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1.
Cell ; 185(17): 3081-3083, 2022 08 18.
Article in English | MEDLINE | ID: mdl-35985285

ABSTRACT

The newborn mouse's retina senses light even before the eye opens, informing the developing brain of the visual world. Without this information, the brain forms fewer connections and the adult mouse learns sluggishly.


Subject(s)
Neurons , Retina , Animals , Brain , Learning , Light , Mice , Neurons/physiology , Retina/physiology
2.
Cell ; 176(5): 1222-1237.e22, 2019 02 21.
Article in English | MEDLINE | ID: mdl-30712875

ABSTRACT

High-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >60 cell types match between the two regions but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved. In contrast, projection neuron types and programs diverge, despite exhibiting conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 7 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.


Subject(s)
Fovea Centralis/physiology , Primates/physiology , Retina/physiology , Aged , Animals , Callithrix , Female , Humans , Macaca , Male , Retina/anatomy & histology , Retinal Ganglion Cells/metabolism
3.
Cell ; 175(3): 637-639, 2018 10 18.
Article in English | MEDLINE | ID: mdl-30340036

ABSTRACT

Animal photoreceptors divide into two fundamental classes, ciliary and rhabdomeric. Jiang and colleagues demonstrate that this boundary is disregarded by the intrinsically photosensitive retinal ganglion cells of mammals. These neurons draw from phototransduction mechanisms of both classes, enriching the signals that they produce to drive a diversity of visual functions.


Subject(s)
Retinal Ganglion Cells , Rod Opsins , Animals , Light Signal Transduction , Nucleotides
4.
PLoS Biol ; 22(3): e3002535, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38470868

ABSTRACT

Light enables vision and exerts widespread effects on physiology and behavior, including regulating circadian rhythms, sleep, hormone synthesis, affective state, and cognitive processes. Appropriate lighting in animal facilities may support welfare and ensure that animals enter experiments in an appropriate physiological and behavioral state. Furthermore, proper consideration of light during experimentation is important both when it is explicitly employed as an independent variable and as a general feature of the environment. This Consensus View discusses metrics to use for the quantification of light appropriate for nonhuman mammals and their application to improve animal welfare and the quality of animal research. It provides methods for measuring these metrics, practical guidance for their implementation in husbandry and experimentation, and quantitative guidance on appropriate light exposure for laboratory mammals. The guidance provided has the potential to improve data quality and contribute to reduction and refinement, helping to ensure more ethical animal use.


Subject(s)
Animal Experimentation , Animals, Laboratory , Animals , Reproducibility of Results , Circadian Rhythm/physiology , Mammals
5.
Nature ; 457(7227): 281-7, 2009 Jan 15.
Article in English | MEDLINE | ID: mdl-19118382

ABSTRACT

A subset of retinal ganglion cells has recently been discovered to be intrinsically photosensitive, with melanopsin as the pigment. These cells project primarily to brain centres for non-image-forming visual functions such as the pupillary light reflex and circadian photoentrainment. How well they signal intrinsic light absorption to drive behaviour remains unclear. Here we report fundamental parameters governing their intrinsic light responses and associated spike generation. The membrane density of melanopsin is 10(4)-fold lower than that of rod and cone pigments, resulting in a very low photon catch and a phototransducing role only in relatively bright light. Nonetheless, each captured photon elicits a large and extraordinarily prolonged response, with a unique shape among known photoreceptors. Notably, like rods, these cells are capable of signalling single-photon absorption. A flash causing a few hundred isomerized melanopsin molecules in a retina is sufficient for reaching threshold for the pupillary light reflex.


Subject(s)
Photons , Retinal Ganglion Cells/metabolism , Retinal Ganglion Cells/radiation effects , Rod Opsins/metabolism , Action Potentials/radiation effects , Animals , Brain/metabolism , Kinetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Pupil/physiology , Pupil/radiation effects , Reflex, Pupillary/radiation effects
6.
Neuron ; 112(14): 2261-2262, 2024 Jul 17.
Article in English | MEDLINE | ID: mdl-39024917

ABSTRACT

The pupil is the eye's adjustable aperture. Fitzpatrick et al. find that visual contrast constricts the pupil, increasing contrast.1 This process improves behavioral performance. Its retinal origin has unorthodox elements, like interneurons that make connections in unusual locales and photoreceptive ganglion cells.


