RESUMEN
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.
Asunto(s)
Luz , Proteínas de la Membrana/metabolismo , Opsinas/metabolismo , Retina/citología , Retina/metabolismo , Animales , Relojes Circadianos/fisiología , Ritmo Circadiano/fisiología , Femenino , Masculino , Mamíferos , Proteínas de la Membrana/genética , Ratones , Opsinas/genética , Células Fotorreceptoras Retinianas Conos/citología , Células Fotorreceptoras Retinianas Conos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TemperaturaRESUMEN
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.
Asunto(s)
Encéfalo/fisiología , Relojes Circadianos/genética , Ritmo Circadiano/genética , Papio anubis/genética , Papio anubis/fisiología , Transcriptoma , Animales , Encéfalo/metabolismo , Genómica , MasculinoRESUMEN
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, 1.17×10(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.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Retinopatía Diabética/metabolismo , Dopamina/genética , Regulación de la Expresión Génica/fisiología , Proteínas Circadianas Period/genética , Activación Transcripcional/efectos de la radiación , Animales , Cromatografía Líquida de Alta Presión , Relojes Circadianos/genética , Inmunohistoquímica , Luz , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Proto-Oncogénicas c-fos/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Retina/metabolismo , Retina/efectos de la radiación , Núcleo Supraquiasmático/metabolismoRESUMEN
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.
Asunto(s)
Envejecimiento/fisiología , Cristalino/fisiología , Fotometría/métodos , Percepción Visual , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Reproducibilidad de los Resultados , Percepción Visual/fisiología , Adulto JovenRESUMEN
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 20weeks 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 1h light/1h 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.
Asunto(s)
Trastornos Cronobiológicos/etiología , Proteínas de Unión al ADN/genética , Dopamina/metabolismo , Mesencéfalo/metabolismo , Proteínas Mitocondriales/genética , Enfermedad de Parkinson , Factores de Transcripción/genética , Actividades Cotidianas , Factores de Edad , Animales , Distribución de Chi-Cuadrado , Trastornos Cronobiológicos/genética , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Mesencéfalo/patología , Ratones , Ratones Transgénicos , Proteínas Mitocondriales/metabolismo , Actividad Motora/genética , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Factores de Transcripción/metabolismoRESUMEN
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.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Intoxicación por MPTP/metabolismo , Animales , Radioisótopos de Carbono/farmacocinética , Cognición/efectos de los fármacos , Cognición/fisiología , Cuerpo Estriado/diagnóstico por imagen , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Femenino , Estudios Longitudinales , Intoxicación por MPTP/diagnóstico por imagen , Macaca fascicularis , Nortropanos/farmacocinética , Tomografía de Emisión de PositronesRESUMEN
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.
Asunto(s)
Diabetes Mellitus Experimental/genética , Retinopatía Diabética/genética , Proteínas Circadianas Period/genética , Activación Transcripcional/efectos de la radiación , Animales , Relojes Circadianos , Diabetes Mellitus Experimental/metabolismo , Retinopatía Diabética/metabolismo , Expresión Génica , Luz , Masculino , Ratones Endogámicos C57BL , Actividad Motora/efectos de la radiación , Opsinas/genética , Opsinas/metabolismo , Proteínas Circadianas Period/metabolismo , Fotoperiodo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Retina/metabolismo , Retina/efectos de la radiación , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/efectos de la radiaciónRESUMEN
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.
Asunto(s)
Encéfalo/fisiología , Función Ejecutiva/fisiología , Función Ejecutiva/efectos de la radiación , Luz , Memoria/fisiología , Memoria/efectos de la radiación , Adulto , Encéfalo/efectos de la radiación , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
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.
Asunto(s)
Envejecimiento , Luz , Sueño , Adulto , Relojes Circadianos , Ritmo Circadiano , Femenino , Humanos , Cristalino/fisiología , Masculino , Melatonina/sangre , Persona de Mediana Edad , Adulto JovenRESUMEN
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 lightâ¶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.
