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![The ipRGC is a hybrid of known melanopsin-expressing ganglion cell types, some of which stratify exclusively in the uppermost OFF sublayer (site 3), others in the ON sublayer (e.g., site 2), and still others in both (see text). Jagged lines represent gap junctional contacts between AII amacrine cells and ON cone bipolar terminals (site 1) and between rods and cones (site 4). The primary rod pathway is shown in red, the secondary rod pathway in green, and a novel pathway from rods to ON cone bipolar cells in blue [35]. All of these pathways have been considered to relay to ganglion cells in the ON sublayer (site2), but they may also pass through ectopic ON cone bipolar terminals in the OFF sublayer to the dendrites of some ipRGCs (site 3; see text). A pathway directly linking rod bipolar cells to ipRGCs, proposed by Ostergaard et al. (2007) [17], is shown in gold. R: rod; C: cone; RB: rod bipolar cell; CBon: ON cone bipolar cell; AII: AII amacrine cell; ipRGC: intrinsically photosensitive retinal ganglion cell. Horizontal gray lines indicate the ON and OFF sublayers of the inner plexiform layer.](profile/David-Berson/publication/237816326/figure/fig9/AS:214105030959114@1428058025668/The-ipRGC-is-a-hybrid-of-known-melanopsin-expressing-ganglion-cell-types-some-of-which.png)
The ipRGC is a hybrid of known melanopsin-expressing ganglion cell types, some of which stratify exclusively in the uppermost OFF sublayer (site 3), others in the ON sublayer (e.g., site 2), and still others in both (see text). Jagged lines represent gap junctional contacts between AII amacrine cells and ON cone bipolar terminals (site 1) and between rods and cones (site 4). The primary rod pathway is shown in red, the secondary rod pathway in green, and a novel pathway from rods to ON cone bipolar cells in blue [35]. All of these pathways have been considered to relay to ganglion cells in the ON sublayer (site2), but they may also pass through ectopic ON cone bipolar terminals in the OFF sublayer to the dendrites of some ipRGCs (site 3; see text). A pathway directly linking rod bipolar cells to ipRGCs, proposed by Ostergaard et al. (2007) [17], is shown in gold. R: rod; C: cone; RB: rod bipolar cell; CBon: ON cone bipolar cell; AII: AII amacrine cell; ipRGC: intrinsically photosensitive retinal ganglion cell. Horizontal gray lines indicate the ON and OFF sublayers of the inner plexiform layer.
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INTRINSICALLY PHOTOSENSITIVE RETINAL GANGLION CELLS (IPRGCS) ARE DEPOLARIZED BY LIGHT BY TWO MECHANISMS: directly, through activation of their photopigment melanopsin; and indirectly through synaptic circuits driven by rods and cones. To learn more about the rod and cone circuits driving ipRGCs, we made multielectrode array (MEA) and patch-clamp re...
Citations
... Shaded region in E and F represents mean ± SEM 'bright' preference across tested irradiances, with one sample t-tests vs. a hull hypothesis of 0 preference. * and ** represent P < 0.05 and P < 0.01, respectively useful information about irradiance [33][34][35] or support robust visually-guided behaviour [36][37][38]), and previous data on photoreceptor contributions to light avoidance [8,9,25], we reasoned that cones and/or melanopsin signals may be particularly important in influencing the animal's preference. ...
... That conclusion is supported by extensive prior literature demonstrating a substantial contribution of melanopsin to negative masking responses [18-22, 26, 43] as well as the well-documented dynamic ranges for rod and melanopsin responses to dark-light transitions (e.g. [30,[33][34][35][44][45][46][47][48][49]). Strikingly, however, by comparison to the behaviour observed under the reference spectra, Opn1mw R mice reliably exhibited increased activity levels (Fig. 3D, E) when presented with an otherwise identical stimulus providing a 1 log unit higher irradiance just for S-cone opsin ('spectra 3'), thereby providing a colour that mimicked the blue-shift in ambient illumination experienced by mice during twilight [16] (Additional file 1: Fig. S3F,G). ...
