Biology subjects

Baden, T.

Publications and source records attributed to Baden, T..

At least 19 recordsLinked to original sources

bioRxiv2026

On-Off coding is latent in vertebrate visual circuits

Across sensory systems, neurons often encode stimulus changes of opposite sign as On and Off signals, a fundamental strategy for representing deviations from baseline. In vertebrate vision, this computation is classically attributed to an early, hardwired split in the retina, with segregated pathways subsequently propagated through downstream circuits. Here, we challenge this view. Combining comparative transcriptomics, pharmacology, genetics, in vivo imaging and electrophysiology in zebrafish, with validation in mouse retina, we show that On-Off coding is a latent and intrinsic property of visual circuits. Bipolar cells frequently co-express receptor systems of opposing polarity and can generate mixed responses that are normally suppressed by inhibitory circuitry. Disrupting inhibition or selectively blocking receptor pathways unmasks robust On-Off signalling. In addition, mixed On-Off responses emerge naturally as effective light input increases, including during development and at higher light levels. Across processing stages, including retinal ganglion cells and central neurons, inhibition repeatedly enforces apparent polarity segregation. Thus, polarity splitting is a distributed, dynamically regulated computation rather than a fixed circuit feature. HIGHLIGHTSO_LIMixed On-Off signals are latent across visual processing stages C_LIO_LIInhibition actively sculpts polarity, not just refines it C_LIO_LIPolarity splitting is a dynamic, distributed and reusable computation C_LIO_LIConserved mechanism revealed in zebrafish and mouse C_LI

neuroscience↗

bioRxiv2026

Nanodiamonds for spatial resolution benchmarking in two-photon microscopy

Reliable and reproducible measurement of spatial resolution is essential for validating and comparing the performance of two-photon microscopy systems. We present fluorescent nanodiamonds as robust, photostable, reusable, and biocompatible probes for benchmarking spatial resolution. Owing to their nanoscale dimensions and stable fluorescence, nanodiamonds act as near-ideal point-like emitters, enabling accurate characterisation of the point spread function across varying imaging conditions. We demonstrate that nanodiamond-based phantoms serve as a reliable alternative to conventional fluorescent beads embedded in agarose, while at the same time offering advantages in stability and optical properties. Our results position nanodiamond phantoms as a next-generation calibration material that bridges ease of use and reproducibility, advancing quantitative imaging and cross-platform comparability in modern fluorescence microscopy.

neuroscience↗

bioRxiv2025

A median eye origin of the vertebrate retina explains its unique circuitry

The vertebrate retina is a uniquely complex and evolutionarily conserved structure among bilaterians, combining ciliary (rods and cones) and rhabdomeric (ganglion, amacrine, and horizontal) photoreceptor lineages within a multilayered circuit. This arrangement contrasts with the ancestral bilaterian cephalic pattern, where rhabdomeric photoreceptors dominate lateral eyes and ciliary photoreceptors are limited to unpigmented, non-visual median positions. We propose that the vertebrate retina evolved through the lateralization of a complex median photoreceptive organ already containing both photoreceptor types. This shift likely followed the loss of lateral rhabdomeric eyes in a burrowing, suspension-feeding deuterostome ancestor and the retention of a median eye. In the early chordates leading to vertebrates, this structure diversified into the pineal/parapineal complex and lateral retinas. Central to this transformation was the emergence of a bipolar cellular identity, linking ciliary and rhabdomeric circuits--an unusual feature in animal nervous systems. We suggest bipolar cells have dual evolutionary origins: Off bipolar cells from a ciliary effector lineage and rod- On bipolar cells from a chimeric sensory cell. This model explains key similarities between retina and pineal and supports a scenario in which vertebrate vision emerged by integrating and repurposing preexisting circuits. It reframes the retina not as a de novo innovation, but as a modified and lateralized, solution to sensory challenges faced by early chordates.

