Biology subjects

Favre-Bulle, I. A.

Publications and source records attributed to Favre-Bulle, I. A..

11 recordsLinked to original sources

bioRxiv2026

Whole-brain cellular-resolution functional network properties of seizure susceptibility

Despite its prevalence and clinical impacts, epilepsy remains incompletely understood in terms of the population dynamics that mediate seizure susceptibility, initiation, and propagation across brain-wide networks. In this study, we have performed calcium imaging in zebrafish, brain-wide and at cellular resolution, at baseline and as seizures are induced using the GABAA receptor antagonist pentylenetetrazol (PTZ). We have then modeled the network architecture in wild-type and scn1lab-/- larvae, which are seizure-prone and serve as a model for Dravet syndrome. scn1lab-/- larvae show increased pair-wise correlations between neurons when exposed to PTZ, and graph analyses of these correlations revealed genotype-specific network alterations during seizures, identifying regions and metrics linked to seizure onset. Using generative network modeling, we then explored the wiring rules that govern activity in these networks, identifying specific network properties linked to seizure susceptibility that were only detectable using large-scale, cellular-resolution data. Even at baseline in the absence of seizures, these rules differed by genotype in a way that enabled the identification of scn1lab-/- larvae and predicted individuals seizure risk independently of their observable phenotype. These findings uncover the cellular-resolution network properties of a zebrafish model of Dravet syndrome and establish a predictive framework for seizure susceptibility grounded in multi-scale functional connectivity.

neuroscience↗

bioRxiv2024

Brain-wide circuitry underlying altered auditory habituation in zebrafish models of autism.

Auditory processing is widely understood to occur differently in autism, though the patterns of brain activity underlying these differences are not well understood. The diversity of autism also means brain-wide networks may change in various ways to produce similar behavioral outputs. We used larval zebrafish to investigate auditory habituation in four genetic lines relevant to autism: fmr1, mecp2, scn1lab and cntnap2. In free-swimming behavioral tests, we found each line had a unique profile of auditory hypersensitivity and/or delayed habituation. Combining the optical transparency of larval zebrafish with genetically encoded calcium indicators and light-sheet microscopy, we then observed brain-wide activity at cellular resolution during auditory habituation. As with behavior, each line showed unique alterations in brain-wide spontaneous activity, auditory processing, and adaptation in response to repetitive acoustic stimuli. We also observed commonalities in activity across our genetic lines that indicate shared circuit changes underlying certain aspects of their behavioral phenotypes. These were predominantly in regions involved in sensory integration and sensorimotor gating rather than primary auditory areas. Overlapping phenotypes include differences in the activity and functional connectivity of the telencephalon, thalamus, dopaminergic regions, and the locus coeruleus, and excitatory/inhibitory imbalance in the cerebellum. Unique phenotypes include loss of activity in the habenula in scn1lab, increased activity in auditory regions in fmr1, and differences in network activity over time in mecp2 and cntnap2. Comparing these distinct but overlapping brain-wide auditory networks furthers our understanding of how diverse genetic factors can produce similar behavioral effects through a range of circuit- and network-scale mechanisms.

neuroscience↗

bioRxiv2024

Phylogenetically-Preserved Multiscale Neuronal Activity: Iterative Coarse-Graining Reconciles Scale-Dependent Theories of Brain Function

Brain recordings collected at different resolutions support statistically distinct signatures of information processing, leading to scale-dependent theories of brain function. Here, we demonstrate that these disparate neural-coding signatures emerge from the same multiscale functional organisation of neuronal activity across calcium-imaging recordings collected from the whole brains of zebrafish and nematode, as well as sensory regions of the fly, mouse, and macaque brain. Network simulations show that hierarchical-modular structural connectivity facilitates multiscale functional coordination, enhancing information processing benefits such as a maximal dynamic range. Finally, we demonstrate that this cross-scale organisation supports distinct behavioural states across species by reconfiguring functional affiliation and temporal dynamics at the mesoscale. Our findings suggest that self-similar scaling of neuronal activity is a universal principle that reconciles scale-dependent theories of brain function, facilitating both efficiency and resiliency while enabling significant reconfiguration of mesoscale cellular ensembles to accommodate behavioural demands.

