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Connections of dopaminergic and AII amacrine cells. AII amacrine cells transfer rod signals from rod bipolars to the axonal endings of on- and off-cone bipolars. The synapses of DA cells onto the perikaryon of AII amacrines (arrowheads) are situated near the origin of the primary dendrite(s). Because there is no comprehensive morphological analysis of the rodent retina, neurons in the diagram are drawn in the style of Polyak (42).
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In the retina, dopaminergic amacrine (interplexiform) cells establish multiple synapses on the perikarya of AII amacrines, the neurons that distribute rod signals to on- and off-cone bipolars. We used triple-label immunocytochemistry and confocal microscopy to identify the receptors contained within the postsynaptic active zone of these synapses in...
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... crine he dopaminergic (DA) cells], neurons either amacrine of the retina or interplexiform [dopaminergic ama- cells, establish synapses on AII amacrines (1–4), a neuronal type inserted in series along the pathway that carries dim light signals to ganglion cells ( Fig. 1). The neurotransmitter released at these synapses is not known but, in addition to dopamine, ␥ -aminobu- tyric acid (GABA) is a candidate, because both this molecule and its synthetic enzyme glutamic acid decarboxylase are present in the perikarya of DA cells (5–7). In addition to this conven- tional synaptic output onto AII amacrines, DA cells act on more distant targets, because the released dopamine, diffusing throughout the intercellular spaces of the retina, binds to a family of metabotropic receptors distributed on the surface of most retinal neurons and thus participates in setting the gain of the retina for vision in bright light (8). Colocalization of dopamine with other transmitters seems to be the rule in the central nervous system: GABA is contained in periglomerular cells of the olfactory bulb (5) and in a subpopu- lation of neurons of the substantia nigra (9), whereas glutamate may be present in the remaining nigral neurons and in those of the ventral tegmental area (VTA) (10, 11). VTA neurons make excitatory glutamatergic autapses when maintained as micro- cultures (11); however, in the intact tissue it is not known which transmitter is released at the synapse and the identity of the postsynaptic receptors. The contacts between DA cells and AII amacrines in the rodent retina represent an ideal site to identify the postsynaptic receptors by immunocytochemistry and triple-label confocal microscopy. First, the synaptic partners can be stained with antibodies to different cell-filling antigens: DA cells contain tyrosine hydroxylase (TH), the rate-limiting enzyme in dopa- mine biosynthesis (12–14), whereas AII amacrines contain Dab1, the product of the disabled-1 gene, in the mouse (15) and the calcium-binding protein parvalbumin (PV) in the rat (16). Second, AII amacrine cells are the most common amacrine cell type in the mammalian retina (17). Third, in stratum S1 of the inner plexiform layer (IPL) the dendro-somatic DA-to-AII amacrine cell synapses are numerous (3, 18) and easily identified, because they occur at the site where the processes of DA cells form a ring around the origin of the primary dendrite(s) of AII amacrines (2, 19, 20). In this article, we report that the relative distribution of pre- and postsynaptic markers strongly suggests that the DA-to-AII amacrine cell synapses are GABAergic. Electron Immunocytochemistry. Microscopy. A Adult transgenic C57BL mouse ͞ 6J mice line was and used Long–Evans in which rats DA were cells given in the a lethal retina dose expressed of sodium human pentobarbital placental and alkaline their eyes phosphatase were enucleated. (PLAP) on Posterior the outer eyecups surface were of the immersed cell membrane. in Ames medium, These animals and retinas were were obtained separated by introducing from the remaining into the mouse ocular tunics. genome The PLAP specimens