neuroscience↗

bioRxiv2024

Vertebrate vision is ancestrally based on competing cone circuits

Vision first evolved in the water, where light becomes increasingly monochromatic with viewing distance. The presence of spectrally broad ( white) light is therefore the exclusive remit of the visual foreground. However, if and how aquatic visual systems exploit this white effect as an inductive bias, for example to judge distance, remains unknown. By combining two-photon imaging with hyperspectral stimulation, genetic cone-type ablation, and behaviour, we here show that zebrafish suppress neural responses to the visual background by contrasting greyscale and colour circuits that emerge at the first synapse of vision. To do so, zebrafish use an early retinal architecture that fundamentally differs from that of mammals: Rather than combining cone signals to drive the retinal output leading to behaviour, zebrafish vision is built around competing ancestral cone systems: Red/UV versus green/blue. Of these, the non-opponent red and UV cones, which are retained in mammals, are necessary and sufficient for vision. By contrast, the colour opponent green and blue cones, which are lost in mammals, form a net-suppressive auxiliary system that shape the core drive from red and UV cones. Our insights challenge the long-held notions that cones act in concert to drive visual behaviour, and that their spectral diversity primarily serves colour vision. Instead, we posit that vertebrate vision is ancestrally built upon opposing cone systems that emerged to exploit the strong spectral interactions of light with water. This alternative view points at terrestrialisation, not nocturnalisation, as the leading driver for visual circuit reorganisation in mammals.

neuroscience↗

bioRxiv2024

Comparative transcriptomic insights into the evolutionary origin of the tetrapod double cone

The tetrapod double cone is a pair of tightly associated cones called the "principal" and the "accessory" member. It is found in amphibians, reptiles, and birds, as well as monotreme and marsupial mammals but is absent in fish and eutherian mammals. To explore the potential evolutionary origins of the double cone, we analyzed single-cell and -nucleus transcriptomic atlases of photoreceptors from six vertebrate species: zebrafish, chicken, lizard, opossum, ground squirrel, and human. Computational analyses separated the principal and accessory members in chicken and lizard, identifying molecular signatures distinguishing either member from single cones and rods in the same species. Comparative transcriptomic analyses suggest that both the principal and accessory originated from ancestral red cones. Furthermore, the gene expression variation among cone subtypes mirrors their spectral order (red[->] green[->] blue[->] UV), suggesting a constraint in their order of emergence during evolution. Finally, we find that rods are equally dissimilar to all cone types, suggesting that they emerged before the spectral diversification of cones.

evolutionary biology↗

bioRxiv2024

A heterogeneous population code at the first synapse of vision

Vision begins when photoreceptors convert light fluctuations into temporal patterns of glutamate release that drive the retinal network. The input-output relation at this first stage has not been systematically measured in vivo so it is not known how it operates across a photoreceptor population. Using kHz-rate glutamate imaging in zebrafish, we find that individual red cones encode visual stimuli with high reliability and time-precision, but routinely vary in sensitivity to luminance, contrast, and frequency across the population. Variations in input-output relations are generated by feedback from the horizontal cell network that effectively decorrelate feature representation. A model capturing how zebrafish sample their visual environment indicates that this heterogeneity expands the dynamic range of the retina to improve the coding of natural scenes. Moreover, we find that different kinetic release components are used to encode distinct stimulus features in parallel: sustained release linearly encodes low amplitude light and dark contrasts, but transient release encodes large amplitude dark contrasts. Together, this study reveals an unprecedented degree of functional heterogeneity within same-type photoreceptors and illustrates how separation of different visual features begins in the first synapse in vision.

neuroscience↗

bioRxiv2023

Restoration of Cone Circuit Functionality in the Regenerating Adult Zebrafish Retina

