. Our results show that diabetes induces morphological changes of ipRGCs, including soma swelling and dendritic varicosities, with no reduction in their total number, associated with decreased c-Fos and clock genes induction by light in the SCN at 12 weeks post-onset of diabetes. In addition, STZ-diabetic mice exhibited a reduction of overall locomotor activity, a decrease of circadian sensitivity to light at low intensities, and a delay in the time to re-entrain after a phase advance of the LD cycle. These novel findings demonstrate that diabetes alters clock genes and behavioral responses of the circadian timing system to light and suggest that diabetic patients may show an increased propensity for circadian disturbances, in particular when they are exposed to chronobiological challenges.