cDNA linked were to immersed a promoter in 2% sequence formaldehyde of the gene in 0.15 for TH M (21). S ̈renson Details phosphate of the technique buffer (pH of specimen 7.4) in 30-mm preparation petri dishes and staining and fixed for for alkaline 15–17 phosphatase s in a microwave activity oven were (Pelco; described Ted Pella, (21). Briefly, Inc., Redding, adult mice, CA). homozygous Upon irradiation, for PLAP the temperature cDNA, were of the anesthetized fixative increased by i.p. injection by 30–40°C. of 0.1 ml Retinas of a solution were subsequently containing rinsed 5% ketamine in PBS HCl (pH (Ketaset; 7.4), cryoprotected Fort Dodge in Laboratories, 20% sucrose, Fort and frozen Dodge, in IA) the and liquid 1% xylazine phase of (Rompun; partially solidified Bayer, Shawnee monochlorodi- Mission, fluoromethane. KS). They were perfused Radial and through horizontal the heart sections with 2% 5–10 formalde- m in hyde and 1% glutaraldehyde in S ̈rensen phosphate buffer (pH 7.4), after rinsing the vascular tree with carboxygenated Ames medium (Sigma) containing 40 mM glucose. Whole retinas were kept in the fixative fluid for 2 h at room temperature, heated in PBS at 65°C for 30 min, and carefully rinsed with 5% sucrose in 0.2 M cacodylate buffer (pH 7.4) to eliminate phosphate ions. Specimens were then incubated for 8–24 h at room temperature under constant, mild agitation in a  -glycerophosphate, alkaline lead citrate solution (21). They were subsequently postfixed in 3% glutaraldehyde, followed by osmium-ferrocyanide and stain- ing en bloc with uranyl acetate. After embedding and thin sectioning, micrographs were obtained with a JEOL 1200EX electron microscope. Immunocytochemistry. Adult C57BL ͞ 6J mice and Long–Evans rats were given a lethal dose of sodium pentobarbital and their eyes were enucleated. Posterior eyecups were immersed in Ames medium, and retinas were separated from the remaining ocular tunics. The specimens were immersed in 2% formaldehyde in 0.15 M S ̈renson phosphate buffer (pH 7.4) in 30-mm petri dishes and fixed for 15–17 s in a microwave oven (Pelco; Ted Pella, Inc., Redding, CA). Upon irradiation, the temperature of the fixative increased by 30–40°C. Retinas were subsequently rinsed in PBS (pH 7.4), cryoprotected in 20% sucrose, and frozen in the liquid phase of partially solidified monochlorodi- fluoromethane. Radial and horizontal sections 5–10 m in thickness Antibodies were and Dilutions. obtained Primary. in a Rabbit cryostat polyclonal and stained to Dab1, with a gift the indirect from B. Howell fluorescence (Neurogenetics, antibody technique. National Institute of Neurolog- ical Disorders and Stroke ͞ National Institutes of Health, Be- thesda), 1:500; rabbit polyclonal to PV (no. PC255L, Oncogene Research Products, Boston), 1:4,000; mouse monoclonal to PV Antibodies and Dilutions. Primary. Rabbit polyclonal to Dab1, a gift from B. Howell (Neurogenetics, National Institute of Neurolog- ical Disorders and Stroke ͞ National Institutes of Health, Be- thesda), 1:500; rabbit polyclonal to PV (no. PC255L, Oncogene Research Products, Boston), 1:4,000; mouse monoclonal to PV clone PARV-19 (no. P3088, Sigma), 1:1,000; sheep polyclonal to TH (no. NB 300-110, Novus Biologicals, Littleton, CO), 1:500; rabbit polyclonal to TH (no. AB152, Chemicon), 1:500; mouse monoclonal to TH (no. 22941, DiaSorin, Stillwater, MN), 1:100; guinea pig polyclonal to the ␣ 3 subunit of the G 〈〉〈 type A (GABA A ) receptor, a gift from J.