Unlike humans, teleosts like zebrafish exhibit robust retinal regeneration after injury from endogenous stem cells. However, understanding the functional recovery of the regenerated retina remains a challenge. In particular, it is unclear if regenerating cone-photoreceptors can regain physiological function and integrate correctly into post-synaptic circuits. To bridge this gap, we employed two-photon calcium imaging of living retina, focusing on photoreceptor responses before and after an intense light-induced lesion in the adult zebrafish retina. To assess the functional recovery of cones and their downstream circuits, we exploited the colour opponency in adult zebrafish cones. We find that UV cones exhibit an intrinsic Off-response to short-wavelength blue light, but an On-response to longer-wavelength green light, which depends on feedback signals from outer retinal circuits. Accordingly, we examined the presence and quality of Off-versus On-responses, to assess the functional recovery of cones and their correct integration into outer retinal circuits. We find that regenerated UV cones regain both Off-responses to short-wavelength and On-responses to long-wavelength within 3 months after light lesion. Hence, physiological circuit functionality is restored in regenerated cone photoreceptors, suggesting that inducing endogenous regeneration is a promising strategy for human retinal repair. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=179 SRC="FIGDIR/small/566441v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@c9f038org.highwire.dtl.DTLVardef@1ba255borg.highwire.dtl.DTLVardef@1ea7f60org.highwire.dtl.DTLVardef@50adf3_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Ancient origin of the rod bipolar cell pathway in the vertebrate retina

Vertebrates rely on rod photoreceptors for vision in low-light conditions1. Mammals have a specialized downstream circuit for rod signaling called the primary rod pathway, which comprises specific cell types and wiring patterns that are thought to be unique to this lineage2-6. Thus, it has been long assumed that the primary rod pathway evolved in mammals3, 5-7. Here, we challenge this view by demonstrating that the mammalian primary rod pathway is conserved in zebrafish, which diverged from extant mammals [~]400 million years ago. Using single-cell RNA-sequencing, we identified two bipolar cell (BC) types in zebrafish that are related to mammalian rod BCs (RBCs) of the primary rod pathway. By combining electrophysiology, histology, and ultrastructural reconstruction of the zebrafish RBCs, we found that, like mammalian RBCs8, both zebrafish RBC types connect with all rods and red-cones in their dendritic territory, and provide output largely onto amacrine cells. The wiring pattern of the amacrine cells post-synaptic to one RBC type is strikingly similar to that of mammalian RBCs. This suggests that the cell types and circuit design of the primary rod pathway may have emerged before the divergence of teleost fish and amniotes (mammals, bird, reptiles). The second RBC type in zebrafish, which forms separate pathways from the first RBC type, is either lost in mammals or emerged in fish to serve yet unknown roles. Highlights- Zebrafish have two rod bipolar cell types (RBC1/2). - Synaptic connectivity of RBC1 resembles that of the mammalian RBCs. - The primary rod pathway therefore probably evolved more than 400 million years ago. - The second zebrafish RBC type, RBC2, forms a separate pathway from RBC1.

neuroscience↗

bioRxiv2022

Birds multiplex spectral and temporal visual information via retinal On- and Off-channels

Early retinal circuits divide incoming visual information into functionally opposite elementary signals: On and Off, transient and sustained, chromatic and achromatic. Together these signals can yield an efficient representation of the scene for transmission to the brain via the optic nerve. For example, primate On- and Off-parasol circuits are transient, while On- and Off-midget circuits are sustained. But this long-standing interpretation of retinal function is based on mammals, and it is unclear whether this functional arrangement is common to all vertebrates. Here we show that poultry chicks use a fundamentally different strategy to communicate information from the eye to the brain. Rather than using functionally opposite pairs of retinal output channels, chicks encode the polarity, timing, and spectral composition of visual stimuli in a highly correlated manner: fast achromatic information is encoded by Off-circuits, and slow chromatic information overwhelmingly by On-circuits. Moreover, most retinal output channels combine On- and Off-circuits to simultaneously encode, or multiplex, both achromatic and chromatic information. Our results from birds conform to evidence from fish, amphibians, and reptiles which retain the full ancestral complement of four spectral types of cone photoreceptors. By contrast, mammals lost two of these cones early in their evolution, and we posit that this loss drove a radical simplification and reorganisation of retinal circuits, while birds and many other extant non-mammalian lineages retain the ancestral strategy for retinal image processing. HIGHLIGHTSO_LIFirst large-scale survey of visual functions in an avian retina C_LIO_LIOff-circuits are fast and achromatic, On-circuits are slow and chromatic C_LIO_LIMost avian RGCs are OnOff and encode both types of information C_LIO_LIColour and greyscale information can be decoded based on the kinetics C_LI

neuroscience↗

bioRxiv2022

Amacrine cells shape retinal functions while dynamically preserving circuits for colour vision