... Hence while rods can still contribute to physiological and behavioural responses to light-dark transitions at high irradiances (e.g. [13,57]), we find irradiance-dependent (and cone-independent) reductions in behavioural activity for stimuli more than 10 times brighter than the saturation point for rod responses to light-dark transitions (and well-within the range of melanopsin-driven responses; [30,[33][34][35][44][45][46][47][48][49]). Consistent with our interpretation that such effects originate with melanopsin, it is well-established than knockout or knockdown of melanopsin substantially impairs negative masking [18,19,43] while melanopsin only (rd/rd cl, rd/ rd) animals robustly retain such responses with no loss of sensitivity relative to wildtype [20,21,26]. ...
Background
Animal survival depends on the ability to adjust behaviour according to environmental conditions. The circadian system plays a key role in this capability, with diel changes in the quantity (irradiance) and spectral content (‘colour’) of ambient illumination providing signals of time-of-day that regulate the timing of rest and activity. Light also exerts much more immediate effects on behaviour, however, that are equally important in shaping daily activity patterns. Hence, nocturnal mammals will actively avoid light and dramatically reduce their activity when light cannot be avoided. The sensory mechanisms underlying these acute effects of light are incompletely understood, particularly the importance of colour.
Results
To define sensory mechanisms controlling mouse behaviour, we used photoreceptor-isolating stimuli and mice with altered cone spectral sensitivity (Opn1mwR), lacking melanopsin (Opn1mwR; Opn4−/−) or cone phototransduction (Cnga3−/−) in assays of light-avoidance and activity suppression. In addition to roles for melanopsin-dependent irradiance signals, we find a major influence of spectral content in both cases. Hence, remarkably, selective increases in S-cone irradiance (producing a blue-shift in spectrum replicating twilight) drive light-seeking behaviour and promote activity. These effects are opposed by signals from longer-wavelength sensitive cones, indicating a true spectrally-opponent mechanism. Using c-Fos-mapping and multielectrode electrophysiology, we further show these effects are associated with a selective cone-opponent modulation of neural activity in the key brain site implicated in acute effects of light on behaviour, the subparaventricular zone.
Conclusions
Collectively, these data reveal a mechanism whereby blue-shifts in the spectrum of environmental illumination, such as during twilight, promote mouse exploratory behaviour.
... The non-image forming effects of light are mediated by the intrinsically photosensitive retinal ganglion cells (ipRGCs) (Fu et al., 2005;Mure, 2021;Schmidt et al., 2008;Weng et al., 2013). The ipRGCs capture light using the photopigment melanopsin, which is maximally sensitive to blue light at 480 nm wavelengths (Schmidt et al., 2008). ...
Background:
Bright light therapy (BLT) is the first-line treatment for seasonal affective disorder. However, the neural mechanisms underlying BLT are unclear. To begin filling this gap, the present study examined the impact of BLT on sleep/wakefulness, daily rhythms, and the wakefulness-promoting orexin/hypocretin system in a diurnal rodent, Nile grass rats (Arvicanthis niloticus).
Methods:
Male and female grass rats were housed under a 12:12 h light/dark cycle with dim light (50 lx) during the day. The experimental group received daily 1-h early morning BLT (full-spectrum white light, 10,000 lx), while the control group received narrowband red light for 4 weeks. Sleep/wakefulness and in-cage locomotor activity were monitored, followed by examination of hypothalamic prepro-orexin and orexin receptors OX1R and OX2R expression in corticolimbic brain regions.
Results:
The BLT group had higher wakefulness during light treatment, better nighttime sleep quality, and improved daily rhythm entrainment compared to controls. The impact of BLT on the orexin system was sex- and brain region-specific, with males showing higher OX1R and OX2R in the CA1, while females showed higher prepro-orexin but lower OX1R and OX2R in the BLA, compared to same-sex controls.
Limitations:
The present study focused on the orexin system in a limited number of brain regions at a single time point. Sex wasn't a statistical factor, as male and female cohorts were run independently.
Conclusions:
The diurnal grass rats show similar behavioral responses to BLT as humans, thus could be a good model for further elucidating the neural mechanisms underlying the therapeutic effects of BLT.