-M. Fritschy (University of Zurich, Zurich), 1:1,000; rabbit polyclonal to the ␣ 1 subunit of the GABA A receptor, a gift from W. Sieghart (University of Vienna, Vienna), 1.8 g ͞ ml; rabbit polyclonal to GABA (no. AB141, Chemicon), 1:300; rabbit polyclonal to the vesicular GABA transporter, a gift from R. H. Edwards (University of California, San Francisco), 1:2,000; rabbit polyclonal to the vesicular monoamine transporter-2, a gift from R. H. Edwards, 1:1,000; rat monoclonal antibody to dopamine receptor D1, clone 1-1-F11 s.E6 (no. D-187, Sigma), 1:400; and rabbit poly- clonal to dopamine receptors D2 ͞ 3 (no. 3949-1007, Biogenesis, Kingston, NH), 1:100. Primary antibodies were diluted in 2% BSA (Sigma) in PBS. Secondary. FITC donkey anti-guinea pig (no. 706-095-148, Jack- son ImmunoResearch), 1:200; Oregon green 488 donkey anti-rat (no. A-21208, Molecular Probes), 1:150; Oregon green 488 goat anti-rabbit (no. 0-638, Molecular Probes), 1:200; Alexafluor 568 goat anti-mouse (no. A-11031, Molecular Probes), 1:200; Alex- afluor 568 goat anti-rabbit (no. A-1103, Molecular Probes), 1:200; Alexafluor 660 donkey anti-sheep (no. A-21101, Molec- ular Probes), 1:200; Alexaf luor 660 goat anti-mouse (no. A-21054, Molecular Probes), 1:200; and Alexafluor 660 goat anti-rabbit (no. A-21054, Molecular Probes), 1:200. Secondary antibodies were diluted with 2% BSA, 1% normal goat serum (Vector Laboratories), and 0.2% fish gelatin (Goldmark Bio- logicals, Phillipsburg, NJ) in PBS. Staining. Sections were preincubated in 2% BSA, 10% normal goat serum, and 2% fish gelatin in PBS; incubated ...
Citations
... It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted September 5, 2023. ; https://doi.org/10.1101/2023.09.05.556383 doi: bioRxiv preprint dopaminergic amacrine cells around the cell bodies of postsynaptic AII amacrine cells (Voigt and Wassle, 1987;Casini et al., 1995;Contini and Raviola, 2003) . Dendro-somatic synaptic interactions were also shown to occur at regular ganglion cell bodies with great functional impact (Grimes et al., 2022) and could represent a circuit motif for amacrine-dRGCs interactions in the INL as well. ...
The mammalian retina contains many distinct types of ganglion cells, which form mosaics to evenly tile the retina with cells of each type at each position of the visual field. It is well known that displaced retinal ganglion cells (dRGCs) exist with cell bodies in the inner nuclear layer, along with regularly placed RGCs with cell bodies in the ganglion cell layer. A prominent example of dRGCs are M1-type intrinsically photosensitive ganglion cells (ipRGCs) which exist in various species including humans and non-human primates. Little is known, however, about their spatial relationship with regularly placed ipRGCs.
Here, we identified mouse ipRGC types M1, M2, and M4/sONɑ by immunohistochemistry and light microscopy to anatomically investigate the distribution of displaced and regularly placed cells. Reconstruction of immunolabeled dendritic mosaics from M1 and sONɑ RGCs indicated that dRGCs tiled the retina evenly with their regularly placed RGC partners. Multi-electrode array recordings revealed conventional receptive fields of displaced sONɑ RGCs which fit into the functional mosaic of their regularly placed counterparts. We further analyzed the RGC distributions across complete retinas. The analysis of regularly placed M1 ipRGCs and ɑRGCs revealed distinct density gradients where ∼16% and ∼8% occurred as dRGCs, respectively. The density distributions of dRGCs showed type-specific patterns which followed neither the global density distribution of all ganglion cells nor the local densities of corresponding cell types.
Our study shows that the displacement of ganglion cell bodies into the inner nuclear layer occurs in a type-dependent manner, where dRGCs are positioned to form complete mosaics with their regularly placed RGC partners. Our data suggest that dRGCs and regularly placed RGCs serve the same functional role within their corresponding population of ganglion cells.
Significance statement
We applied large-scale anatomical and electrophysiological experiments in mice to show that displaced intrinsically photosensitive retinal ganglion cells (ipRGCs) complete the mosaics of their regularly placed counterparts with their dendritic trees and receptive fields. Therefore, displaced ipRGCs likely serve the same functional role as corresponding regularly placed cells. The density distributions of displaced ipRGCs showed distinct, type-specific patterns. Interestingly, they followed neither the global density distribution of all ganglion cells nor the local densities of corresponding cell types.