In vertebrate vision, the feature-extracting circuits of the inner retina are driven by photoreceptors whose outputs are already pre-processed. In zebrafish, for example, outer retinal circuits split "colour" from "greyscale" information across all four cone-photoreceptor types. How does the inner retina process this incoming spectral information while also combining cone-signals to shape new greyscale functions? We address this question by imaging the light driven responses of amacrine cells (ACs) and bipolar cells (BCs) in larval zebrafish, in the presence and pharmacological absence of inner retinal inhibition. We find that amacrine cells exert distinct effects on greyscale processing depending on retinal region, as well as contributing to the generation of colour opponency in the central retina. However, in the peripheral retina amacrine cells enhanced opponency in some bipolar cells while at the same time suppressing pre-existing opponency in others, such that the net change in the number of colour-opponent units was essentially zero. To achieve this dynamic balance ACs counteracted intrinsic colour opponency of BCs via the On-channel. Consistent with these observations, Off-stratifying ACs were exclusively achromatic, while all colour opponent ACs stratified in the On-sublamina. This study reveals that the central and peripheral retina of larval zebrafish employ fundamentally distinct inhibitory circuits to control the interaction between greyscale- and colour-processing. Differential actions on the On- and Off-channels control the transmission of colour-opponent signals in the periphery.

neuroscience↗

bioRxiv2021

Spectral inference reveals principal cone-integration rules of the zebrafish inner retina

In the vertebrate retina, bipolar cells integrate the signals from different cone types at two main sites: directly, via dendritic inputs in the outer retina, and indirectly, via axonal inputs in the inner retina. Of these, the functional wiring of the indirect route, involving diverse amacrine cell circuits, remains largely uncharted. However, because cone-photoreceptor types differ in their spectral sensitivities, insights into the total functional cone-integration logic of bipolar cell might be gained by linking spectral responses across these two populations of neurons. To explore the feasibility of such a "spectral-circuit-mapping" approach, we here recorded in vivo responses of bipolar cell presynaptic terminals in larval zebrafish to widefield but spectrally resolved flashes of light. We then mapped the results onto the previously established spectral sensitivity functions of the four cones. We find that this approach could explain [~]95% of the spectral and temporal variance of bipolar cell responses by way of a simple linear model that combined weighted inputs from the cones with four stereotyped temporal components. This in turn revealed several notable integration rules of the inner retina. Overall, bipolar cells were dominated by red-cone inputs, often alongside equal sign inputs from blue- and green-cones. In contrast, UV-cone inputs were uncorrelated with those of the remaining cones. This led to a new axis of spectral opponency which was mainly set-up by red-/green-/blue-cone "Off" circuits connecting to "natively-On" UV-cone circuits in the outermost fraction of the inner plexiform layer - much as how key colour opponent circuits are established in mammals. Beyond this, and despite substantial temporal diversity that was not present in the cones, bipolar cell spectral tunings were surprisingly simple. They either approximately resembled both opponent and non-opponent spectral motifs already present in the cones or exhibited a stereotyped non-opponent broadband response. In this way, bipolar cells not only preserved the efficient spectral representations in the cones, but also diversified them to set up a total of six dominant spectral motifs which included three axes of spectral opponency. More generally, our results contribute to an emerging understanding of how retinal circuits for colour vision in ancestral cone-tetrachromats such as zebrafish may be linked to those found in mammals.

neuroscience↗

bioRxiv2021

Center-surround interactions underlie bipolar cell motion sensing in the mouse retina

Motion is a critical aspect of vision. We studied the representation of motion in mouse retinal bipolar cells and found, surprisingly, that some bipolar cells possess motion-sensing capabilities that rely on their center-surround receptive fields. Using a glutamate sensor, we directly observed motion-sensitive bipolar cell synaptic output, which was strongest for local motion and dependent on the motions origin. We characterized bipolar cell receptive fields and found that there are motion and non-motion sensitive bipolar cell types, the majority being motion sensitive. Next, we used these bipolar cell receptive fields along with connectomics to design biophysical models of downstream cells. The models and experiments demonstrated that bipolar cells pass motion-sensitive excitation to starburst amacrine cells through direction-specific signals mediated by bipolar cells center-surround receptive field structure. As bipolar cells provide excitation to most amacrine and ganglion cells, their motion sensitivity may contribute to motion processing throughout the visual system.

