Biology subjects

Bui, T. V.

Publications and source records attributed to Bui, T. V..

8 recordsLinked to original sources

bioRxiv2026

Validation of optogenetic approach to investigate fatigable weakness using a zebrafish model of congenital myasthenic syndrome

Congenital myasthenic syndromes (CMS) are rare inherited diseases of the neuromuscular junction (NMJ). There are 40 identified CMS genes, but many patients go without genetic diagnosis, which suggests new genes have yet to be discovered and characterised. Here, we describe an optogenetic approach to study fatigable muscle weakness and NMJ function in larval zebrafish to facilitate screening approaches for uncovering novel CMS genes. Using blue-light illumination of spinal motoneurons that express channelrhodopsin-2 (ChR2) to induce muscle contraction, we measure motor defects at the behavioural, synaptic, and genetic level through a novel behavioural assay, standard whole-cell electrophysiology of individual muscle fibers and a customized NMJ gene panel. We employ this approach in synaptotagmin-2 (syt2) morphant zebrafish, an identified CMS gene model, to validate its usefulness. Our customized optogenetic behavioural assay successfully demonstrates reduced, fatigable, locomotor response during repeated activation of spinal motoneurons. Whole-cell electrophysiology recordings of optogenetically-elicited endplate currents in muscle fibers reveal similarities to altered properties of NMJ function in syt2 morphants reported in other studies using the standard paired motoneuron-muscle electrophysiology technique. Finally, we develop a genetic panel of CMS and NMJ-related genes to characterize the expression landscape of syt2 morphants to elucidate potential pathomechanisms and novel therapeutic targets. We propose that this three-tiered approach successfully links behaviour, synaptic motor function, and genetic expression and can be used as a tool in the screening of novel genes associated with CMS.

neuroscience↗

bioRxiv2025

Neuromodulation of zebrafish primary motoneuron firing is shaped by developmental changes in the M-current

Movements during development are refined through the ongoing maturation of the spinal circuits that mediate them. In many vertebrates, including zebrafish, this maturation process involves neuromodulators such as acetylcholine, serotonin, and dopamine; however, the targets of this neuromodulation remain largely unknown. Recent work has revealed distinct developmental dynamics of the non-inactivating subthreshold potassium current - the M-current - in primary motoneurons of larval zebrafish. Considering that neuromodulators play a role in the maturation of locomotor control in larval zebrafish, we asked whether neuromodulators might target the M-current in primary motoneurons during development. Our patch-clamp experiments in primary motoneurons of zebrafish aged 3 to 5 days post-fertilization (dpf) reveal distinct modulation of the M-current by serotonin and acetylcholine that is age-dependent. Our data demonstrates an inhibitory influence of serotonin signaling via 5HT1A receptors that promotes repetitive firing in primary motoneurons specifically at 3 dpf. We also show that acetylcholine, likely via M2/M4 receptors, enhances the M-current and limits repetitive firing in primary motoneurons but does so only after 3 dpf. Modulation of the M-current in primary motoneurons was not observed across all neuromodulators as dopamine had no effect at any age. Considering that the M-current transiently peaks at 3 dpf and is reduced at 4 and 5 dpf, our findings suggest that the developmental changes in this current can shape how neuromodulators modulate firing properties of primary motoneurons. Key pointsO_LIThe amplitude of the M-current is subject to modulation by several neuromodulators such as acetylcholine and serotonin C_LIO_LISerotonin via 5HT1A inhibits the M-current in primary motoneurons at 3 dpf C_LIO_LIMuscarinic agonist enhances the M-current in primary motoneurons after 3 dpf C_LIO_LINeuromodulation of motoneuron firing properties by 5-HT1A and muscarinic agonist is consistent with modulation of the M-current C_LI

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bioRxiv2025

Spinal dI3 neurons are involved in sustained motor adaptation elicited by low-threshold cutaneous afferents