... There are a series of small oscillations visible on the ascending limb of the b-wave, termed the oscillatory potentials (OPs) that derive from spiking amacrine cells that use dopamine, GABA, and glycine as their main neurotransmitters (Wachtmeister and Dowling, 1978;Wachtmeister, 1980Wachtmeister, , 1981Wachtmeister, , 1998Contini and Raviola, 2003;Diamond, 2017). The descending limb of the b-wave is shaped by contribution from the retinal ganglion cells (RGCs; Viswanathan et al., 2001) and is termed the photopic negative response (PhNR; Frishman et al., 2018). ...
The retina and brain share similar neurochemistry and neurodevelopmental origins, with the retina, often viewed as a “window to the brain.” With retinal measures of structure and function becoming easier to obtain in clinical populations there is a growing interest in using retinal findings as potential biomarkers for disorders affecting the central nervous system. Functional retinal biomarkers, such as the electroretinogram, show promise in neurological disorders, despite having limitations imposed by the existence of overlapping genetic markers, clinical traits or the effects of medications that may reduce their specificity in some conditions. This narrative review summarizes the principal functional retinal findings in central nervous system disorders and related mouse models and provides a background to the main excitatory and inhibitory retinal neurotransmitters that have been implicated to explain the visual electrophysiological findings. These changes in retinal neurochemistry may contribute to our understanding of these conditions based on the findings of retinal electrophysiological tests such as the flash, pattern, multifocal electroretinograms, and electro-oculogram. It is likely that future applications of signal analysis and machine learning algorithms will offer new insights into the pathophysiology, classification, and progression of these clinical disorders including autism, attention deficit/hyperactivity disorder, bipolar disorder, schizophrenia, depression, Parkinson’s, and Alzheimer’s disease. New clinical applications of visual electrophysiology to this field may lead to earlier, more accurate diagnoses and better targeted therapeutic interventions benefiting individual patients and clinicians managing these individuals and their families.
... 210 GABA(A) and GABA(C) agonists decreases DA release in the retina, whereas GABA antagonists increase DA release.209,211 Moreover, amacrine cells release GABA molecules which bind to fast-acting ionotropic receptors in the retina.212,213 In FDM, the DA and GABAergic neurotransmitter pathways interact. ...
Myopia is far beyond its inconvenience and represents a true, highly prevalent, sight-threatening ocular condition, especially in Asia. Without adequate interventions, the current epidemic of myopia is projected to affect 50% of the world population by 2050, becoming the leading cause of irreversible blindness. Although blurred vision, the predominant symptom of myopia, can be improved by contact lenses, glasses or refractive surgery, corrected myopia, particularly high myopia, still carries the risk of secondary blinding complications such as glaucoma, myopic maculopathy and retinal detachment, prompting the need for prevention. Epidemiological studies have reported an association between outdoor time and myopia prevention in children. The protective effect of time spent outdoors could be due to the unique characteristics (intensity, spectral distribution, temporal pattern, etc.) of sunlight that are lacking in artificial lighting. Concomitantly, studies in animal models have highlighted the efficacy of light and its components in delaying or even stopping the development of myopia and endeavoured to elucidate possible mechanisms involved in this process. In this narrative review, we (1) summarize the current knowledge concerning light modulation of ocular growth and refractive error development based on studies in human and animal models, (2) summarize potential neurobiological mechanisms involved in the effects of light on ocular growth and emmetropization and (3) highlight a potential pathway for the translational development of noninvasive light-therapy strategies for myopia prevention in children.
... A panel of monoclonal and polyclonal antibodies was generated against full-length recombinant human TH (Fig. 1a), and quality assessment was performed by standard ELISA, Western blotting, and appropriate cell and tissue staining. These novel antibodies behaved in all respects similar to a widely used commercial TH antibody (Fig. 1b, AB152, Millipore-Sigma) [48][49][50][51] . A mouse monoclonal antibody, MCA-4H2, and a rabbit polyclonal, RPCA-TH, were selected as ELISA capture and detection antibodies, respectively. ...
