Biology subjects

Lagnado, L.

Publications and source records attributed to Lagnado, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Distinct Disinhibitory Circuits Link Short-Term Adaptation to Familiarity and Reward Learning in Visual Cortex

Sensory cortices filter repeated inputs through rapid adaptation over seconds and experience-driven learning over days. Although these forms of plasticity occur simultaneously, it is not known how they interact within cortical circuits. We combined two-photon calcium imaging, data-driven circuit modelling and optogenetics to investigate how short-term adaptation in layer 2/3 of mouse V1 is shaped by stimulus familiarity and reward association. Habituation reduced the fraction of pyramidal cells responsive to a visual stimulus, whereas reward association maintained overall responsivity. In contrast, both forms of learning shifted pyramidal cell adaptation from depression toward sensitization, but through distinct circuit mechanisms. Habituation reduced disinhibition through the VIP[->]SST[->]PC pathway by weakening feedback activation of VIPs and VIP[->]SST connections. Reward association counteracted this effect by increasing disinhibition through the SST[->]PV[->]PC pathway, strengthening SST[->]PV connections while reducing SST[->]PC inputs. Despite engaging distinct disinhibitory circuits and producing divergent effects on pyramidal cell responsivity, both forms of learning converged on a reduced PV:SST input ratio to pyramidal cells, thereby biasing V1 toward sensitizing adaptation. These results identify changes in cortical circuits that link the plasticity of fast adaptation to simple forms of learning.

neuroscience↗

bioRxiv2025

Locomotion Selectively Amplifies Sensitizing Neurons in Primary Visual Cortex

Sensory processing in the cortex reflects both adaptation to external stimuli and changes in internal state. To investigate how these processes interact in layer 2/3 of mouse V1 we combined calcium imaging, optogenetics and circuit modelling. We find that locomotion preferentially increases the responses of pyramidal cells (PCs) that sensitize during visual stimulation compared to those that depress. A model explains this differential modulation through: (i) variations in the strength of PV and SST connectivity to individual PCs, (ii) broad locomotion-dependent weakening of PC and PV synapses, and (iii) reduced SST inhibition targeting sensitizing PCs. Differences in PV:SST input ratios across sensitizing and depressing PCs can be reproduced by a random-connectivity model based on measured interneuron densities, connection probabilities and synaptic strengths. Thus, stochastic variation in local inhibitory connectivity can explain much of the functional heterogeneity across PCs, while state-dependent modulation of inhibitory synapses reorganizes this balance during locomotion to bias cortical population activity towards sensitizing dynamics. The apparently paradoxical combination of increased PC response but decreased synaptic strength is consistent with a state-dependent gating mechanism that boosts signals leaving V1 while simultaneously preventing disruption of the local excitatory-inhibitory balance required for stable computation.

neuroscience↗

bioRxiv2024

Random connectivity generates inhibitory microcircuits that decorrelate adaptation in visual cortex

Inhibitory neurons are fundamental to sensory processing in the cortex but the rules governing their connections with excitatory neurons are unclear. Are pyramidal cells with different functions generated through specific or random connections? We used two-photon imaging, optogenetics and modelling to investigate opposing forms of adaptation in layer 2/3 of mouse visual cortex. We find that a slow modulatory drive acts differentially depending on the relative strength of inputs that individual pyramidal cells receive from parvalbumin-positive and somatostatin-positive interneurons. The number of depressing and sensitizing pyramidal cells could be explained quantitatively by the simplest connectivity rule - all inhbitory synapses made randomly. The functional heterogeneity of the pyramidal cell population therefore begins with general statistics of the connectome - interneurons are much sparser and connect with probabilities far less than one. The resulting "patchwork" of inhibitory microcircuits causes modulatory inputs to strongly decorrelate pyramidal cells on the behavioural time-scale of seconds.