Subject(s)
Contrast Sensitivity , Pupil , Pupil/physiology , Animals , Contrast Sensitivity/physiology , Humans , Retinal Ganglion Cells/physiology
7.
Article in English | MEDLINE | ID: mdl-37994345

ABSTRACT

Melanopsin is a light-activated G protein coupled receptor that is expressed widely across phylogeny. In mammals, melanopsin is found in intrinsically photosensitive retinal ganglion cells (ipRGCs), which are especially important for "non-image" visual functions that include the regulation of circadian rhythms, sleep, and mood. Photochemical and electrophysiological experiments have provided evidence that melanopsin has at least two stable conformations and is thus multistable, unlike the monostable photopigments of the classic rod and cone photoreceptors. Estimates of melanopsin's properties vary, challenging efforts to understand how the molecule influences vision. This article seeks to reconcile disparate views of melanopsin and offer a practical guide to melanopsin's complexities.

8.
Science ; 379(6630): 376-381, 2023 01 27.
Article in English | MEDLINE | ID: mdl-36701440

ABSTRACT

Light regulates physiology, mood, and behavior through signals sent to the brain by intrinsically photosensitive retinal ganglion cells (ipRGCs). How primate ipRGCs sense light is unclear, as they are rare and challenging to target for electrophysiological recording. We developed a method of acute identification within the live, ex vivo retina. Using it, we found that ipRGCs of the macaque monkey are highly specialized to encode irradiance (the overall intensity of illumination) by blurring spatial, temporal, and chromatic features of the visual scene. We describe mechanisms at the molecular, cellular, and population scales that support irradiance encoding across orders-of-magnitude changes in light intensity. These mechanisms are conserved quantitatively across the ~70 million years of evolution that separate macaques from mice.


Subject(s)
Biological Evolution , Lighting , Retinal Ganglion Cells , Animals , Mice , Light , Retinal Ganglion Cells/physiology , Macaca
9.
J Neurosci ; 31(45): 16094-101, 2011 Nov 09.
Article in English | MEDLINE | ID: mdl-22072661

ABSTRACT

Melanopsin imparts an intrinsic photosensitivity to a subclass of retinal ganglion cells (ipRGCs). Generally thought of as irradiance detectors, ipRGCs target numerous brain regions involved in non-image-forming vision. ipRGCs integrate their intrinsic, melanopsin-mediated light information with rod/cone signals relayed via synaptic connections to influence light-dependent behaviors. Early observations indicated diversity among these cells and recently several specific subtypes have been identified. These subtypes differ in morphological and physiological form, controlling separate functions that range from biological rhythm via circadian photoentrainment, to protective behavioral responses including pupil constriction and light avoidance, and even image-forming vision. In this Mini-Symposium review, we will discuss some recent findings that highlight the diversity in both form and function of these recently discovered atypical photoreceptors.


Subject(s)
Avoidance Learning/physiology , Light Signal Transduction/physiology , Retinal Ganglion Cells/metabolism , Rod Opsins/metabolism , Animals , Humans , Light/adverse effects , Nerve Net/physiology , Photoreceptor Cells/physiology , Retinal Ganglion Cells/classification , Retinal Ganglion Cells/cytology , Visual Pathways
11.
Neuron ; 110(4): 564-565, 2022 02 16.
Article in English | MEDLINE | ID: mdl-35176239

ABSTRACT

In this issue of Neuron, Shah et al. reveal that coding of visual space by the primate retina varies across individuals and sexes. A computational model provides insight into themes and variations of coding. Implications for sight restoration are explored.


Subject(s)
Retina , Vision, Ocular , Animals , Neurons/physiology , Primates , Retina/physiology
12.
J Comp Neurol ; 530(9): 1470-1493, 2022 06.
Article in English | MEDLINE | ID: mdl-35029299