Asunto(s)
Ritmo Circadiano , Dopamina/deficiencia , Trastornos Parkinsonianos/fisiopatología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Femenino , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Macaca fascicularis , Macaca mulatta , Masculino , Actividad Motora , Neuropéptidos/metabolismo , Orexinas , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/metabolismo , Fotoperiodo , Retina/metabolismo , Retina/patología , Opsinas de Bastones/metabolismo , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/patologíaRESUMEN
Light is a potent stimulus for regulating circadian, hormonal, and behavioral systems. In addition, light therapy is effective for certain affective disorders, sleep problems, and circadian rhythm disruption. These biological and behavioral effects of light are influenced by a distinct photoreceptor in the eye, melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to conventional rods and cones. We summarize the neurophysiology of this newly described sensory pathway and consider implications for the measurement, production, and application of light. A new light-measurement strategy taking account of the complex photoreceptive inputs to these non-visual responses is proposed for use by researchers, and simple suggestions for artificial/architectural lighting are provided for regulatory authorities, lighting manufacturers, designers, and engineers.
Asunto(s)
Fototerapia/tendencias , Opsinas de Bastones/fisiología , Animales , Ritmo Circadiano/fisiología , Humanos , Células Fotorreceptoras/metabolismo , Células Ganglionares de la Retina/metabolismoRESUMEN
In addition to the hallmark motor disorders in Parkinson's disease (PD) patients, nonmotor symptoms have attracted increasing attention. Among the nonmotor symptoms, sleep disturbances and cognitive deficits are frequently reported and contribute to a decrease in the quality of life. The pathophysiology of cognitive and sleep-wake abnormalities in PD is poorly understood partially due to the lack of appropriate animal models that fully replicate the entire pathological and behavioral spectrum of the disease. In this study, we undertook a long-term evaluation of circadian, locomotor and cognitive abilities in both acute and chronic MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mouse models. Activity rhythms and locomotor activity were assayed under light-dark cycles, constant darkness, or constant light, re-entrainment to shifts of the light-dark cycle, and a behavioral masking paradigm. Cognitive abilities were assessed using a radial water maze task. Although both acute and chronic treatment regimes induced 70% degeneration of dopaminergic neurons in the substantia nigra, neither circadian nor cognitive alterations were observed even after nearly 1 yr. During aging, there was a significant decrease of locomotor activity and of several circadian parameters without any exacerbation in MPTP-treated animals. These results emphasize the limitations of the MPTP-treated mouse as an animal model of nonmotor symptoms of PD in addition to the already well-documented inadequacy to replicate cardinal motor features of the disease.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/administración & dosificación , Ritmo Circadiano/efectos de los fármacos , Cognición/efectos de los fármacos , Locomoción/efectos de los fármacos , Enfermedad de Parkinson/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Trastornos del Conocimiento , Modelos Animales de Enfermedad , Dopaminérgicos/administración & dosificación , Aprendizaje/efectos de los fármacos , Masculino , Aprendizaje por Laberinto , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The retinal circadian clock is crucial for optimal regulation of retinal physiology and function, yet its cellular location in mammals is still controversial. We used laser microdissection to investigate the circadian profiles and phase relations of clock gene expression and Period gene induction by light in the isolated outer (rods/cones) and inner (inner nuclear and ganglion cell layers) regions in wild-type and melanopsin-knockout (Opn 4 (-/-) ) mouse retinas. In the wild-type mouse, all clock genes are rhythmically expressed in the photoreceptor layer but not in the inner retina. For clock genes that are rhythmic in both retinal compartments, the circadian profiles are out of phase. These results are consistent with the view that photoreceptors are a potential site of circadian rhythm generation. In mice lacking melanopsin, we found an unexpected loss of clock gene rhythms and of the photic induction of Per1-Per2 mRNAs only in the outer retina. Since melanopsin ganglion cells are known to provide a feed-back signalling pathway for photic information to dopaminergic cells, we further examined dopamine (DA) synthesis in Opn 4 (-/-) mice. The lack of melanopsin prevented the light-dependent increase of tyrosine hydroxylase (TH) mRNA and of DA and, in constant darkness, led to comparatively high levels of both components. These results suggest that melanopsin is required for molecular clock function and DA regulation in the retina, and that Period gene induction by light is mediated by a melanopsin-dependent, DA-driven signal acting on retinal photoreceptors.