neuroscience↗

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↗

bioRxiv2022

Control algorithms underlying the translational optomotor response

The optomotor response (OMR) is central to the locomotory behavior in diverse animal species including insects, fish and mammals. Furthermore, the study of the OMR in larval zebrafish has become a key model system for investigating the neural basis of sensorimotor control. However, a comprehensive understanding of the underlying control algorithms is still outstanding. In fish it is often assumed that the OMR, by reducing average optic flow across the retina, serves to stabilize position with respect to the ground. Yet the degree to which this assumption is true, and how this could emerge from the intermittent burst dynamics of larval zebrafish swimming is unclear. Here, we combine detailed computational modeling with a new approach to free-swimming experiments, in which feedback gain - i.e., the degree of sensory feedback produced by swimming - is manipulated by varying the height of larval zebrafish above a moving stimulus. We develop an account of underlying feedback control mechanisms that describes not only bout initiation but also the control of swim speed during bouts. We observe that the degree to which fish stabilize their position is only partial and gain-dependent, suggesting that the OMR may not primarily function in fish to prevent drift. We find the speed profile during bouts follows a fixed temporal pattern independent of bout intensity, suggesting that bout termination and bout duration are not explicitly controlled. We also find that the reverse optic flow, experienced when the fish is swimming faster than the stimulus, plays a minimal role in control of the OMR despite carrying most of the sensory information about self-movement. These results shed new light on the underlying dynamics of the OMR in larval zebrafish and will be crucial for future work aimed at identifying the neural basis of this behavior. Author SummaryIn many animals vision is central to the control of locomotory behaviors. In particular, innate motor responses to optic flow allow flying animals to react to gusts of air and fish to changes of current. As fish are washed downstream, for example, movement of the riverbed image across the retina evokes forward movement in bouts (short periods of swimming followed by rest periods). It is typically assumed that this translational optomotor response stabilizes the fishs position to prevent it drifting downstream. In larval zebrafish, this response has become a key model system for investigating the neural basis of sensorimotor behaviors in a vertebrate. Here, we combine behavioral experiments and computational modeling to elucidate the underlying control algorithms. We unpick the detailed relationship between visual stimuli and the initiation, termination and intensity of swim bouts. We find initiation and intensity are controlled separately, and that termination is not explicitly controlled. Surprisingly we also found that the degree of stabilization is only partial and varies systematically with height above ground, raising questions of the function of this response. These findings shed new light on the underlying dynamics which will be crucial for future work to identify the neural basis of this behavior.

animal behavior and cognition↗

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

Multivesicular Release Increases the Efficiency of InformationTransmission at Sensory Synapses

The statistics of vesicle release determine how information is transferred at the synapse but the classical Poisson model of independent fusion does not hold at the first stages of vision and hearing. There, ribbon synapses encoding analogue signals can coordinate the release of two or more vesicles as a single event. The implications of such multivesicular release (MVR) for spike generation are not known. Here we investigate the hypothesis that MVR might provide advantages over Poisson synapses. We used leaky integrate-and-fire models incorporating the statistics of release measured experimentally from glutamatergic synapses of retinal bipolar cells and compared these with models assuming Poisson inputs constrained to operate at the same average rates. We find that MVR can increase the number of spikes generated per vesicle while reducing interspike intervals and latency to first spike. The combined effect was to increase the efficiency of information transfer (bits per spike) over a range of conditions mimicing retinal ganglion cells of different size. MVR was most advantageous in neurons with short time-constants and reliable synaptic inputs, when a lower degree of convergence was required to trigger spikes. In the special case of a single input driving a neuron with short time-constant, as occurs at the first synapse in hearing, MVR increased information transfer whenever spike generation required more than one vesicle. This study demonstrates how presynaptic integration of vesicles by MVR has the potential to compensate for less effective summation post-synaptically to increase the efficiency with which sensory information is transmitted.

neuroscience↗

bioRxiv2021

Diurnal modulation of multivesicular release controls the efficiency of information transmission at a sensory synapse

