Biology subjects

Yaksi, E.

Publications and source records attributed to Yaksi, E..

17 recordsLinked to original sources

bioRxiv2026

Snurportin-1 maintains muscle niche integrity and myogenic progenitor homeostasis

Loss-of-function variants in SNUPN, encoding the nuclear import factor Snurportin-1 (SPN1) required for spliceosomal small nuclear ribonucleoprotein (snRNP) transport, cause a recently described form of limb-girdle muscular dystrophy (LGMD). However, the role of SPN1 in skeletal muscle homeostasis remains poorly understood, in part due to the lack of a suitable in vivo model. Here, we generated a zebrafish snupn loss-of-function model that recapitulates key features of the skeletal muscle phenotype observed in patients. Mutant larvae developed severe locomotor impairment by 6 days post-fertilization (dpf), accompanied by sarcomeric disorganization and impaired muscle fiber integrity. Transcriptomic profiling at 6 dpf revealed widespread alternative splicing and transcriptional dysregulation, with prominent alterations in extracellular matrix and basement membrane components, together with upregulation of stress- and inflammation-associated genes. Notably, these late-stage abnormalities were preceded by disruption of the muscle progenitor population at 2 dpf, with reduced Pax7 progenitor abundance and myogenic gene expression together with altered muscle differentiation and organization. Together, these findings identify SPN1 as a key regulator of skeletal muscle homeostasis linking RNA processing to extracellular niche integrity and myogenic progenitor maintenance. This zebrafish model provides an in vivo platform for dissecting LGMD-associated disease mechanisms and developing therapeutic strategies aimed at restoring muscle function and regenerative capacity.

genetics↗

bioRxiv2025

Hierarchical processing of sensory information across topographically organized thalamocortical-like circuits in the zebrafish brain

Thalamocortical projections contribute to the spatial organization and functional hierarchies of the mammalian cortex. Primary sensory cortices receive topographically segregated information from first-order thalamic nuclei, which process distinct sensory modalities. In contrast, higher-order cortical regions integrate information from multiple information channels. While such hierarchical processing and integration of information is the foundation for neural computations in the mammalian cortex, the fundamental principles of thalamocortical computations in non-mammalian vertebrates remains unexplored. The zebrafish pallium, located in the dorsal telencephalon, is regarded as the homolog of the mammalian cortex. However, it remains unclear how the zebrafish pallium receives and processes sensory information, and how the architecture and function of these processes compare to the thalamocortical circuits in other vertebrates. Using anatomical tracing, electrophysiological circuit mapping, and in vivo Ca2+ imaging, we revealed a thalamocortical-like pathway in the zebrafish brain. We found that the preglomerular nucleus (PG) is the primary source of visual and mechano-vibrational information to the zebrafish pallium. We demonstrated that PG neurons and their pallial projections exhibit sensory-specific and topographically organized responses. In contrast, the sensory responses of pallial neurons display multiple layers of topographically organized hierarchies, ranging from simple sensory-specific responses to multimodal and coincidence-detecting nonlinear responses. Notably, we observed a progressive increase in the complexity of sensory computations, which is organized topographically along the posterior-anterior axis of the zebrafish pallium. Collectively, our results suggest that hierarchical sensory processing across topographically organized pallial regions is a conserved functional feature of the vertebrate pallium.

neuroscience↗

bioRxiv2025

Topographically organized dorsal raphe activity modulates forebrain sensory-motor computations and adaptive behaviors.

The dorsal raphe nucleus (DRN) plays an important role in shaping a wide range of behaviors, including mood, motivation, appetite, sleep, and social interactions. Reflecting these diverse roles, the DRN is composed of molecularly distinct and topographically organized groups of neurons that target specific regions of the forebrain. Despite these insights, fundamental questions remain regarding how DRN neurons process sensory information, what do DRN communicate to forebrain, and the role of DRN inputs in forebrain computations and animal behavior. To address these questions, we investigated the spatiotemporal activity patterns of DRN neurons, along with DRN axons and their targets in the juvenile zebrafish forebrain. Our findings revealed a remarkable topographic organization of ongoing activity and sensory-motor responses within the DRN. We discovered that a large fraction of DRN neurons are primarily driven by animals locomotor activity. We also observed that an anterior group of DRN neurons, marked by Gad1, exhibited distinct activity patterns during rest, locomotor activity and sensory stimulation. DRN axons broadly innervating the forebrain exhibit topographically organized excitation and inhibition in response to sensory stimulation and motor activity. Notably, we observed significant and rapid covariation between the activity of DRN axons and nearby forebrain neurons. Chemogenetic ablation of the DRN led to a marked reduction in the synchrony and sensory-motor responses across forebrain neurons, accompanied by significant deficits in adaptive behaviors. Collectively, our findings revealed the functional diversity of DRN neurons and their role in transmitting sensory and locomotor signals via topographically organized projections, which can regulate forebrain activity and play a crucial role in modulating animal behavior.