Adaptation of muscle activity to meet a certain target or intention is traditionally attributed to supraspinal structures. However, evidence is mounting that this process can occur within the spinal cord through intrinsic plasticity and circuit reorganization. Here, we investigate the role of a class of excitatory spinal interneurons, called dorsal interneuron 3 (dI3), in the acquisition of novel motor behaviors independent of supraspinal input. Using a real-time closed-loop stimulation paradigm in spinalized mice, we promoted a persistent adaptation in the hindlimb position to be higher than its resting level by delivering saphenous nerve stimulation contingent on toe elevation. The stimulation intensities were calibrated to selectively recruit low-threshold mechanoreceptors (LTMRs). To test the contribution of dI3s in this motor adaptation, inhibitory DREADD (hM4Di) receptors were expressed in Isl1/Vglut2 cells, achieving reversible, cell-type-specific silencing of dI3s. Our results demonstrate that stimulation of cutaneous inputs to the spinal cord contingent on a certain positional goal can generate sustained changes in motor activity, in this case, in the form of elevation of toe position above a preset vertical threshold. Chemogenetic silencing of dI3s abolished this motor adaptation induced by activation of LTMRs. These findings indicate that dI3 activity is essential for a particular type of motor adaptation driven primarily by LTMR input. NEW & NOTEWORTHYWe developed a real-time, closed-loop stimulation paradigm in spinalized mice using kinematic video tracking to trigger electrical stimulation of the saphenous nerve. We discovered that low-threshold stimulations targeting non-nociceptive cutaneous afferents can elicit sustained motor adaptations independently from supraspinal input. Furthermore, using two chemogenetic techniques to transiently inhibit a population of spinal neurons, called dI3s, we found that these neurons are crucial for integrating these low-threshold stimuli to elicit sustained changes in motor behaviour.

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bioRxiv2025

Evidence of spinal cord comparator modules for rapid corrections of movements

Successful movement requires continuous adjustments in response to changes in internal and external environments. To do so, neural circuits continuously compare efference copies of motor commands with sensory feedback to respond to sensory prediction errors. Some responses need to be very fast, indicating that they likely occur within spinal cord circuits. Here, we describe spinal cord circuits involving dI3 neurons, showing that they receive multimodal sensory inputs and direct efferent copies from both Renshaw cells and motor neurons. We further show that they form connections to motor pools. Reducing dI3 neuronal activity diminished stumbling responses, as did disrupting Renshaw cell circuits, providing evidence for a comparator role of dI3 neurons for online corrections. Together, our findings reveal a pivotal role for dI3 neurons functioning as comparators of efference copies and external sensory feedback to mediate rapid corrections of ongoing movements.

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bioRxiv2024

Mapping of dI3 neuron sensorimotor circuits across the cervical and lumbar spinal cord

From the fine control of hand movements to the dynamic corrective adjustments during locomotion, spinal circuits integrate descending supraspinal and sensory inputs to modulate diverse motor functions. The integration of such a wide range of signals across the spinal cord is primarily mediated by propriospinal interneurons. In this study, we investigate the connectivity of a population of propriospinal interneurons marked by the expression of Isl1, called dI3 neurons. These dI3s integrate supraspinal and sensory signals to facilitate many important functions, such as hand grasp, locomotion, and motor recovery after spinal cord injury; however, we have a limited understanding of how subpopulations of dI3s modulate network activity across the spinal cord to contribute to these behaviors. Their functional connectivity to motor circuits across the cervical and lumbar spinal cord was assessed through optogenetic activation of dI3s localized in different spinal segments. Our data demonstrates that cervical and lumbar dI3 subpopulations can form local, commissural, intersegmental, and long propriospinal pathways. Furthermore, dI3 subpopulations can be tonically stimulated to elicit locomotor activity. These extensive projection patterns of dI3s across the cervical and lumbar spinal cord suggest that dI3 subpopulations can modulate the activity of multiple motor networks within their respective spinal cord segments or across distant forelimb and hindlimb segments to facilitate a wide variety of motor functions.