neuroscience↗

bioRxiv2024

Evidence for auditory stimulus-specific adaptation but not deviance detection in larval zebrafish brains

Animals receive a constant stream of sensory input, and detecting changes in this sensory landscape is critical to their survival. One signature of change detection in humans is the auditory mismatch negativity (MMN), a neural response to unexpected stimuli that deviate from a predictable sequence. This process requires the auditory system to adapt to specific repeated stimuli while remaining sensitive to novel input (stimulus-specific adaptation). MMN was originally described in humans, and equivalent responses have been found in other mammals and birds, but it is not known to what extent this deviance detection circuitry is evolutionarily conserved. Here we present the first evidence for stimulus-specific adaptation in the brain of a teleost fish, using whole-brain calcium imaging of larval zebrafish at single-neuron resolution with selective plane illumination microscopy. We found frequency-specific responses across the brain with variable response amplitudes for frequencies of the same volume, and created a loudness curve to model this effect. We presented an auditory oddball stimulus in an otherwise predictable train of pure tone stimuli, and did not find a population of neurons with specific responses to deviant tones that were not otherwise explained by stimulus-specific adaptation. Further, we observed no deviance responses to an unexpected omission of a sound in a repetitive sequence of white noise bursts. These findings extend the known scope of auditory adaptation and deviance responses across the evolutionary tree, and lay groundwork for future studies to describe the circuitry underlying auditory adaptation at the level of individual neurons.

neuroscience↗

bioRxiv2024

Brain-wide impacts of sedation on spontaneous activity and auditory processing in larval zebrafish

Despite their widespread use, we have limited knowledge of the mechanisms by which sedatives mediate their effects on brain-wide networks. This is, in part, due to the technical challenge of observing activity across large populations of neurons in normal and sedated brains. In this study, we examined the effects of the sedative dexmedetomidine, and its antagonist atipamezole, on spontaneous brain dynamics and auditory processing in zebrafish larvae. Our brain-wide, cellular-resolution calcium imaging reveals, for the first time, the brain regions involved in these network-scale dynamics and the individual neurons that are affected within those regions. Further analysis reveals a variety of dynamic changes in the brain at baseline, including marked reductions in spontaneous activity, correlation, and variance. The reductions in activity and variance represent a "quieter" brain state during sedation, an effect that causes highly correlated evoked activity in the auditory system to stand out more than it does in un-sedated brains. We also observe a reduction in auditory response latencies across the brain during sedation, suggesting that the removal of spontaneous activity leaves the core auditory pathway free of impingement from other non-auditory information. Finally, we describe a less dynamic brain-wide network during sedation, with a higher energy barrier and a lower probability of brain state transitions during sedation. In total, our brain-wide, cellular-resolution analysis shows that sedation leads to quieter, more stable, and less dynamic brain, and that against this background, responses across the auditory processing pathway become sharper and more prominent. Significance StatementAnimals brain states constantly fluctuate in response to their environment and context, leading to changes in perception and behavioral choices. Alterations in perception, sensorimotor gating, and behavioral selection are hallmarks of numerous neuropsychiatric disorders, but the circuit- and network-level underpinnings of these alterations are poorly understood. Pharmacological sedation alters perception and responsiveness and provides a controlled and repeatable manipulation for studying brain states and their underlying circuitry. Here, we show that sedation of larval zebrafish with dexmedetomidine reduces brain-wide spontaneous activity and locomotion but leaves portions of brain-wide auditory processing and behavior intact. We describe and computationally model changes at the levels of individual neurons, local circuits, and brain-wide networks that lead to altered brain states and sensory processing during sedation.