neuroscience↗

bioRxiv2024

Inhibition mediated by group III mGluRs regulates habenula activity and defensive behaviors

Inhibition contributes to various brain computations from sensory motor transformations to cognitive operations. While most studies on inhibition focus on GABA, the main excitatory neurotransmitter of the brain, glutamate, can also elicit inhibition via metabotropic glutamate receptors (mGluRs). The function of mGluR-mediated inhibition remains largely elusive. Here, we investigated the role of group III mGluR-dependent inhibition in the habenula. This primarily glutamatergic and conserved forebrain region acts as a hub between multiple forebrain inputs and neuromodulatory mid- and hindbrain targets that regulate adaptive behaviors. We showed that both zebrafish and mice habenula express group III mGluRs. We identified that group III mGluRs regulate the membrane potential and calcium activity of zebrafish dorsal habenula. Pharmacological and genetic perturbation of group III mGluRs increased sensory-evoked excitation and reduced selectivity of habenular neurons to different sensory modalities. We also observed that inhibition is the main channel of communication between primarily glutamatergic habenula neurons. Blocking group III mGluRs reduced inhibition within habenula and increased correlations during spontaneous activity. In line with such inhibition within habenula, we identified that multi-sensory information is integrated mainly through competition and suppression across habenular neurons, which in part relies on group III mGluRs. Finally, genetic perturbation of a habenula-specific group III mGluR, mGluR6a, amplified neural responses and defensive behaviors evoked by sensory stimulation and environmental changes. Altogether, our results revealed that mGluR driven inhibition is essential in encoding, integration, and communication of information between Hb neurons, ultimately playing a critical role in regulating defensive and adaptive behaviors.

neuroscience↗

bioRxiv2024

Cilia-mediated cerebrospinal fluid flow modulates neuronal and astroglial activity in the zebrafish larval brain.

The brain uses a specialized system to transport cerebrospinal fluid (CSF). This system consists of interconnected ventricles lined by ependymal cells, which generate a directional flow upon beating of their motile cilia. Motile cilia act jointly with other physiological factors, including active CSF secretion and cardiac pressure gradients, to regulate CSF dynamics. The content and movement of CSF are thought to be important for brain physiology. Yet, the link between cilia-mediated CSF flow and brain function is poorly understood. In this study, we addressed the role of motile cilia-mediated CSF flow on brain development and physiology using zebrafish larvae as a model system. By analyzing mutant animals with paralyzed cilia, we identified that loss of ciliary motility did not alter progenitor proliferation, overall brain morphology, or spontaneous neural activity. Instead, we identified that cilia paralysis led to randomization of brain asymmetry. We also observed altered neuronal responses to photic stimulation, especially in the optic tectum and hindbrain. Since astroglia contact CSF at the ventricular walls and are essential for regulating neuronal activity, we next investigated astroglial activity in motile cilia mutants. Our analyses revealed a striking reduction in astroglial calcium signals both during spontaneous and light-evoked activity. Altogether, our findings highlight a novel role of motile cilia-mediated flow in regulating brain physiology through modulation of neural and astroglial networks.

neuroscience↗

bioRxiv2023

Loss of cilia after neurulation impacts brain development and neuronal activity in larval zebrafish