Most, if not all, peripheral immune cells in humans and animals express tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis. Since TH is typically studied in the context of brain catecholamine signaling, little is known about changes in TH production and function in peripheral immune cells. This knowledge gap is due, in part, to the lack of an adequately sensitive assay to measure TH in immune cells expressing lower TH levels compared to other TH expressing cells. Here, we report the development of a highly sensitive and reproducible Bio-ELISA to quantify picogram levels of TH in multiple model systems. We have applied this assay to monocytes isolated from blood of persons with Parkinson’s disease (PD) and to age-matched, healthy controls. Our study unexpectedly revealed that PD patients’ monocytes express significantly higher levels of TH protein in peripheral monocytes relative to healthy controls. Tumor necrosis factor (TNFα), a pro-inflammatory cytokine, has also been shown to be increased in the brains and peripheral circulation in human PD, as well as in animal models of PD. Therefore, we investigated a possible connection between higher levels of TH protein and the known increase in circulating TNFα in PD. Monocytes isolated from healthy donors were treated with TNFα or with TNFα in the presence of an inhibitor. Tissue plasminogen activator (TPA) was used as a positive control. We observed that TNFα stimulation increased both the number of TH+ monocytes and the quantity of TH per monocyte, without increasing the total numbers of monocytes. These results revealed that TNFα could potentially modify monocytic TH production and serve a regulatory role in peripheral immune function. The development and application of a highly sensitive assay to quantify TH in both human and animal cells will provide a novel tool for further investigating possible PD immune regulatory pathways between brain and periphery.
... A panel of monoclonal and polyclonal antibodies was generated against full-length recombinant human TH (Fig. 1a), and quality assessment was performed by standard ELISA, Western blotting, and appropriate cell and tissue staining. These novel antibodies behaved in all respects similar to a widely used commercial TH antibody (Fig. 1b, AB152, Millipore-Sigma) [48][49][50][51] . A mouse monoclonal antibody, MCA-4H2, and a rabbit polyclonal, RPCA-TH, were selected as ELISA capture and detection antibodies, respectively. ...
Most, if not all, peripheral immune cells in humans and animals express tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis. Since TH is typically studied in the context of brain catecholamine signaling, little is known about changes in TH production and function in peripheral immune cells. This knowledge gap is due, in part, to the lack of an adequately sensitive assay to measure TH in immune cells expressing lower TH levels compared to other TH expressing cells. Here, we report the development of a highly sensitive and reproducible Bio-ELISA to quantify picogram levels of TH in multiple model systems. We have applied this assay to monocytes isolated from blood of persons with Parkinson's disease (PD) and to age-matched, healthy controls. Our study unexpectedly revealed that PD patients' monocytes express significantly higher levels of TH protein in peripheral monocytes relative to healthy controls. Tumor necrosis factor (TNF), a pro- inflammatory cytokine, has also been shown to be increased in the brains and peripheral circulation in human PD, as well as in animal models of PD. Therefore, we investigated a possible connection between higher levels of TH protein and the known increase in circulating TNF in PD. Monocytes isolated from healthy donors were treated with TNF or with TNF in the presence of an inhibitor. Tissue plasminogen activator (TPA) was used as a positive control. We observed that TNF stimulation increased both the number of TH+ monocytes and the quantity of TH per monocyte, without increasing the total numbers of monocytes. These results revealed that TNF could potentially modify monocytic TH production and serve a regulatory role in peripheral immune function. The development and application of a highly sensitive assay to quantify TH in both human and animal cells will provide a novel tool for further investigating possible PD immune regulatory pathways between brain and periphery.
... In the mouse, the DACs have a small cell body, their ramifications reach the S3 layer (Contini et al. 2010;Zhang et al. 2004Zhang et al. , 2007 and receive input from the ON BCs (Contini et al. 2010;Zhang et al. 2007) via the rod pathway (Pérez-Fernández et al. 2019;Zhao et al. 2017). DACs also release GABA like other ACs (Contini & Raviola 2003;Hirasawa et al. 2009Hirasawa et al. , 2012Hirasawa et al. , 2015. Dopamine receptors are found both in the OPL and IPL, respectively on HCs (Flood et al. 2018;Klaassen et al. 2011;Mazade et al. 2019;Pflug et al. 2008;Teranishi et al. 1983;Vaney 1994;Veruki & Wässle 1996), RGCs (Cui et al. 2017;Dearry et al. 1991;Ikeda et al. 1986;Jensen & Daw 1984;Thier & Alder 1984;Veruki & Wässle 1996;Wagner et al. 1993) and ACs, acting onto the gap junctions between ACs in the IPL (Hampson et al. send the output to the brain via the optic nerve and the optic tract (Lettvin et al. 1959). ...