Asunto(s)
Relojes Circadianos , Dopamina/metabolismo , Regulación de la Expresión Génica , Luz , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/metabolismo , Opsinas de Bastones/fisiología , Animales , Ritmo Circadiano , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Circadianas Period/genética , Opsinas de Bastones/genética , Transducción de Señal , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Many physiological and pathological conditions are associated with a change in the crystalline lens transmittance. Estimates of lens opacification, however, generally rely on subjective rather than objective measures in clinical practice. The goal of our study was to develop an improved psychophysical heterochromatic flicker photometry technique combined with existing mathematical models to evaluate the spectral transmittance of the human ocular media noninvasively. Our results show that it is possible to accurately estimate ocular media density in vivo in humans. Potential applications of our approach include basic research and clinical settings on visual and nonimage-forming visual systems.
Asunto(s)
Cristalino/fisiología , Fotometría/métodos , Adulto , Anciano , Envejecimiento/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fotometría/instrumentación , Percepción Visual/fisiologíaRESUMEN
Light emitting diodes (LEDs) are being used increasingly as light sources in life sciences applications such as in vision research, fluorescence microscopy and in brain-computer interfacing. Here we present an inexpensive but effective visual stimulator based on light emitting diodes (LEDs) and open-source Arduino microcontroller prototyping platform. The main design goal of our system was to use off-the-shelf and open-source components as much as possible, and to reduce design complexity allowing use of the system to end-users without advanced electronics skills. The main core of the system is a USB-connected Arduino microcontroller platform designed initially with a specific emphasis on the ease-of-use creating interactive physical computing environments. The pulse-width modulation (PWM) signal of Arduino was used to drive LEDs allowing linear light intensity control. The visual stimulator was demonstrated in applications such as murine pupillometry, rodent models for cognitive research, and heterochromatic flicker photometry in human psychophysics. These examples illustrate some of the possible applications that can be easily implemented and that are advantageous for students, educational purposes and universities with limited resources. The LED stimulator system was developed as an open-source project. Software interface was developed using Python with simplified examples provided for Matlab and LabVIEW. Source code and hardware information are distributed under the GNU General Public Licence (GPL, version 3).
Asunto(s)
Computadores , Estimulación Luminosa/instrumentación , Programas Informáticos , LuzRESUMEN
Many nonvisual functions are regulated by light through a photoreceptive system involving melanopsin-expressing retinal ganglion cells that are maximally sensitive to blue light. Several studies have suggested that the ability of light to modulate circadian entrainment and to induce acute effects on melatonin secretion, subjective alertness, and gene expression decreases during aging, particularly for blue light. This could contribute to the documented changes in sleep and circadian regulatory processes with aging. However, age-related modification in the impact of light on steady-state pupil constriction, which regulates the amount of light reaching the retina, is not demonstrated. We measured pupil size in 16 young (22.8±4 years) and 14 older (61±4.4 years) healthy subjects during 45-second exposures to blue (480 nm) and green (550 nm) monochromatic lights at low (7×10(12) photons/cm2/s), medium (3×10(13) photons/cm2/s), and high (10(14) photons/cm2/s) irradiance levels. Results showed that young subjects had consistently larger pupils than older subjects for dark adaptation and during all light exposures. Steady-state pupil constriction was greater under blue than green light exposure in both age groups and increased with increasing irradiance. Surprisingly, when expressed in relation to baseline pupil size, no significant age-related differences were observed in pupil constriction. The observed reduction in pupil size in older individuals, both in darkness and during light exposure, may reduce retinal illumination and consequently affect nonvisual responses to light. The absence of a significant difference between age groups for relative steady-state pupil constriction suggests that other factors such as tonic, sympathetic control of pupil dilation, rather than light sensitivity per se, account for the observed age difference in pupil size regulation. Compared to other nonvisual functions, the light sensitivity of steady-state pupil constriction appears to remain relatively intact and is not profoundly altered by age.