Neuromodulators adapt sensory circuits to changes in the external world or the animals internal state and synapses are key control sites for such plasticity. Less clear is how neuromodulation alters the amount of information transmitted through the circuit. We investigated this question in the context of the diurnal regulation of visual processing in the retina of zebrafish, focusing on ribbon synapses of bipolar cells. We demonstrate that contrast-sensitivity peaks in the afternoon accompanied by a four-fold increase in the average Shannon information transmitted from an active zone. This increase reflects higher synaptic gain, lower spontaneous "noise" and reduced variability of evoked responses. Simultaneously, an increase in the probability of multivesicular events with larger information content increases the efficiency of transmission (bits per vesicle) by factors of 1.5-2.7. This study demonstrates the multiplicity of mechanisms by which a neuromodulator can adjust the synaptic transfer of sensory information.

neuroscience↗

bioRxiv2020

μSPIM: A Software Platform for Selective Plane Illumination Microscopy

Selective Plane Illumination Microscopy (SPIM) is a fluorescence imaging technique that allows volumetric imaging at high spatio-temporal resolution to monitor neural activity in live organisms such as larval zebrafish. A major challenge in the construction of a custom SPIM microscope is the control and synchronization of the various hardware components. Here we present a control toolset, SPIM, built around the open-source MicroManager platform that has already been widely adopted for the control of microscopy hardware. Installation of SPIM is relatively straightforward, involving a single C++ executable and a Java-based extension to Micro-Manager. Imaging protocols are defined through the SPIM extension to Micro-Manager. The extension then synchronizes the camera shutter with the galvanometer mirrors to create a light-sheet that is scanned in the z-dimension, in synchrony with the imaging objective, to produce volumetric recordings. A key advantage of SPIM is that a series of calibration procedures optimizes acquisition for a given set-up making it relatively independent of the optical design of the microscope, or the hardware used to build it. Two laser illumination arms can be used while also allowing for the introduction of illumination masks. SPIM allows imaging of calcium activity throughout the brain of larval zebrafish at rates of 100 planes per second with single cell resolution as well as slower imaging to reconstruct cell populations, for example, in the cleared brains of mice.

neuroscience↗

bioRxiv2020

Modulation of the vesicle code transmitting the visual signal in the retina

Multivesicular release (MVR) allows retinal bipolar cells to transmit visual signals as changes in both the rate and amplitude of synaptic events. How do neuromodulators reguate this vesicle code? By imaging larval zebrafish, we find that the variability of calcium influx is a major source of synaptic noise. Dopamine increases synaptic gain up to 15-fold while Substance P reduces it 7-fold, both by acting on the presynaptic calcium transient to alter the distribution of amplitudes of multivesicular events. An increase in gain is accompanied by a decrease in the temporal precision of transmission and a reduction in the efficiency with which vesicles transfer visual information. The decrease in gain caused by Substance P was also associated with a shift in temporal filtering from band-pass to low-pass. This study demonstrates how neuromodulators act on the synaptic transformation of the visual signal to alter the way information is coded with vesicles.

neuroscience↗

bioRxiv2020

Opposing forms of adaptation in mouse visual cortex are controlled by distinct inhibitory microcircuits and gated by locomotion

Cortical processing of sensory signals adjusts to changes in both the external world and the internal state of the animal. We investigated the neural circuitry by which these processes interact in the primary visual cortex of mice. An increase in contrast caused as many pyramidal cells (PCs) to sensitize as depress, reflecting the dynamics of adaptation in different types of interneuron (PV, SST and VIP). Optogenetic manipulations demonstrate that the net effect within PCs reflects the balance of PV inputs, driving depression, and a subset of SST interneurons, driving sensitization. Locomotor behaviour increased the gain of PC responses by disinhibition through both the VIP->SST and SST->PV pathways, thereby maintaining the balance between opposing forms of plasticity. These experiments reveal how inhibitory microcircuits interact to purpose different subsets of PCs for the signalling of increases or decreases in contrast while also allowing for behavioural control of gain across the population.

neuroscience↗

bioRxiv2019

Motor behaviour selectively inhibits hair cells activated by forward motion in the lateral line of Zebrafish