ABSTRACT

Immunoreactivity for calcium-/calmodulin-dependent protein kinase II (CaMKII) in the primate dorsal lateral geniculate nucleus (dLGN) has been attributed to geniculocortical relay neurons and has also been suggested to arise from terminals of retinal ganglion cells. Here, we combined immunostaining with single-cell injections to investigate the expression of CaMKII in retinal ganglion cells of three primate species: macaque (Macaca fascicularis, M. nemestrina), human, and marmoset (Callithrix jacchus). We found that in all species, about 2%-10% of the total ganglion cell population expressed CaMKII. In all species, CaMKII was expressed by multiple types of wide-field ganglion cell including large sparse, giant sparse (melanopsin-expressing), broad thorny, and narrow thorny cells. Three other ganglion cells types, namely, inner and outer stratifying maze cells in macaque and tufted cells in marmoset were also found. Double labeling experiments showed that CaMKII-expressing cells included inner and outer stratifying melanopsin cells. Nearly all CaMKII-expressing ganglion cell types identified here are known to project to the koniocellular layers of the dLGN as well as to the superior colliculus. The best characterized koniocellular projecting cell type-the small bistratified (blue ON/yellow OFF) cell-was, however, not CaMKII-positive in any species. Our results indicate that the pattern of CaMKII expression in retinal ganglion cells is largely conserved across different species of primate suggesting a common functional role. But the results also show that CaMKII is not a marker for all koniocellular projecting retinal ganglion cells.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 2 , Retinal Ganglion Cells , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Callithrix , Geniculate Bodies , Humans , Macaca fascicularis/metabolism , Retina/metabolism , Retinal Ganglion Cells/physiology
13.
J Comp Neurol ; 530(6): 923-940, 2022 04.
Article in English | MEDLINE | ID: mdl-34622958

ABSTRACT

Recent advances in single-cell RNA sequencing have enabled the molecular distinction of ganglion cell populations in mammalian retinas. Here we used antibodies against the transcription factor special AT-rich binding protein 1 (Satb1, a protein which is expressed by on-off direction-selective ganglion cells in mouse retina) to study Satb1 expression in the retina of marmosets (Callithrix jacchus), macaques (Macaca fascicularis), and humans. In all species, Satb1 was exclusively expressed in retinal ganglion cells. The Satb1 cells made up ∼2% of the ganglion cell population in the central retina of all species, rising to a maximum ∼7% in peripheral marmoset retina. Intracellular injections in marmoset and macaque retinas revealed that most Satb1 expressing ganglion cells are widefield ganglion cells. In marmoset, Satb1 cells have a densely branching dendritic tree and include broad and narrow thorny, recursive bistratified, and parasol cells, all of which show some costratification with the outer or inner cholinergic amacrine cells. The recursive bistratified cells showed the strongest costratification but did not show extensive cofasciculation as reported for on-off direction-selective ganglion cells in rabbit and rodent retinas. In macaque, Satb1 was not expressed in recursive bistratified cells, but in large sparsely branching cells. Our findings further support the idea that the expression of transcription factors in retinal ganglion cells is not conserved across Old World (human and macaque) and New World (marmoset) primates and provides a further step to link a molecular marker with specific cell types.


Subject(s)
Matrix Attachment Region Binding Proteins/metabolism , Retinal Ganglion Cells/metabolism , Animals , Callithrix , Humans , Macaca fascicularis , Species Specificity
14.
Neuron ; 108(2): 335-348.e7, 2020 10 28.
Article in English | MEDLINE | ID: mdl-32846139

ABSTRACT

The fovea is a neural specialization that endows humans and other primates with the sharpest vision among mammals. This performance originates in the foveal cones, which are extremely narrow and long to form a high-resolution pixel array. Puzzlingly, this form is predicted to impede electrical conduction to an extent that appears incompatible with vision. We observe the opposite: signal flow through even the longest cones (0.4-mm axons) is essentially lossless. Unlike in most neurons, amplification and impulse generation by voltage-gated channels are dispensable. Rather, sparse channel activity preserves intracellular current, which flows as if unobstructed by organelles. Despite these optimizations, signaling would degrade if cones were lengthier. Because cellular packing requires that cone elongation accompanies foveal expansion, this degradation helps explain why the fovea is a constant, miniscule size despite multiplicative changes in eye size through evolution. These observations reveal how biophysical mechanisms tailor form-function relationships for primate behavioral performance.