neuroscience↗

bioRxiv2020

Broad frequency sensitivity and complex neural coding in the larval zebrafish auditory system

Most animals have complex auditory systems that identify salient features of the acoustic landscape to direct appropriate responses. In fish, these features include the volume, frequency, complexity, and temporal structure of auditory stimuli transmitted through water. Larval fish have simple brains compared to adults, but swim freely and depend on sophisticated sensory processing for survival. Zebrafish larvae, an important model for studying brain-wide neural networks, have thus far been found to possess a rudimentary auditory system, sensitive to a narrow range of frequencies and without evident sensitivity to auditory features that are salient and ethologically important to adult fish. Here, we have combined a novel method for delivering water-borne sounds, a diverse assembly of acoustic stimuli, and whole-brain calcium imaging to describe the responses of individual auditory neurons across the brains of zebrafish larvae. Our results reveal responses to frequencies ranging from 100Hz to 4kHz, with evidence of frequency discrimination from 100Hz to 2.5kHz. Frequency-selective neurons are located in numerous regions of the brain, and neurons responsive to the same frequency are spatially grouped in some regions. Using functional clustering, we identified categories of neurons that are selective for pure tones of a single frequency, white noise, the sharp onset of auditory stimuli, and stimuli involving a gradual crescendo. These results suggest a more nuanced auditory system than has previously been described in larval fish and provide insights into how a young animals auditory system can both function acutely and serve as the scaffold of a more complex adult system.

neuroscience↗

bioRxiv2020

Sound generation in zebrafish with Bio-Opto-Acoustics (BOA)

Hearing is a crucial sense in underwater environments for communication, hunting, attracting mates, and detecting predators. However, the tools currently used to study hearing are limited, as they cannot controllably stimulate specific parts of the auditory system. To date, the contributions of hearing organs have been identified through lesion experiments that inactivate an organ, but this makes it difficult to gauge the specific stimuli to which each organ is sensitive, or the ways in which inputs from multiple organs are combined during perception. Here, we introduce Bio-Opto-Acoustic (BOA) stimulation, using optical forces to generate localized sound in vivo, and demonstrate stimulation of the auditory system of zebrafish larvae with unprecedented control. We use a rapidly oscillated optical trap to generate vibrations in individual otolith organs that are perceived as sound, while adjacent otoliths are either left unstimulated or similarly stimulated with a second optical laser trap. The resulting brain-wide neural activity is characterized using fluorescent calcium indicators, thus linking each otolith organ to its individual neuronal network in a way that would be impossible using traditional sound delivery methods. The results reveal integration and cooperation of the utricular and saccular otoliths, which were previously described as having separate biological functions, during hearing.

biophysics↗

bioRxiv2020

Brain-wide mapping of water flow perception in zebrafish

Information about water flow, detected by lateral line organs, is critical to the behavior and survival of fish and amphibians. While certain specific aspects of water flow processing have been revealed through electrophysiology, we lack a comprehensive description of the neurons that respond to water flow and the network that they form. Here, we use brain-wide calcium imaging in combination with microfluidic stimulation to map out, at cellular resolution, all neurons involved in perceiving and processing water flow information in larval zebrafish. We find a diverse array of neurons responding to forward flow, reverse flow, or both. Early in this pathway, in the lateral line ganglia, these are almost exclusively neurons responding to the simple presence of forward or reverse flow, but later processing includes neurons responding specifically to flow onset, representing the accumulated volume of flow during a stimulus, or encoding the speed of the flow. The neurons reporting on these more nuanced details are located across numerous brain regions, including some not previously implicated in water flow processing. A graph theory-based analysis of the brain-wide water flow network shows that a majority of this processing is dedicated to forward flow detection, and this is reinforced by our finding that details like flow velocity and the total volume of accumulated flow are only encoded for the simulated forward direction. The results represent the first brain-wide description of processing for this important modality, and provide a departure point for more detailed studies of the flow of information through this network. Significance statementIn aquatic animals, the lateral line is important for detecting water flow stimuli, but the brain networks that interpret this information remain mysterious. Here, we have imaged the activity of individual neurons across the entire brains of larval zebrafish, revealing all response types and their brain locations as water flow processing occurs. We find some neurons that respond to the simple presence of water flow, and others that are attuned to the flows direction, speed, duration, or the accumulated volume of water that has passed during the stimulus. With this information, we modeled the underlying network, describing a system that is nuanced in its processing of water flow simulating forward motion but rudimentary in processing flow in the reverse direction.