How do sensory systems disambiguate events in the external world from signals generated by the motor behaviour of the animal? One strategy is to suppress the sensory input whenever the motor system is active, but the cellular mechanisms remain unclear. We investigated how motor behaviour modulates signals transmitted by the lateral line of zebrafish, which senses pressure changes around the body of the animal. Activation of motor neurons during fictive swimming caused co-activation of efferent fibers and suppression of synaptic transmission from the primary mechanoreceptors, the hair cells. In some hair cells, a single motor spike inhibited glutamate release by about 50% and block was often complete within 50-100 ms of the start of swimming. All hair cells polarized to be activated by posterior deflections, as would occur during forward swimming, were suppressed by >90%, while only half of those polarized in the anterior direction were inhibited and by an average of just 45%. The selective inhibition of hair cells activated during motor behaviour provides a mechanism for the suppression of self-generated signals while maintaining sensitivity to stimuli originating in the external world.

neuroscience↗

bioRxiv2019

Correction of z-motion artefacts to allow population imaging of synaptic activity in awake behaving mice

Functional imaging of head-fixed, awake, behaving mice using two-photon imaging of fluorescent activity reporters has become a powerful tool in the studying the function of the brain. Motion artefacts are an inevitable problem during such experiments and are routinely corrected for in x and y dimensions. However, axial (z) shifts of several microns can also occur, leading to intensity fluctuations in structures such as synapses that are small compared to the axial point-spread function of the microscope. Here we present a simple strategy to correct z-motion artefacts arising over the course of a time-series experiment in a single optical plane. Displacement in z was calculated using dye-filled blood vessels as an anatomical marker, providing high contrast images and accuracy to within [~]0.1 {micro}m. The axial profiles of ROIs corresponding to synapses were described using a Moffat function and this \"ROI-spread function\" used to correct activity traces on an ROI-by-ROI basis. We demonstrate the accuracy and utility of the procedures in simulation experiments using fluorescent beads and then apply them to correcting measurements of synaptic activity in populations of vasoactive-intestinal peptide (VIP) interneurons expressing the synaptic reporter SyGCaMP6f. Correction of z-motion artefacts had a substantial impact on the apparent correlation between synaptic activity and running speed, demonstrating the importance of correcting for these artefacts for the interpretation of in vivo imaging experiments in awake mice.\n\nSummary of Key PointsO_LIMotion artefacts associated with motor behaviour are an inevitable problem of multiphoton imaging in awake behaving animals, particularly imaging synapses.\nC_LIO_LICorrection of axial motion usually requires volumetric imaging resulting in slower rates of acquisition.\nC_LIO_LIWe describe a method that is easy to implement to correct z-motion artefacts that allows population imaging of synaptic activity while scanning a single plane in a standard multiphoton microscope.\nC_LIO_LIThe method uses a reference volume acquired in two colour channels - an activity reporter and an anatomical marker of blood vessels. The procedure estimates the z-displacement in every frame and applies an intensity correction in which the z point-spread function for each synapse is modelled as a Moffat function.\nC_LIO_LIWe demonstrate that the method allows synaptic calcium activity signals to be collected from populations of synaptic boutons in mouse primary visual cortex during locomotion.\nC_LI

neuroscience↗

bioRxiv2019

Approximate Bayesian Inference for a Mechanistic Model of Vesicle Release at a Ribbon Synapse

The inherent noise of neural systems makes it difficult to construct models which accurately capture experimental measurements of their activity. While much research has been done on how to efficiently model neural activity with descriptive models such as linear-nonlinear-models (LN), Bayesian inference for mechanistic models has received considerably less attention. One reason for this is that these models typically lead to intractable likelihoods and thus make parameter inference difficult. Here, we develop an approximate Bayesian inference scheme for a fully stochastic, biophysically inspired model of glutamate release at the ribbon synapse, a highly specialized synapse found in different sensory systems. The model translates known structural features of the ribbon synapse into a set of stochastically coupled equations. We approximate the posterior distributions by updating a parametric prior distribution via Bayesian updating rules and show that model parameters can be efficiently estimated for synthetic and experimental data from in vivo two-photon experiments in the zebrafish retina. Also, we find that the model captures complex properties of the synaptic release such as the temporal precision and outperforms a standard GLM. Our framework provides a viable path forward for linking mechanistic models of neural activity to measured data.