The retinopetal system is composed of neurons located in the brain which send signals to the retina by passing their axons through the optic nerve. In mammals, it is suggested that these neurons reside in regions such as the dorsal raphe nucleus (serotonergic) and the posterior hypothalamus (histaminergic), and some physiological effects of serotonin and histamine in the retina have been demonstrated at the single-neuron level by ex vivo studies. However, it remains to be clarified what the exact origins and targets of the retinopetal system are, and how it affects the visual signals processing in the retina in vivo. Ex vivo recordings of the retina are standards in the field; however, the procedure to obtain such recordings requires to cut the optic nerve, and therefore disrupt the retinopetal fibres. To study the retinal functions while keeping the retinopetal system intact, I have established an in vivo electrophysiological recording technique from the axons of retinal ganglion cells inside the optic tract of a mouse in response to a set of visual stimuli. I have also established an analysis pipeline of such recordings and others, such as two-photon Calcium imaging data from retinal ganglion cell axons in the superior colliculus. By comparing the retinal outputs in awake mice with those under anesthesia, I found a substantial improvement in the speed and sensitivity of the visual responses in awake mice. These results confirm the importance of in vivo recordings to fully understand retinal function and demonstrate the impact of anaesthesia on retinal processing, thus advising caution with the use of anaesthetics for studying the visual system. My thesis study will thus serve as a milestone for a future study of the retinopetal system.
... Dies bedeutet, dass die antagonistische Struktur der rezeptiven Felder der BZ und GZ verkleinert wird, da die HZ darauf einen inhibitorischen Effekt haben. Außerdem wurde beschrieben, dass die Glutamatübertragung an den Photorezeptoren durch DA dahingehend verändert wird, dass Zapfensignale verstärkt werden und Stäbchensignale vermindert werden (Witkovsky, 2004;Witkovsky et al., 1989 (Contini & Raviola, 2003;Hampson et al., 1992;Witkovsky, 2004). ...
Die Aufmerksamkeitsdefizit-Hyperaktivitätsstörung im Erwachsenenalter unterliegt wahrscheinlich einem Ungleichgewicht der Neurotransmitter Dopamin und Noradrenalin im Gehirn. Eine verminderte Dopaminaktivität geht dabei mit einem erhöhten neuronalen Rauschen im präfrontalen Kortex einher, wie Tierstudien zeigen. Dopamin spielt auch in der Retina eine wichtige Rolle bei der Kontrastwahrnehmung, die mittels Pattern-Elektroretinogramm gemessen werden kann. ADHS-Patienten zeigen an der Retina ein erhöhtes Hintergrundrauschen. Zum einen soll hier dieser Befund überprüft werden und der Einfluss von Kontrast und Mustergröße auf die Rauschamplitude weiter untersucht werden. Zum anderen soll mit Methylphenidat der Einfluss eines dopaminwirksamen Medikaments beobachtet werden.
Bei 20 erwachsenen ADHS-Patienten und 21 Kontrollpersonen wurde die Rauschamplitude der Retina mittels PERG zu zwei Zeitpunkten gemessen, welche bei den Patienten vor und während der Therapie mit MPH stattfanden. Es wurden Schachbrettmuster mit drei verschiedenen Mustergrößen (0.17°, 1.4° und 16°) und zwei Kontrasten (16% und 50%) dargeboten.