... It is possible, therefore, that the approach used here preferentially reveals the M1-subtype of ipRGC. Moreover, in keeping with previous studies that have investigated outer retinal inputs to M1 cells in mouse retina (Schmidt et al., 2008;Weng et al., 2013), we found that the cone response of these ipRGCs (tested prior to the synaptic blockade) was relatively weak ( Figure 3F) with no evidence of colour opponency across any of the identified units. ...
... Nonetheless, consistent with the view this population is enriched for M1 cells, we found their response to cone-modulating stimuli was consistently weak. Moreover, in line with a previous study specifically targeting the M1 subtype (Weng et al., 2013), we found no evidence that such cells exhibited cone-mediated colour opponent responses. Hence the widespread appearance of cone opponent responses in SCN neurons is most unlikely to be directly inherited from the M1 ipRGC subtype that dominates retinal input to that structure (Beier et al., 2021). ...
Introduction: Intrinsically photosensitive retinal ganglion cells (ipRGCs) integrate melanopsin and rod/cone-mediated inputs to signal to the brain. Whilst originally identified as a cell type specialised for encoding ambient illumination, several lines of evidence indicate a strong association between colour discrimination and ipRGC-driven responses. Thus, cone-mediated colour opponent responses have been widely found across ipRGC target regions in the mouse brain and influence a key ipRGC-dependent function, circadian photoentrainment. Although ipRGCs exhibiting spectrally opponent responses have also been identified, the prevalence of such properties have not been systematically evaluated across the mouse retina or yet been found in ipRGC subtypes known to influence the circadian system. Indeed, there is still uncertainty around the overall prevalence of cone-dependent colour opponency across the mouse retina, given the strong retinal gradient in S and M-cone opsin (co)-expression and overlapping spectral sensitivities of most mouse opsins. Methods: To address this, we use photoreceptor isolating stimuli in multielectrode recordings from human red cone opsin knock-in mouse (Opn1mwR) retinas to systematically survey cone mediated responses and the occurrence of colour opponency across ganglion cell layer (GCL) neurons and identify ipRGCs based on spectral comparisons and/or the persistence of light responses under synaptic blockade. Results: Despite detecting robust cone-mediated responses across the retina, we find cone opponency is rare, especially outside of the central retina (overall ~3% of GCL neurons). In keeping with previous suggestions we also see some evidence of rod-cone opponency (albeit even more rare under our experimental conditions), but find no evidence for any enrichment of cone (or rod) opponent responses among functionally identified ipRGCs. Conclusion: In summary, these data suggest the widespread appearance of cone-opponency across the mouse early visual system and ipRGC-related responses may be an emergent feature of central visual processing mechanisms.
... The expression 'steady-state pupil' refers to when the size of the pupil is held steady under continuous light. The ipRGCs also receive input from retinal cones and rods (Dacey et al., 2005;Weng et al., 2013), although the cone input continues for less than a minute to pupillary constriction when constant levels of light are used. Rods may contribute longer, but only at light levels below saturation of the rod response (McDougal & Gamlin, 2010). ...
... Regardless of intensity, red light did not affect cow pupil size in Paper I. A melanopsin-driven function could explain this, since pupillary constriction to steady light is primarily mediated through ipRGCs. However, these lightsensitive ganglion cells also receive input from retinal cones and rods (Dacey et al., 2005;Weng et al., 2013). Since the pupil remained dilated even with almost a 100-fold increase in photon flux, a higher number of photons reached the retina. ...