neuroscience↗

bioRxiv2019

Retinal outputs depend on behavioural state

The operating mode of the visual system depends on behavioural states such as arousal1,2. This dependence is seen both in primary visual cortex3-7 (V1) and in subcortical brain structures receiving direct retinal input4,8. Here we show that this effect arises as early as in the output of the retina. We first measured activity in a region that receives retinal projections9, the superficial superior colliculus (sSC), and found that this activity strongly depended on behavioural state. This modulation was not mediated by feedback inputs from V1 as it was immune to V1 inactivation. We then used Neuropixels probes10 to record activity in the optic tract, and we found some retinal axons whose activity significantly varied with arousal, even in darkness. To characterize these effects on a larger sample of retinal outputs, we imaged the activity of retinal boutons11,12 in sSC during behaviour using a calcium indicator. The activity of these boutons correlated with arousal as strongly as that of sSC neurons, and this correlation persisted also during darkness. These results reveal a novel property of retinal function in mice, which could be observed only during behaviour: retinal outputs are modulated by behavioural state before they reach the rest of the brain.

neuroscience↗

bioRxiv2018

A retinal circuit generating a dynamic predictive code for orientated features

Sensory systems must reduce the transmission of redundant information to function efficiently. One strategy is to continuously adjust the sensitivity of neurons to suppress responses to common features of the input while enhancing responses to new ones. Here we image both the excitatory synaptic inputs and outputs of retinal ganglion cells to understand how such dynamic predictive coding is implemented in the analysis of spatial patterns. Synapses of bipolar cells become tuned to orientation through presynaptic inhibition generating lateral antagonism in the orientation domain. Individual ganglion cells receive excitatory synapses tuned to different orientations but feedforward inhibition generates a high-pass filter that only transmits the initial activation of these inputs, thereby removing redundancy. These results demonstrate how a dynamic predictive code can be implemented by circuit motifs common to many parts of the brain.

neuroscience↗

bioRxiv2018

An amplitude code increases the efficiency of information transmission across a visual synapse

Most neurons in the brain transmit information digitally using sequences of spikes that trigger release of synaptic vesicles of fixed size. The first stages of vision and hearing are distinct in operating with analogue signals, but it is unclear how these are recoded for synaptic transmission. By imaging the release of glutamate in live zebrafish, we demonstrate how ribbon synapses of retinal bipolar cells transmit analogue visual signals by changes in both the rate and amplitude of synaptic events. Higher contrasts released glutamate packets composed of more vesicles and coding by amplitude often continued after rate coding had saturated. Glutamate packets equivalent to five vesicles transmitted four times as many bits of information per vesicle compared to independent release events. By discretizing analogue signals into sequences of numbers ranging up to eleven, ribbon synapses increase the dynamic range, temporal precision and efficiency with which visual information is transmitted.

neuroscience↗

bioRxiv2018

Spikeling: a low-cost hardware implementation of a spiking neuron for neuroscience teaching and outreach.

Understanding of how neurons encode and compute information is fundamental to our study of the brain, but opportunities for hands-on experience with neurophysiological techniques on live neurons are scarce in science education. Here, we present Spikeling, an open source {pound}25 in silico implementation of a spiking neuron that mimics a wide range of neuronal behaviours for classroom education and public neuroscience outreach. Spikeling is based on an Arduino microcontroller running the computationally efficient Izhikevich model of a spiking neuron. The microcontroller is connected to input ports that simulate synaptic excitation or inhibition, dials controlling current injection and noise levels, a photodiode that makes Spikeling light-sensitive and an LED and speaker that allows spikes to be seen and heard. Output ports provide access to variables such as membrane potential for recording in experiments or digital signals that can be used to excite other connected Spikelings. These features allow for the intuitive exploration of the function of neurons and networks. We also report our experience of using Spikeling as a teaching tool for undergraduate and graduate neuroscience education in Nigeria and the UK.

scientific communication and education↗