Therapienaive ADHS-Patienten hatten eine signifikant höhere retinale Rauschamplitude als gesunde Kontrollpersonen. Diese war unabhängig vom Stimulus und zeigte bei mittelgroßen Schachbrettmustern mit geringem Kontrast den stärksten Gruppenunterschied. Therapierte Patienten zeigten eine signifikant niedrigere Rauschamplitude als vor der Therapie, welche auf das Niveau der Kontrollpersonen absank. Die Kontrollpersonen zeigten in einer Wiederholungsmessung keine signifikante Änderung der Rauschamplitude.
Die Ergebnisse unterstützen die Hypothese, dass neuronales Hintergrundrauschen an der Retina ein neurobiologisches Korrelat der ADHS darstellt. Mit dem PERG stünde somit eine objektive Methode zur Unterstützung der Diagnostik zur Verfügung. Auch ein Therapiemonitoring wäre damit in Zukunft denkbar.
... M1 ipRGCS are postsynaptic to dopaminergic amacrine cells (and also drive them reciprocally (Zhang et al., 2008), which release both dopamine and GABA (Contini and Raviola, 2003;Vugler et al., 2007;Do and Yau, 2010). Dopamine has diverse effects in the retina, and thus ipRGCs could regulate retinal physiology. ...
At the sensitivity limit of vision, the quantal fluctuations of light and neural noise in the retina and the brain limit the detection of light signals. The challenge for vision, as for all senses, lies in separating the weakest signals from the neural noise originating within the sensory system. In this thesis, I studied sparse signal detection in the vertebrate visual system (mouse and frog) at low light levels from single retinal neurons to behavioral performance.
First, we determined the sensitivity limit of amphibian color vision at low light levels. Unlike most vertebrates, amphibians are potential dichromats even at night, with two spectrally distinct classes of rod photoreceptors: common vertebrate rods (peak sensitivity at 500 nm) and an additional class called “green rods” (peak sensitivity at 430 nm). We showed that frogs in a phototaxis experiment can distinguish blue from green down to their absolute visual threshold, meaning that they have wavelength discrimination as soon as they start seeing anything. Remarkably, the behavioral blue/green discrimination approached theoretical limits set by photon fluctuations and rod noise, highlighting the sensitivity of the system comparing signals from the two different photoreceptors. Additionally, we show that the amphibian threshold for color discrimination is task- and context-dependent, underlining that sensory discrimination is not universally driven to absolute physical limits, but depends on evolutionary trade-offs and flexible brain states.
In the second paper, we studied the impact of the circadian rhythm on the sensitivity limit of mouse vision. The retina has its own intrinsic circadian rhythms, which has led to the hypothesis that the sensitivity limit of vision would be under circadian control. We used a simple photon detection task, which allowed us to link well-defined retinal output signals to visually guided behavior. We found that mice have strikingly better performance in the visual task at night, so that they can reliably detect 10-fold dimmer light in the night than in the day. Interestingly, and contrary to previous hypotheses, this sensitivity difference did not arise in the retina, as assessed by spike recordings from retinal ganglion cells. Instead, mice utilize a more efficient search strategy in the task during the night. They are even able to apply the more efficient strategy at day once they have first performed the task during the night. Measured differences in search strategy explain only part of the day/night difference, however. We hypothesize that in addition there are diurnal changes in the state of brain circuits reading out the retinal input and making decisions.
In the third paper, we determined the sensitivity limit of decrement (shadow) detection of mouse vision. Compared with the question of ultimate limit for detecting light, the question of sensitivity limits for detecting light decrements (negative contrast) has been remarkably neglected. We recorded the OFF responses of the most sensitive retinal ganglion cells at dim background light levels and correlated the thresholds to visually guided behavior in tightly matched conditions. We show that compared with an ideal- observer model most of the losses happen in the retina and remarkably, the behavioral performance is very close to an optimal read-out of the retinal ganglion cells.
I have shown across visual tasks and in two different species how closely behavior in specific conditions can approach the performance limit set by physical constraints, rejecting noise and making use of every available photon. However, the actual performance strongly depends on the behavioral context and relevance of the task and state of the brain.