neuroscience↗

bioRxiv2019

Brain-wide visual habituation networks in wild type and fmr1 zebrafish

Habituation is a form of learning during which animals stop responding to repetitive stimuli, and deficits in habituation are characteristics of several psychiatric disorders. Due to the technical challenges of measuring brain activity comprehensively and at cellular resolution, the brain-wide networks mediating habituation are poorly understood. Here we report brain-wide calcium imaging during visual learning in larval zebrafish as they habituate to repeated threatening loom stimuli. We show that different functional categories of loom-sensitive neurons are located in characteristic locations throughout the brain, and that both the functional properties of their networks and the resulting behavior can be modulated by stimulus saliency and timing. Using graph theory, we identify a principally visual circuit that habituates minimally, a moderately habituating midbrain population proposed to mediate the sensorimotor transformation, and downstream circuit elements responsible for higher order representations and the delivery of behavior. Zebrafish larvae carrying a mutation in the fmr1 gene have a systematic shift towards sustained premotor activity in this network, and show slower behavioral habituation. This represents the first description of a visual learning network across the brain at cellular resolution, and provides insights into the circuit-level changes that may occur in people with Fragile X syndrome and related psychiatric conditions.

neuroscience↗

bioRxiv2019

Altered brain-wide auditory networks in fmr1-mutant larval zebrafish

Altered sensory processing is characteristic of several psychiatric conditions, including autism and fragile X syndrome (FXS). Here, we use whole-brain calcium imaging at cellular resolution to map sensory processing in wild type larval zebrafish and mutants for fmr1, which causes FXS in humans. Using functional analyses and graph theory, we describe increased transmission and reduced filtering of auditory information, resulting in network-wide hypersensitivity analogous to the auditory phenotypes seen in FXS.

neuroscience↗

bioRxiv2018

Cellular resolution imaging of vestibular processing across the larval zebrafish brain

The vestibular system, which reports on motion and gravity, is essential to postural control, balance, and egocentric representations of movement and space. The motion needed to stimulate the vestibular system complicates studying its circuitry, so we previously developed a method for fictive vestibular stimulation in zebrafish, using optical trapping to apply physical forces to the otoliths. Here, we combine this fictive stimulation with whole-brain calcium imaging at cellular resolution, delivering a comprehensive map of the brain regions and cellular responses involved in basic vestibular processing. We find these responses to be broadly distributed across the brain, with unique profiles of cellular responses and topography in each brain region. The most widespread and abundant responses involve excitation that is rate coded to the stimulus strength. Other responses, localized to the telencephalon and habenulae, show excitation that is only weakly rate coded and that is sensitive to weak stimuli. Finally, numerous brain regions contain neurons that are inhibited by vestibular stimuli, and these inhibited neurons are often tightly localised spatially within their regions. By exerting separate control over the left and right otoliths, we explore the laterality of brain-wide vestibular processing, distinguishing between neurons with unilateral and bilateral vestibular sensitivity, and revealing patterns by which conflicting vestibular signals from the two ears can be mutually cancelling. Our results show a broader and more extensive network of vestibular responsive neurons than has previously been described in larval zebrafish, and provides a framework for more targeted studies of the underlying functional circuits.

neuroscience↗