Cilia are slender, hair-like structures extending from cell surfaces and playing essential roles in diverse physiological processes. Within the nervous system, primary cilia contribute to signaling and sensory perception, while motile cilia facilitate cerebrospinal fluid flow. Here, we investigated the impact of ciliary loss on neural circuit development using a zebrafish line displaying ciliogenesis defects. We found that cilia loss after neurulation affects neurogenesis and brain morphology, and lead to altered gene expression profiles. Using whole brain calcium imaging, we measured reduced light-evoked and spontaneous neuronal activity in all brain regions. By shedding light on the intricate role of cilia in neural circuit formation and function in the zebrafish, our work highlights their evolutionary conserved role in the brain and set the stage for future analysis of ciliopathy models.

neuroscience↗

bioRxiv2023

Foxj1 controls olfactory ciliogenesis and differentiation program of the olfactory sensory neurons

In vertebrates, olfactory receptors localize on multiple cilia elaborated on dendritic knobs of olfactory sensory neurons (OSNs). Although olfactory cilia dysfunction can cause anosmia, how their differentiation is programmed at the transcriptional level has remained largely unexplored. We discovered in zebrafish and mice that Foxj1, a forkhead domain-containing transcription factor linked with motile cilia biogenesis, is expressed in OSNs and required for olfactory epithelium (OE) formation. In keeping with the immotile nature of olfactory cilia, we observed that ciliary motility genes are repressed in zebrafish, mouse, and human OSNs. Strikingly, we also found that besides ciliogenesis, Foxj1 controls the differentiation of the OSNs themselves by regulating their cell type-specific gene expression, such as that of olfactory marker protein (omp) involved in odor-evoked signal transduction. In line with this, response to bile acid, an odor detected by OMP-positive OSNs, was significantly diminished in foxj1 mutant zebrafish. Taken together, our findings establish how the canonical Foxj1-mediated motile ciliogenic transcriptional program has been repurposed for the biogenesis of immotile olfactory cilia and for development of the OSNs.

neuroscience↗

bioRxiv2022

Elevated photic response is followed by a rapid decay and depressed state in ictogenic networks

The switch between non-seizure and seizure states involves profound alterations in network excitability and synchrony. Both increased and decreased excitability may underlie the state transitions, as shown in epilepsy patients and animal models. Inspired by video-electroencephalography recordings in patients, we developed a framework to study spontaneous and photic-evoked neural and locomotor activity in zebrafish larvae. We combined high-throughput behavioral tracking and whole-brain in vivo two-photon calcium imaging to perform side-by-side comparison of multiple zebrafish seizure and epilepsy models. Our setup allowed us to dissect behavioral and physiological features that are divergent or convergent across multiple models. We observed that locomotor and neural activity during interictal and spontaneous ictal periods exhibit great diversity across models. Yet, during photic stimulation, hyperexcitability and rapid response dynamics was well conserved across multiple models, highlighting the reliability of photic-evoked seizure activity for high-throughput assays. Intriguingly, in several models, we observed that the initial elevated photic response is often followed by fast decay of neural activity and a prominent depressed state. We argue that such depressed states are likely due to homeostatic mechanisms triggered by excessive neural activity. An improved understanding of the interplay between elevated and depressed excitability states might suggest tailored epilepsy therapies. KEY POINTSO_LIFeatures of spontaneous locomotor and neural activity varies across zebrafish epilepsy and seizure models. C_LIO_LIWe propose photic stimulation as a reliable tool to investigate behavioral and physiological phenotypes in zebrafish epilepsy and seizure models. C_LIO_LIWe observed elevated activity with faster dynamics in response to photic stimulation in all tested zebrafish models. C_LIO_LIPhotic-evoked neural responses were often followed by depressed state in seizure-prone networks C_LI

neuroscience↗

bioRxiv2021

Experience-dependent plasticity modulates ongoing activity in the antennal lobe and enhance odor representations

Ongoing neural activity has been observed across several brain regions and thought to reflect the internal state of the brain. Yet, it is not fully understood how ongoing brain activity interacts with sensory experience and shape sensory representations. Here, we show that projection neurons of the fruit fly antennal lobe exhibit spatiotemporally organized ongoing activity in the absence of odor stimulation. Upon repeated exposure to odors, we observe a gradual and long-lasting decrease in the amplitude and frequency of spontaneous calcium events, as well as a reorganization of correlations between olfactory glomeruli during ongoing activity. Accompanying these plastic changes, we find that repeated odor experience reduces trial-to-trial variability and enhances the specificity of odor representations. Our results reveal a previously undescribed experience-dependent plasticity of ongoing and sensory driven activity at peripheral levels of the fruit fly olfactory system.