Light can be used as a management tool to increase milk yield in dairy cows and improve the working conditions for barn staff. It is known that a long day photoperiod, with 16 hours of light and 8 hours of darkness, can increase milk yield in an ongoing lactation. Modern LED lighting can be designed to emit specific wavelengths, opening up possibilities for discussing the most favorable type of light for dairy cows. This thesis investigated the role of light environment and the impact of light intensity, spectral composition and uniformity on dairy cows. In initial studies, a light lab with a controlled light environment and no external light was used. The response to red, blue, and white light of increasing intensity on pupil size was evaluated in five pregnant non-lactating cows. Red light did not constrict the pupil but the other light colors did, indicating that direct stimulation of ipRGCs may be required for a pupillary response to steady background light. A five-week study on 40 pregnant and lactating cows involving 16 hours of blue, red or white light in daytime and 8 hours of dim, white light at night did not show effects of light color during daytime on milk production. Plasma melatonin concentration was higher in dim night light than in daylight for all light treatments. To examine cow movements in light of different intensity, spectrum and uniformity, 12 pregnant, non-lactating cows were tested in an obstacle course in the light lab. A dark environment did not limit the cows’ ability to walk through the obstacle course, but they reduced walking speed when subjected to non-uniform, low-intensity red light, indicating the importance of avoiding non-uniform light in dairy barns. Quantification of light environments on four Swedish dairy farms, using a range of measuring methods, showed that the light environment differed between farms, but that light of low intensity and uniformity was commonly used. Light environment is important for dairy cows, as it can affect their physiology and behavior. The light environment can be more objectively described using multiple measuring methods.
... How do RBCs convey the signal to downstream circuitry to drive the photopic PLR? Although this is beyond the scope of this study, we speculated regarding the potential circuit pathways that might allow rods to drive M1 ipRGCs, the main light relays for the PLR and circadian photoentrainment (G€ uler et al., 2008;Lee et al., 2019;Weng et al., 2013;Zhao et al., 2014). There are at least three possibilities: (1) RBCs synapse directly onto M1 ipRGCs (Østergaard et al., 2007); (2) RBC signals are routed to M1 ipRGCs via the AII amacrine cell inhibitory glycinergic synapse, likely via another amacrine cell (Graydon et al., 2018;Newkirk et al., 2013;Pé rez-Ferná ndez et al., 2019;Reifler et al., 2015;Roy and Field, 2019;Sabbah et al., 2017Sabbah et al., , 2018Tsukamoto and Omi, 2017); or (3) RBC signals are routed to M1 ipRGCs via the AII amacrine cell gap junction with Type 6 ON CBCs (Tsukamoto and Omi, 2017). ...
... Non-image-forming vision requires the most sensitive retinal pathway for normal function Electrophysiological evidence has suggested that ipRGCs receive light information from the primary rod pathway, but it has remained unknown whether this connection is behaviorally relevant (Weng et al., 2013). It has been shown more recently that the intrinsic melanopsin-dependent response is sensitive to scotopic light stimulation ex vivo (Lee et al., 2019), but the melanopsin contribution to the scotopic PLR is small (Keenan et al., 2016). ...
Article Divergent outer retinal circuits drive image and non-image visual behaviors Graphical abstract Highlights d The OFF pathway drives image-forming vision but not non-image-forming vision d Non-image-forming vision requires the most sensitive retinal pathway d The primary rod pathway is necessary and sufficient for the pupillary light response d The primary and secondary rod pathways drive the photopic pupillary light response Correspondence samer.hattar@nih.gov (S.H.), johan.pahlberg@nih.gov (J.P.) In brief Beier et al. show that light information diverges at the visual system's first synapse to control major visual functions: image formation and non-image behaviors, such as circadian photoentrainment and pupil constriction. Like image formation, the non-image system depends on the most sensitive retinal circuit under dim light conditions. SUMMARY Image-and non-image-forming vision are essential for animal behavior. Here we use genetically modified mouse lines to examine retinal circuits driving image-and non-image-functions. We describe the outer retinal circuits underlying the pupillary light response (PLR) and circadian photoentrainment, two non-image-forming behaviors. Rods and cones signal light increments and decrements through the ON and OFF pathways, respectively. We find that the OFF pathway drives image-forming vision but cannot drive circadian photoen-trainment or the PLR. Cone light responses drive image formation but fail to drive the PLR. At photopic levels, rods use the primary and secondary rod pathways to drive the PLR, whereas at the scotopic and mesopic levels, rods use the primary pathway to drive the PLR, and the secondary pathway is insufficient. Circuit dynamics allow rod ON pathways to drive two non-image-forming behaviors across a wide range of light intensities , whereas the OFF pathway is potentially restricted to image formation.