Asunto(s)
Luz , Pupila/fisiología , Adulto , Factores de Edad , Anciano , Envejecimiento , Ritmo Circadiano/fisiología , Femenino , Humanos , Masculino , Melatonina/metabolismo , Persona de Mediana Edad , Estimulación Luminosa , Opsinas de Bastones/metabolismo , Visión OcularRESUMEN
BACKGROUND: It is increasingly recognized that non-motor symptoms are a prominent feature of Parkinson's disease and in the case of cognitive deficits can precede onset of the characteristic motor symptoms. Here, we examine in 4 monkeys chronically treated with low doses of the neurotoxin MPTP the early and long-term alterations of rest-activity rhythms in relationship to the appearance of motor and cognitive symptoms. METHODOLOGY/PRINCIPAL FINDINGS: Behavioral activity recordings as well as motor and cognitive assessments were carried out continuously and in parallel before, during and for several months following MPTP-treatment (12-56 weeks). Cognitive abilities were assessed using a task that is dependent on the functional integrity of the fronto-striatal axis. Rest-activity cycles were monitored continuously using infrared movement detectors of locomotor activity. Motor impairment was evaluated using standardized scales for primates. Results show that MPTP treatment led to an immediate alteration (within one week) of rest-activity cycles and cognitive deficits. Parkinsonian motor deficits only became apparent 3 to 5 weeks after initiating chronic MPTP administration. In three of the four animals studied, clinical scores returned to control levels 5-7 weeks following cessation of MPTP treatment. In contrast, both cognitive deficits and chronobiological alterations persisted for many months. Levodopa treatment led to an improvement of cognitive performance but did not affect rest-activity rhythms in the two cases tested. CONCLUSIONS/SIGNIFICANCE: Present results show that i) changes in the rest activity cycles constituted early detectable consequences of MPTP treatment and, along with cognitive alterations, characterize the presymptomatic stage; ii) following motor recovery there is a long-term persistence of non-motor symptoms that could reflect differential underlying compensatory mechanisms in these domains; iii) the progressive MPTP-monkey model of presymptomatic ongoing parkinsonism offers possibilities for in-depth studies of early non-motor symptoms including sleep alterations and cognitive deficits.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Modelos Animales de Enfermedad , Enfermedad de Parkinson , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/administración & dosificación , Ciclos de Actividad , Animales , Conducta Animal , Cognición , Haplorrinos , Destreza Motora , Neurotoxinas/administración & dosificación , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/fisiopatologíaRESUMEN
This study investigates the possibility of an endogenous circadian rhythm in retinal cone function in humans. A full-field cone electroretinogram (ERG) was performed every 2 h for 24 h under continuous rod-saturating ambient white light (53 ± 30 lux; pupils dilated) in nine healthy subjects. Distinct circadian variations were superimposed upon a gradual decrease in cone responsiveness to light, demonstrated most reliably in the implicit times of b-wave and oscillatory potentials, and to a lesser extent in amplitude and a-wave implicit times. After mathematical correction of the linear trend, the cone response was found to be greatest around 20:00 h and least around 06:00 h. The phase of the ERG circadian rhythm was not synchronized with the phase of the salivary melatonin rhythm measured the previous evening. Melatonin levels measured under constant light on the day of ERG assessments were suppressed by 53% on average compared to melatonin profiles obtained previously under near-total darkness in seven participants. The progressive decline in cone responsiveness to light over the 24 h may reflect an adaptation of the cone-driven retinal system to constant light, although the mechanism is unclear. The endogenous rhythm of cone responsiveness to light may be used as an additional index of central or retinal circadian clock time.