neuroscience↗

bioRxiv2021

Loss of the glial glutamate transporter eaat2a leads to a combined developmental and epileptic encephalopathy in zebrafish

Astroglial excitatory amino acid transporter 2 (EAAT2, GLT-1, SLC1A2) regulates the duration and extent of neuronal excitation by removing glutamate from the synaptic cleft. Hence, an impairment in EAAT2 function could lead to an imbalanced neural network excitability. Here, we investigated the functional alterations of neuronal and astroglial networks associated with the loss of function in the astroglia predominant eaat2a gene in zebrafish. We observed that eaat2a-/- mutant zebrafish larvae display recurrent spontaneous and light-induced seizures in neurons and astroglia, which coincide with an abrupt increase in extracellular glutamate levels. In stark contrast to this hyperexcitability, basal neuronal and astroglial activity was surprisingly reduced in eaat2a-/- mutant animals, which manifested in decreased overall locomotion. Our results reveal an essential and mechanistic contribution of EAAT2a in balancing brain excitability, and its direct link to epileptic seizures.

neuroscience↗

bioRxiv2021

Diversity and Function of Motile Ciliated Cell Types within Ependymal Lineages of the Zebrafish Brain

Motile cilia defects impair cerebrospinal fluid (CSF) flow, and can cause brain and spine disorders. To date, the development of ciliated cells, their impact on CSF flow and their function in brain and axial morphogenesis are not fully understood. Here, we have characterized motile ciliated cells within the zebrafish brain ventricles. We show that the ventricular surface undergoes significant restructuring through development, involving a transition from mono- to multiciliated cells (MCCs) driven by gmnc. MCCs are translationally polarized, co-exist with monociliated cells and generate directional flow patterns. Moreover, these ciliated cells have different developmental origins, and are genetically heterogenous with respect to expression of the Foxj1 family of ciliary master regulators. Finally, we show that cilia loss from specific brain regions or global perturbation of multiciliation does not affect overall brain or spine morphogenesis, but results in enlarged ventricles. Our findings establish that motile ciliated cells are generated by complementary and sequential transcriptional programs to support ventricular development.

neuroscience↗

bioRxiv2021

Ongoing habenular activity is driven by forebrain networks and modulated by olfactory stimuli

Ongoing neural activity, which represents internal brain states, is constantly modulated by the sensory information that is generated by the environment. In this study, we show that the habenular circuits act as a major brain hub integrating the structured ongoing activity of the limbic forebrain circuitry and the olfactory information. We demonstrate that ancestral homologs of amygdala and hippocampus in zebrafish forebrain are the major drivers of ongoing habenular activity. We also reveal that odor stimuli can modulate the activity of specific habenular neurons that are driven by this forebrain circuitry. Our results highlight a major role for the olfactory system in regulating the ongoing activity of the habenula and the forebrain, thereby altering brains internal states.

neuroscience↗

bioRxiv2019

Investigating olfactory behaviors in adult zebrafish

Odor-driven behaviors such as feeding, mating and predator avoidance are crucial for animal survival. While the zebrafish olfactory circuitry is well understood, a comprehensive description of odor-driven behaviors is needed to better relate olfactory computations to animal responses. Here, we used a medium-throughput setup to measure the swimming trajectories of 10 zebrafish in response to 17 ecologically relevant odors. By selecting appropriate locomotor metrics, we constructed ethograms systematically describing odor-induced changes in the swimming trajectory. We found that fish reacted to most odorants, using different behavioral programs and that combination of few relevant behavioral metrics enabled to capture most of the variance in these innate odor responses. We observed that monomolecular odors in similar chemical categories were weakly clustered based on the behavioral responses, likely because natural odors elicited stronger reactions than the monomolecular odors. Finally, we uncovered a previously undescribed intra and inter-individual variability of olfactory behaviors and suggest a small set of odors that elicit robust responses. In conclusion, our setup and results will be useful resources for future studies interested in characterizing olfactory responses in aquatic animals.