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bioRxiv2022

A simple self-decoding model for neural coding

Neural coding is an important tool to discover the inner workings of mind. In this work, we propose and consider a simple but novel self-decoding model for neural coding based on the principle that the neuron body represents ongoing stimulus while dendrites are used to store that stimulus as a memory. In particular, suppose t spiking presynaptic neurons transmit any stimulus directly to a population of n postsynaptic neurons, a postsynaptic neuron spikes if it does not connect to an inhibitory presynaptic neuron, and every stimulus is represented by up to d spiking postsynaptic neurons. Our hypothesis is that the brain is organized to functionally satisfy the following six criteria: (i) decoding objective, i.e., there are up to r-1 [≥] 0 additional spiking postsynaptic neurons in response to a stimulus along with the spiking postsynaptic neurons representing the stimulus, (ii) smoothness, i.e., similar stimuli are encoded similarly by the presynaptic neurons, (iii) optimal information transmission, i.e., t is minimized, (iv) optimal energetic cost, i.e., only the t presynaptic neurons and the postsynaptic neurons representing a stimulus spike, (v) low-dimensional representation, i.e., d = o(n), and (vi) sparse coding, i.e., t = o(n). Our finding is that some criteria cause or correlate with others. Let the characteristic set of a postsynaptic neuron be the set of the presynaptic neurons it connects with. We prove that (i) holds if and only if the union of the r characteristic sets of any r postsynaptic neurons is not included in the union of the d characteristic sets of d other postsynaptic neurons. Consequently, (ii) is attained. More importantly, we suggest that the decoding objective (i) and optimal information transmission (iii) play a fundamental role in neural computation, while (v) and (vi) correlate to each other and correlate with (iii) and (iv). We examine our hypothesis by statistically testing functional connectivity network and the presynaptic-postsynaptic connectivity in layer 2 of the medial entorhinal cortex of a rat.

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bioRxiv2021

Modelling spinal locomotor circuits for movements in developing zebrafish

Many spinal circuits dedicated to locomotor control have been identified in the developing zebrafish. How these circuits operate together to generate the various swimming movements during development remains to be clarified. In this study, we iteratively built models of developing zebrafish spinal circuits coupled to simplified musculoskeletal models that reproduce coiling and swimming movements. The neurons of the models were based upon morphologically or genetically identified populations in the developing zebrafish spinal cord. We simulated intact spinal circuits as well as circuits with silenced neurons or altered synaptic transmission to better understand the role of specific spinal neurons. Analysis of firing patterns and phase relationships helped identify possible mechanisms underlying the locomotor movements of developing zebrafish. Notably, our simulations demonstrated how the site and the operation of rhythm generation could transition between coiling and swimming. The simulations also underlined the importance of contralateral excitation to multiple tail beats. They allowed us to estimate the sensitivity of spinal locomotor networks to motor command amplitude, synaptic weights, length of ascending and descending axons, and firing behaviour. These models will serve as valuable tools to test and further understand the operation of spinal circuits for locomotion.

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bioRxiv2021

Spinal V1 neurons inhibit motor targets locally and sensory targets distally to coordinate locomotion

Rostro-caudal coordination of spinal motor output is essential for locomotion. Most spinal interneurons project axons longitudinally to govern locomotor output, yet their connectivity along this axis remains unclear. In this study, we use larval zebrafish to map synaptic outputs of a major inhibitory population, V1 (Eng1+) neurons, which are implicated in dual sensory and motor functions. We find that V1 neurons exhibit long axons extending rostrally and exclusively ipsilaterally for an average of 6 spinal segments; however, they do not connect uniformly with their post-synaptic targets along the entire length of their axon. Locally, V1 neurons inhibit motor neurons (both fast and slow) and other premotor targets including V2a, V2b and commissural pre-motor neurons. In contrast, V1 neurons make robust inhibitory contacts throughout the rostral extent of their axonal projections onto a dorsal horn sensory population, the Commissural Primary Ascending neurons (CoPAs). In a computational model of the ipsilateral spinal network, we show that this pattern of short range V1 inhibition to motor and premotor neurons is crucial for coordinated rostro-caudal propagation of the locomotor wave. We conclude that spinal network architecture in the longitudinal axis can vary dramatically, with differentially targeted local and distal connections, yielding important consequences for function.

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