... In dark-adapted retinas, a series of 10-s 480-nm light flashes (3.42 × 10 11 to 1.51 × 10 15 photons cm −2 s −1 ) elicited sluggish but very persistent spike discharges in a few MEA channels, typical of melanopsin-based phototransduction. Similar to previous studies (29,30), in retinas from both deprived and fellow eyes, the light-induced spike discharges increased as a function of flash intensity. Representative raster plots of these responses are shown in Fig. 7H. ...
... Spike sorting of the raw recording data followed a protocol previously described using Offline Sorter software (Plexon Inc., USA) with manual correction for clustering errors (29). The resulting timestamps of individual ipRGCs were further processed with OriginPro 2017 (OriginLab Corp., USA) and Microsoft Excel (Microsoft Corporation, USA) to measure two major parameters of light responses: total spike number during light stimulus and peak latency (the interval between light onset and the time point when peak firing rate occurred). ...
The increasing global prevalence of myopia calls for elaboration of the pathogenesis of this disease. Here, we show that selective ablation and activation of intrinsically photosensitive retinal ganglion cells (ipRGCs) in developing mice induced myopic and hyperopic refractive shifts by modulating the corneal radius of curvature (CRC) and axial length (AL) in an opposite way. Melanopsin- and rod/cone-driven signals of ipRGCs were found to influence refractive development by affecting the AL and CRC, respectively. The role of ipRGCs in myopia progression is evidenced by attenuated form-deprivation myopia magnitudes in ipRGC-ablated and melanopsin-deficient animals and by enhanced melanopsin expression/photoresponses in form-deprived eyes. Cell subtype-specific ablation showed that M1 subtype cells, and probably M2/M3 subtype cells, are involved in ocular development. Thus, ipRGCs contribute substantially to mouse eye growth and myopia development, which may inspire novel strategies for myopia intervention.
... The blue wavelength of light from 400 to 490 nm in the visible spectrum contains higher energy, unlike other wavelengths. This can damage the retinal cells as compared to other wavelengths (Grimm et al., 2018) and significantly influences the regulation of the neuroendocrine system such as circadian rhythm and neuronal behavioural regulations in mammals (Weng et al., 2013). Blue light also alters the physiological rhythm including sleepiness, alertness and fluctuations in the glucose metabolism with an increase in cortisol level (Cheung et al., 2016;Wahnschaffe et al., 2013). ...
Blue light exposure induced retinal damage has been extensively studied. Retinal damages are closely associated with cellular and biochemical changes occurring in the vitreous and hence, understanding metabolic changes in vitreous tissue might serve as clinical importance to indicate ocular/vision health. In the present study, we have investigated the influence of blue light-emitting diodes (LED) on the vitreous metabolome and further, we show amelioration of altered metabolite levels upon blue light blocking lenses (BBLs). A total of n=24 (n=6 in each group; control, light exposure without lenses, two different BBLs) male Wistar rats were subjected to blue light exposure (LEDs, 450–500 lux) without or with BBLs (400–490 nm) for 28 days on a 12:12 h light-dark cycle. Post-exposure the vitreous fluid aspirated was subjected for untargeted liquid chromatography/mass spectrometry-based metabolomics analysis. Analyzed vitreous revealed blue light significantly modulated metabolites such as Tyrosine, L-Histidine (p= 0.02), L−Isoleucine (p= 0.007), Valine (p=0.04) and D−Proline (P < 0.001) along with affected homocysteine degradation and nitric oxide signalling pathway. Our findings suggest exposure to blue LED poses a significant hazard to the vitreous as it alters the vitreous metabolites, and it is partially ameliorated by commercially available BBLs.
... Exposure to LEDs has been demonstrated to alter retinal structure and function, as well as other neuroendocrine systems, as evidenced by changes in cortisol levels, circadian rhythms, pupillary responses, mood, and alters behavior [15][16][17][18]. Likewise, exposure to higher levels of blue light significantly disrupts the regulation of circadian rhythms and alters behavior, as has been documented in a range of mammalian species [19][20][21][22][23][24]. ...