animal behavior and cognition↗

bioRxiv2019

Zebrafish dorsal habenula is required for updating learned behaviors

Operant conditioning requires multiple cognitive processes, such as learning, prediction of potential outcomes and decision making. It is less clear how interactions of these processes lead to the behavioral adaptations that allow animals to cope with a changing environment. We showed that juvenile zebrafish can perform conditioned place avoidance learning, with an improving performance across development. Ablation of the dorsolateral habenula (dlHb), a brain region involved in associative learning and prediction of outcomes, led to an unexpected improvement in performance and delayed memory extinction. Interestingly, while the control animals exhibited rapid adaptation to a changing learning rule, dlHb ablated animals failed to adapt. Altogether, our results show that the dlHb plays a central role in switching animals strategies while integrating new evidence with prior experience.

neuroscience↗

bioRxiv2019

Interhemispheric connections between olfactory bulbs improve odor detection

Interhemispheric connections enable interaction and integration of sensory information in bilaterian nervous systems and are thought to optimize sensory computations. However, the cellular and spatial organization of interhemispheric networks as well as the computational properties they mediate in vertebrates are still poorly understood. Thus, it remains unclear to which extent the connectivity between left and right brain hemispheres participates in sensory processing. Here, we show that the zebrafish olfactory bulbs (OBs) receive direct interhemispheric projections from their contralateral counterparts in addition to top-down inputs from the contralateral zebrafish homolog of olfactory cortex. The direct interhemispheric projections between the OBs reach peripheral layers of the contralateral OB and retain a fine-grained topographic organization, which directly connects similarly tuned olfactory glomeruli across hemispheres. In contrast, interhemispheric top-down inputs consist of diffuse projections that broadly innervate the inhibitory granule cell layer. Jointly, these interhemispheric connections elicit a balance of topographically organized excitation and non-topographic inhibition on the contralateral OB and modulate odor responses. We show that the interhemispheric connections in the olfactory system enable the modulation of odor response and improve the detection of a reproductive pheromone, when presented together with competing complex olfactory cues, by boosting the response of the pheromone selective neurons. Taken together, our data shows a previously unknown function for an interhemispheric connection between chemosensory maps of the olfactory system.

neuroscience↗

bioRxiv2019

Functional properties of habenular neurons are determined by developmental stage and sequential neurogenesis

Neural development is not just a linear expansion of the brain. Instead, the structure and function of developing brain circuits undergo drastic alterations that have a direct impact on the animals expanding behavioural repertoire. Here we investigated the developmental changes in the habenula, a brain region that mediates behavioural flexibility during learning, social interactions and aversive experiences. We showed that developing habenular circuits exhibit multiple alterations, which increase the structural and functional diversity of cell types, inputs and functional modules within habenula. As the neural architecture of habenula develops, it sequentially transforms into a multi-sensory brain region that can process visual and olfactory information. Moreover, we also observed that already at early developmental stages, the habenula exhibits spatio-temporally structured spontaneous neural activity that shows prominent alterations and refinement with age. Interestingly, these alterations in spontaneous activity are accompanied by sequential neurogenesis and integration of distinct neural clusters across development. Finally, by combining an in vivo neuronal birthdating method with functional imaging, we revealed that clusters of habenular neurons with distinct functional properties are born sequentially at distinct developmental time windows. Our results highlight a strong link between the function of habenular neurons and their precise birthdate during development, which supports the idea that sequential neurogenesis leads to an expansion of neural clusters that correspond to distinct functional modules in the brain.

neuroscience↗

bioRxiv2019

Glia-neuron interactions underlie state transitions to generalized seizures

Brain activity and connectivity alter drastically during epileptic seizures. Throughout this transition, brain networks shift from a balanced resting state to a hyperactive and hypersynchronous state, spreading across the brain. It is, however, less clear which mechanisms underlie these state transitions. By studying neuronal and glial activity across the zebrafish brain, we observed striking differences between these networks. During the preictal period, neurons displayed a small increase in synchronous activity only locally, while the entire glial network was highly active and strongly synchronized across large distances. We observed that the transition from a preictal state to a generalized seizure leads to an abrupt increase in neuronal activity and connectivity, which is accompanied by a strong functional coupling between glial and neuronal networks. Optogenetic activation of glia induced strong and transient burst of neuronal activity, emphasizing a potential role for glia-neuron connections in the generation of epileptic seizures.

neuroscience↗