Subject(s)
Membrane Potentials , Retinal Cone Photoreceptor Cells/physiology , Vision, Ocular/physiology , Visual Acuity/physiology , Animals , Female , Macaca fascicularis , Macaca mulatta , Male , Retinal Cone Photoreceptor Cells/cytology
15.
Neuron ; 104(2): 205-226, 2019 10 23.
Article in English | MEDLINE | ID: mdl-31647894

ABSTRACT

The mammalian visual system encodes information over a remarkable breadth of spatiotemporal scales and light intensities. This performance originates with its complement of photoreceptors: the classic rods and cones, as well as the intrinsically photosensitive retinal ganglion cells (ipRGCs). IpRGCs capture light with a G-protein-coupled receptor called melanopsin, depolarize like photoreceptors of invertebrates such as Drosophila, discharge electrical spikes, and innervate dozens of brain areas to influence physiology, behavior, perception, and mood. Several visual responses rely on melanopsin to be sustained and maximal. Some require ipRGCs to occur at all. IpRGCs fulfill their roles using mechanisms that include an unusual conformation of the melanopsin protein, an extraordinarily slow phototransduction cascade, divisions of labor even among cells of a morphological type, and unorthodox configurations of circuitry. The study of ipRGCs has yielded insight into general topics that include photoreceptor evolution, cellular diversity, and the steps from biophysical mechanisms to behavior.


Subject(s)
Action Potentials/physiology , Circadian Rhythm/physiology , Light , Retinal Ganglion Cells/physiology , Rod Opsins/metabolism , Vision, Ocular/physiology , Animals , Humans , Light Signal Transduction/physiology , Mice , Reflex, Pupillary/physiology , Retinal Ganglion Cells/metabolism
16.
Neuron ; 39(1): 109-20, 2003 Jul 03.
Article in English | MEDLINE | ID: mdl-12848936

ABSTRACT

Neurons of the subthalamic nucleus (STN) are spontaneously active. By voltage clamping dissociated rat STN neurons with their own firing patterns, we found that pacemaking is driven by two kinds of subthreshold sodium current: a steady-state "persistent" sodium current and a dynamic "resurgent" sodium current, which promotes rapid firing by flowing immediately after a spike. These currents are strongly regulated by a process of slow inactivation that is active at physiological firing frequencies. Slow inactivation of the pacemaking sodium currents promotes a constant frequency of tonic firing in the face of small, steady changes in input and constitutes a form of adaptation at the single-cell level. Driving cells at a high rate (75 Hz) produced pronounced slow inactivation (60%-70%) of resurgent, persistent, and transient components of sodium current. This inactivation is likely to contribute to effects of clinical deep-brain stimulation on STN excitability.


Subject(s)
Action Potentials/physiology , Biological Clocks/physiology , Neural Inhibition/physiology , Neurons/physiology , Sodium Channels/physiology , Animals , Cells, Cultured , Electric Stimulation , Organ Culture Techniques , Parkinson Disease/therapy , Patch-Clamp Techniques , Rats , Rats, Long-Evans , Subthalamic Nucleus/physiology
17.
Curr Opin Neurobiol ; 15(4): 415-22, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16023851

ABSTRACT

It has been accepted for a hundred years or more that rods and cones are the only photoreceptive cells in the retina. The light signals generated in rods and cones, after processing by downstream retinal neurons (bipolar, horizontal, amacrine and ganglion cells), are transmitted to the brain via the axons of the ganglion cells for further analysis. In the past few years, however, convincing evidence has rapidly emerged indicating that a small subset of retinal ganglion cells in mammals is also intrinsically photosensitive. Melanopsin is the signaling photopigment in these cells. The main function of the inner-retina photoreceptors is to generate and transmit non-image-forming visual information, although some role in conventional vision (image detection) is also possible.


Subject(s)
Retinal Ganglion Cells/physiology , Rod Opsins/physiology , Animals , Humans , Retinal Cone Photoreceptor Cells/physiology , Retinal Ganglion Cells/cytology , Retinal Rod Photoreceptor Cells/physiology
18.
Cell Rep ; 21(4): 1048-1062, 2017 Oct 24.
Article in English | MEDLINE | ID: mdl-29069587

ABSTRACT

Intrinsically photosensitive retinal ganglion cells of the M1 type encode environmental irradiance for functions that include circadian and pupillary regulation. Their distinct role, morphology, and molecular markers indicate that they are stereotyped circuit elements, but their physiological uniformity has not been investigated in a systematic fashion. We have profiled the biophysical parameters of mouse M1s and found that extreme variation is their hallmark. Most parameters span 1-3 log units, and the full range is evident in M1s that innervate brain regions serving divergent functions. Biophysical profiles differ among cells possessing similar morphology and between neighboring M1s recorded simultaneously. Variation in each parameter is largely independent of that in others, allowing for flexible individualization. Accordingly, a common stimulus drives heterogeneous spike outputs across cells. By contrast, a population of directionally selective retinal ganglion cells appeared physiologically uniform under similar conditions. Thus, M1s lack biophysical constancy and send diverse signals downstream.