Blue light exposure-induced retinal damage has been extensively studied. Although many
in vitro studies have shown the benefits of blue light-blocking lenses (BBL) there have been few comprehensive in vivo studies to assess the effects of BBL. We investigated the influence of blue light exposure using light-emitting diodes on retinal histology and visual cortex neurons in rodents. We also considered whether retinal and cortical changes induced by blue light could be ameliorated with blue light-blocking lenses. A total of n = 24 (n = 6 in each group; control, light exposure without lenses, two different BBLs)) maleWistar rats were subjected to blue light exposure (LEDs, 450–500 lux) without or with BBLs (400–490 nm) for 28 days on a 12:12 h light–dark cycle. Histological analysis of retinae revealed apoptosis and necrosis of the retinal pigment epithelium (RPE), photoreceptors, and inner retina in the light exposure (LE) group, along with increase caspase-3 immunostaining in the ganglion cell layer (p < 0.001). BBL groups showed less caspase-3 immunostaining compared with the LE group (p < 0.001). V1-L5PNs (primary visual cortex layer 5 pyramidal neurons) demonstrated reduced branching and intersections points for apical (p < 0.001) and basal (p < 0.05) dendrites following blue light exposure. Blue light-blocking lenses significantly improved the number of basal branching points compared with the LE group. Our study shows that prolonged exposure to high levels of blue light pose a significant hazard to the visual system resulting in damage to the retina with the associated remodeling of visual cortex neurons. BBL may offer moderate protection against exposure to high levels of blue light.
... Exposure to LEDs has been demonstrated to alter retinal structure and function, as well as other neuroendocrine systems, as evidenced by changes in cortisol levels, circadian rhythms, pupillary responses, mood, and alters behavior [15][16][17][18]. Likewise, exposure to higher levels of blue light significantly disrupts the regulation of circadian rhythms and alters behavior, as has been documented in a range of mammalian species [19][20][21][22][23][24]. ...
Citation: Theruveethi, N.; Bui, B.V.; Joshi, M.B.; Valiathan, M.; Ganeshrao, S.B.; Gopalakrishnan, S.; Kabekkodu, S.P.; Bhat, S.S.; Surendran, S. Blue Light-Induced Retinal Neuronal Injury and Amelioration by Commercially Available Blue Light-Blocking Lenses.
... In mammals, photic signals reach the SCN via the retinohypothalamic-tract, after initially being absorbed in the retina by classical photoreceptors (rods and cones) and by melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) [2,30]. Although the ipRGCs are independently light sensitive [39,40], evidence now suggests that rods and cones also contribute to non-visual SCN-related processes [4,17,23,70,73]. In the SCN, the circadian clock is reset by the alteration of clock gene expression, which in turn modulates the downstream physiological and behavioural rhythms [22]. ...
The quality and quantity of light changes significantly over the course of the day. The effect of light intensity on physiological and behavioural responses of animals has been well documented, particularly during the scotophase, but the effect of the wavelength of light, particularly during the photophase, less so. We assessed the daily responses in urine production, urinary 6-sulfatoxymelatonin (6-SMT) and glucocorticoid metabolite (uGCM) concentrations in the nocturnal Namaqua rock mouse (Micaelamys namaquensis) and diurnal four striped field mouse (Rhabdomys pumilio) under varying wavelengths of near monochromatic photophase (daytime) lighting. Animals were exposed to a short-wavelength light cycle (SWLC; ∼465-470 nm), a medium-wavelength light cycle (MWLC; ∼515-520 nm) and a long-wavelength light cycle (LWLC; ∼625-630 nm). The SWLC significantly attenuated mean daily urine production rates and the mean daily levels of urinary 6-SMT and of uGCM were inversely correlated with wavelength in both species. The presence of the SWLC greatly augmented overall daily 6-SMT levels, and simultaneously led to the highest uGCM concentrations in both species. In M. namaquensis, the urine production rate and urinary 6-SMT concentrations were significantly higher during the scotophase compared to the photophase under the SWLC and MWLC, whereas the uGCM concentrations were significantly higher during the scotophase under all WLCs. In R. pumilio, the urine production rate and uGCM were significantly higher during the scotophase of the SWLC, not the MWLC and LWLC. Our results illustrate that wavelength in the photophase plays a central role in the entrainment of rhythms in diurnal and nocturnal African rodent species.