Asunto(s)
Ritmo Circadiano/fisiología , Melatonina/metabolismo , Fotoperiodo , Células Fotorreceptoras Retinianas Conos/fisiología , Adulto , Electrorretinografía , Femenino , Regulación de la Expresión Génica/fisiología , Humanos , Masculino , Melatonina/genética , Adulto JovenRESUMEN
African mole-rats (family Bathyergidae) are strictly subterranean rodent species that are rarely exposed to environmental light. Morphological and physiological adaptations to the underground environment include a severely reduced eye size and regressed visual system. Responses of the circadian system to light, however, appear to be intact, since mole-rats are able to entrain their circadian activity rhythms to the light-dark cycle and light induces Fos expression in the suprachiasmatic nucleus (SCN). Social organization varies from solitary species to highly elaborated eusocial structures, characterized by a distinct division of labor and in which one reproductive female regulates the behavior and reproductive physiology of other individuals in the colony. The authors studied light-induced Fos expression in the SCN to increasing light intensities in four mole-rat species, ranging from strictly solitary to highly social. In the solitary Cape mole-rat, light induces significant Fos expression in the SCN, and the number of Fos-immunopositive cells increases with increasing light intensity. In contrast, Fos induction in the SCN of social species was slightly greater than, but not statistically different from, the dark-control animals as is typical of most rodents. One species showed a trend for an increase in expression with increased light, whereas a second species showed no trend in expression. In the naked mole-rat, Fos expression appeared higher in the dark-controls than in the animals exposed to light, although the differences in Fos expression were not significant. These results suggest a gradient in the sensitivity of the circadian system to light in mole-rats, with a higher percentage of individuals that are unresponsive to light in correlation with the degree of sociality. In highly social species, such as the naked mole-rat that live in a relatively stable subterranean milieu in terms of food availability, temperature, constant darkness, and devoid of 24-h cyclic environmental cues, the temporal coordination of rest-wake activities may be dependent on social interactions and social status rather than on photic regulation of the circadian timing system.
Asunto(s)
Luz , Ratas Topo/metabolismo , Estimulación Luminosa , Proteínas Proto-Oncogénicas c-fos/metabolismo , Núcleo Supraquiasmático/metabolismo , Animales , Relojes Circadianos , Ritmo Circadiano/fisiología , Oscuridad , Femenino , Fotoperiodo , Ratas , Núcleo Supraquiasmático/citologíaRESUMEN
The phase and period responses to short light pulses were studied in the jerboa, a seasonal, hibernating, nocturnal rodent from the Atlas region in Morocco. The jerboa, which is a saltatory species, showed precise activity onsets and offsets under a light-dark (LD) cycle using infrared captors to record locomotor activity. When released into constant darkness (DD), the majority of animals showed a circadian period (tau) < 24 h (mean tau = 23.89 +/- 0.13 h) and a lengthening of the activity span, alpha. Animals were subsequently exposed to up to eight 15-min light pulses, each separated by at least 2 wks, for up to 160 days in DD. During this span, most individuals maintained robust circadian rhythmicity, with clearly defined activity onsets and offsets, similar levels of total activity, duration of alpha, and percent activity occurring during the subjective night. The phase response curve (PRC) is typical of other nocturnal rodents, with light eliciting delays during late subjective day and early subjective night (CT8-CT19) and advances during late subjective night to early subjective day (CT19-CT2). A dead zone, when light had no effect on phase, is observed during mid-subjective day (CT3-CT8). A few individuals showed large (> 9 h) Type 0 phase resetting near the singularity region (CT19) that resulted in a complete phase reversal, but otherwise displayed normal phase-shifting responses at other CT times. The tau response curve showed a decrease in period from early to late subjective night with increases at other times, but these changes were small (maximum < 9 min) and highly variable. There was a distinct tendency for animals that had an initial short tau in DD to conserve a short tau during the series of light pulses and, inversely, for animals with long tau to conserve a long tau. This suggests possible constraints on the plasticity of variation of tau in relation to the endogenous period of the animal.