... Classically, these neurons were identified as ETCs (Halász et al., 1981;Davis and Macrides, 1983). However, this classification is no longer used because ETCs are glutamatergic and excitatory (Hayar et al., 2004), while OB dopamine neurons (like retinal dopamine neurons: Wulle and Wagner, 1990;Contini and Raviola, 2003;Hirasawa et al., 2009;Yan et al., 2020) express GAD-67 and GABA and are thus inhibitory (Kosaka et al., 1985(Kosaka et al., , 1987(Kosaka et al., , 1995Gall et al., 1987;Baker, 1990;Wilson and Wood, 1992;Kosaka and Kosaka, 2007;Maher and Westbrook, 2008;Kiyokage et al., 2010;Borisovska et al., 2013;Liu et al., 2013). Currently, OB dopamine neurons are typically classified as either PGCs or SACs. ...
... At photopic light, this reduced coupling may increase acuity by decreasing the receptive fields of inner retinal neurons (BCs, ACs, and RGCs) that receive coupled excitatory or synaptic inhibitory (glycinergic) input from the AII ACs (Demb and Singer, 2012). Dopaminergic retinal neurons further affect the AII ACs by releasing GABA onto the AC somas, likely under the same lighting conditions at which dopamine is released (Contini and Raviola, 2003). This GABAergic inhibition from dopamine neurons also affects the ON-BCs (which provide the excitatory input onto the phasic group of dopamine neurons - Zhang et al., 2007) in the ON (stratum 3) portion of the IPL (Contini et al., 2010). ...
In the central nervous system, dopamine is well-known as the neuromodulator that is involved with regulating reward, addiction, motivation, and fine motor control. Yet, decades of findings are revealing another crucial function of dopamine: modulating sensory systems. Dopamine is endogenous to subsets of neurons in the retina and olfactory bulb (OB), where it sharpens sensory processing of visual and olfactory information. For example, dopamine modulation allows the neural circuity in the retina to transition from processing dim light to daylight and the neural circuity in the OB to regulate odor discrimination and detection. Dopamine accomplishes these tasks through numerous, complex mechanisms in both neural structures. In this review, we provide an overview of the established and emerging research on these mechanisms and describe similarities and differences in dopamine expression and modulation of synaptic transmission in the retinas and OBs of various vertebrate organisms. This includes discussion of dopamine neurons’ morphologies, potential identities, and biophysical properties along with their contributions to circadian rhythms and stimulus-driven synthesis, activation, and release of dopamine. As dysregulation of some of these mechanisms may occur in patients with Parkinson’s disease, these symptoms are also discussed. The exploration and comparison of these two separate dopamine populations shows just how remarkably similar the retina and OB are, even though they are functionally distinct. It also shows that the modulatory properties of dopamine neurons are just as important to vision and olfaction as they are to motor coordination and neuropsychiatric/neurodegenerative conditions, thus, we hope this review encourages further research to elucidate these mechanisms.
... The inputs to the AII somas and proximal (OFF layer) dendrites ( Figure 3B and C1, right) were not considered in as much detail because these were few in number and presumed to arise from dopaminergic ACs (DACs) (Contini and Raviola, 2003;Gustincich et al., 1997;Voigt and Wässle, 1987). Indeed, when we traced 8 neurites presynaptic to the soma and proximal dendrites of a single AII, we identified 113 output synapses in total, 90 (80%) of which were to neighbor AIIs and 23 to other cells ( Figure 3C5). ...
Night vision in mammals depends fundamentally on rod photoreceptors and the well-studied rod bipolar (RB) cell pathway. The central neuron in this pathway, the AII amacrine cell (AC), exhibits a spatially tuned receptive field, composed of an excitatory center and an inhibitory surround, that propagates to ganglion cells, the retina’s projection neurons. The circuitry underlying the surround of the AII, however, remains unresolved. Here, we combined structural, functional and optogenetic analyses of the mouse retina to discover that surround inhibition of the AII depends primarily on a single interneuron type, the NOS-1 AC: a multistratified, axon-bearing GABAergic cell, with dendrites in both ON and OFF synaptic layers, but with a pure ON (depolarizing) response to light. Our study demonstrates generally that novel neural circuits can be identified from targeted connectomic analyses and specifically that the NOS-1 AC mediates long-range inhibition during night vision and is a major element of the RB pathway.