Subject(s)
Photoreceptor Cells/physiology , Retinal Ganglion Cells/physiology , Animals , Female , Male , Mice , Mice, Inbred C57BL , Photoreceptor Cells/classification , Photoreceptor Cells/metabolism , Retinal Ganglion Cells/classification , Retinal Ganglion Cells/metabolism , Rod Opsins/metabolism , Vision, Ocular
19.
J Comp Neurol ; 518(23): 4813-24, 2010 Dec 01.
Article in English | MEDLINE | ID: mdl-20963830

ABSTRACT

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are a subtype of ganglion cell in the mammalian retina that expresses the photopigment melanopsin and drives non-image-forming visual functions. Three morphological subtypes of ipRGCs (M1, M2, and M3) have been described based on their dendritic stratifications in the inner plexiform layer (IPL), but the question of their potential interactions via electrical coupling remains unsettled. In this study, we have addressed this question in the mouse retina by, injecting the tracer Neurobiotin into ipRGCs that had been genetically labelled with the fluorescent protein, tdTomato. We confirmed the presence of the M1-M3 subtypes of ipRGCs based on their distinct dendritic stratifications. All three subtypes were tracer coupled to putative amacrine cells situated within the ganglion cell layer (GCL) but not the inner nuclear layer (INL). The cells tracer coupled to the M1 and M2 cells were shown to be widefield GABA-immunoreactive amacrine cells. We found no evidence of homologous tracer coupling of ipRGCs or heterologous coupling to other types of ganglion cells.


Subject(s)
Amacrine Cells/cytology , Electrical Synapses/ultrastructure , Neural Pathways/cytology , Retina/cytology , Retinal Ganglion Cells/cytology , Vision, Ocular/physiology , Amacrine Cells/physiology , Animals , Electrical Synapses/physiology , Fluorescent Antibody Technique/methods , Mice , Mice, Transgenic , Neural Pathways/physiology , Retina/physiology , Retinal Ganglion Cells/classification , Retinal Ganglion Cells/physiology
20.
J Neurophysiol ; 92(2): 726-33, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15056687

ABSTRACT

In some central neurons, including cerebellar Purkinje neurons and subthalamic nucleus (STN) neurons, TTX-sensitive sodium channels show unusual gating behavior whereby some channels open transiently during recovery from inactivation. This "resurgent" sodium current is effectively activated immediately after action potential-like waveforms. Earlier work using Purkinje neurons suggested that the great majority of resurgent current originates from Na(v)1.6 sodium channels. Here we used a mouse mutant lacking Na(v)1.6 to explore the contribution of these channels to resurgent, transient, and persistent components of TTX-sensitive sodium current in STN neurons. The resurgent current of STN neurons from Na(v)1.6(-/-) mice was reduced by 63% relative to wild-type littermates, a less dramatic reduction than that observed in Purkinje neurons recorded under identical conditions. The transient and persistent currents of Na(v)1.6(-/-) STN neurons were reduced by approximately 40 and 55%, respectively. The resurgent current present in Na(v)1.6(-/-) null STN neurons was similar in voltage dependence to that in wild-type STN and Purkinje neurons, differing only in having somewhat slower decay kinetics. These results show that sodium channels other than Na(v)1.6 can make resurgent sodium current much like that from Na(v)1.6 channels.


Subject(s)
Nerve Tissue Proteins/physiology , Neurons/metabolism , Sodium Channels/physiology , Subthalamic Nucleus/metabolism , Animals , Electric Conductivity , Electrophysiology , Mice , Mice, Knockout , NAV1.6 Voltage-Gated Sodium Channel , Nerve Tissue Proteins/deficiency , Purkinje Cells/physiology , Sodium Channels/deficiency , Subthalamic Nucleus/cytology , Time Factors
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