neuroscience↗

bioRxiv2021

Eye-Region Specific Ribbon Tuning Supports Distinct Modes of Synaptic Transmission in Same-Type Cone-Photoreceptors

Many sensory systems use ribbon-type synapses to transmit their signals to downstream circuits. The properties of this synaptic transfer fundamentally dictate which aspects in the original stimulus will be accentuated or suppressed, thereby partially defining the detection limits of the circuit. Accordingly, sensory neurons have evolved a wide variety of ribbon geometries and vesicle pool properties to best support their diverse functional requirements. However, the need for diverse synaptic functions does not only arise across neuron types, but also within. Here we show that UV-cones, a single type of photoreceptor of the larval zebrafish eye, exhibit striking differences in their synaptic ultrastructure and consequent calcium to glutamate transfer function depending on their location in the eye. We arrive at this conclusion by combining serial section electron microscopy and simultaneous "dual-colour" 2-photon imaging of calcium and glutamate signals from the same synapse in vivo. We further use the functional dataset to fit a cascade-like model of the ribbon synapse with different vesicle pool sizes, transfer rates and other synaptic properties. Exploiting recent developments in simulation-based inference, we obtain full posterior estimates for the parameters and compare these across different retinal regions. The model enables us to extrapolate to new stimuli and to systematically investigate different response behaviours of various ribbon configurations. We also provide an interactive, easy-to-use version of this model as an online tool. Overall, we show that already on the synaptic level of single neuron types there exist highly specialized mechanisms which are advantageous for the encoding of different visual features.

neuroscience↗

bioRxiv2020

Colourfulness as a possible measure of object proximity in the larval zebrafish brain

The encoding of light increments and decrements by separate On- and Off- systems is a fundamental ingredient of vision, which supports the detection of edges in space and time and makes efficient use of limited dynamic range of visual neurons [1]. Theory predicts that the neural representation of On- and Off-signals should be approximately balanced, including across an animals full visible spectrum. Here we find that larval zebrafish violate this textbook expectation: in the fish brain, UV-stimulation near exclusively gives On-responses, blue/green-stimulation mostly Off- responses, and red-light alone elicits approximately balanced On- and Off-responses (see also [2-4]). We link these findings to zebrafish visual ecology, and suggest that the observed spectral tuning boosts the encoding of object "colourfulness", which correlates with object proximity in their underwater world [5].

neuroscience↗

bioRxiv2020

Near-optimal rotation of colour space by zebrafish cones in vivo

For colour vision, retinal circuits separate information about intensity and wavelength. This requires comparison of at least two spectrally distinct photoreceptors, as in the case of most mammals. However, many vertebrates use the full complement of four ancestral cone-types ( red, green, blue, UV), and in those cases the nature and implementation of this computation remains poorly understood. Here, we establish the complete circuit architecture of outer retinal circuits underlying colour processing in larval zebrafish, which involves the full ancestral complement of four cone- and three horizontal cell types. Our findings reveal that the synaptic outputs of red- and green-cones efficiently rotate the encoding of natural daylight in a principal component analysis (PCA)-like manner to yield primary achromatic and spectrally-opponent axes, respectively. Together, these two cones capture 91.3% of the spectral variance in natural light. Next, blue-cones are tuned so as to capture most remaining variance when opposed to green-cones. Finally, UV-cones present a UV-achromatic axis for prey capture. We note that fruit flies - the only other tetrachromat species where comparable circuit-level information is available - use essentially the same strategy to extract spectral information from their relatively blue-shifted terrestrial visual world. Together, our results suggest that rotating colour space into primary achromatic and chromatic axes at the eyes first synapse may be a fundamental principle of colour vision when using more than two spectrally well-separated photoreceptor types.

neuroscience↗

bioRxiv2020

20 years of African Neuroscience: Waking a sleeping giant

Understanding the function and dysfunction of the brain remains one of the key challenges of our time. However, an overwhelming majority of brain research is carried out in the Global North, by a minority of well-funded and intimately interconnected labs. In contrast, with an estimated one neuroscientist per million people in Africa, news about neuroscience research from the Global South remains sparse. Clearly, devising new policies to boost Africa’s neuroscience landscape is imperative. However, the policy must be based on accurate data, which is largely lacking. Such data must reflect the extreme heterogeneity of research outputs across the continent’s 54 countries distributed over an area larger than USA, Europe and China combined. Here, we analysed all of Africa’s Neuroscience output over the past 21 years. Uniquely, we individually verified in each of 12,326 publications that the work was indeed performed in Africa and led by African-based researchers. This step is critical: previous estimates grossly inflated figures, because many of Africa’s high-visibility publications are in fact the result of internationally led collaborations, with most work done outside of Africa. The remaining number of African-led Neuroscience publications was 5,219, on average only ~5 per country and year. From here, we extracted metrics such as the journal and citations, as well as detailed information on funding, international collaborations and the techniques and model systems used. We link these metrics to demographic data and indicators of mobility and economy. For reference, we also extracted the same metrics from 220 randomly selected publications each from the UK, USA, Australia, Japan and Brazil. Our unique dataset allows us to gain accurate and in-depth information on the current state of African Neuroscience research, and to put it into a global context. This in turn allows us to make actionable recommendations on how African research might best be supported in the future.Competing Interest StatementThe authors have declared no competing interest.View Full Text

scientific communication and education↗

bioRxiv2020

LED Zappelin': An open source LED controller for arbitrary spectrum visual stimulation and optogenetics during 2-photon imaging.

Two-photon (2P) microscopy is a cornerstone technique in neuroscience research. However, combining 2P imaging with spectrally arbitrary light stimulation can be challenging due to crosstalk between stimulation light and fluorescence detection. To overcome this limitation, we present a simple and low-cost electronic solution based on an ESP32 microcontroller and a TLC5947 LED driver to rapidly time-interleave stimulation and detection epochs during scans. Implemented for less than $100, our design can independently drive up to 24 arbitrary spectrum LEDs to meet user requirements. We demonstrate the utility of our stimulator for colour vision experiments on the in vivo tetrachromatic zebrafish retina and for optogenetic circuit mapping in Drosophila. https://github.com/BadenLab/LED-Zappelin

neuroscience↗

bioRxiv2020

What the Zebrafish's Eye Tells the Zebrafish's Brain: Retinal Ganglion Cells for Prey Capture and Colour Vision

In vertebrate vision, the tetrachromatic larval zebrafish permits non-invasive monitoring and manipulating of neural activity across the nervous system in vivo during ongoing behaviour. However, despite a perhaps unparalleled understanding of links between zebrafish brain circuits and visual behaviours, comparatively little is known about what their eyes send to the brain in the first place via retinal ganglion cells (RGCs). Major gaps in knowledge include any information on spectral coding, and information on potentially critical variations in RGC properties across the retinal surface to acknowledge asymmetries in the statistics of natural visual space and behavioural demands. Here, we use in vivo two photon (2P) imaging during hyperspectral visual stimulation as well as photolabeling of RGCs to provide the first eye-wide functional and anatomical census of RGCs in larval zebrafish. We find that RGCs functional and structural properties differ across the eye and include a notable population of UV-responsive On-sustained RGCs that are only found in the acute zone, likely to support visual prey capture of UV-bright zooplankton. Next, approximately half of RGCs display diverse forms of colour opponency - long in excess of what would be required to satisfy traditional models of colour vision. However, most information on spectral contrast was intermixed with temporal information. To consolidate this series of unexpected findings, we propose that zebrafish may use a novel "dual-achromatic" strategy segregated by a spectrally intermediate background subtraction system. Specifically, our data is consistent with a model where traditional achromatic image-forming vision is mainly driven by long-wavelength sensitive circuits, while in parallel UV-sensitive circuits serve a second achromatic system of foreground-vision that serves prey capture and, potentially, predator evasion.

neuroscience↗