Biology subjects

Schoppik, D.

Publications and source records attributed to Schoppik, D..

At least 19 recordsLinked to original sources

bioRxiv2026

Pathological tau leads to network hyperexcitability through neuronal-subtype-specific functional impairment

Pathological tau disrupts neuronal activity and brain function in Alzheimer s disease and other tauopathies. However, the underlying mechanisms for neuronal network dysfunction remain largely unknown. Using human inducible pluripotent stem cell (iPSC) - derived neurons, we show that the familial MAPT P301L mutation leads to neuronal network hyperexcitability. Imbalanced excitation and inhibition were attributable to neuronal subtype-specific tau pathology that was associated with different alterations of tau interactomes in excitatory versus inhibitory neurons. Suppressing enhanced excitatory synaptic transmission or blocking Ca2+ influx resulting from enhanced P301L tau/AHNAK interaction in inhibitory neurons rescued the neuronal network hyperexcitability. This study expands our understanding on how disease-causing tau mutations alter the excitatory/inhibitory balance, leading to network dysfunction in human neurons.

neuroscience↗

bioRxiv2026

Transcriptional profiling of extraocular motor neurons reveals sim1a as a candidate strabismus-related gene

Strabismus, or misalignment of the eyes, is a heritable disorder frequently associated with vision loss and decreased quality of life. Incomitant strabismus, where the degree of misalignment differs based on gaze angle, can arise from mutations in genes that regulate the development of extraocular motor neurons. To date, few such genes have been identified. The extraocular motor system is highly conserved across vertebrates, suggesting a comparative transcriptomic discovery approach would be fruitful. Using bulk and single-cell sequencing in a small accessible vertebrate, the larval zebrafish, we identified genes expressed in subpopulations of extraocular motor neurons in cranial nuclei nIII/nIV. We next assessed extraocular motor neuron number and vestibulo-ocular reflex performance after CRISPR/Cas9-mediated mutagenesis of three genes with suggestive expression patterns: sim1a, nav2a, one-cut1, and one known to disrupt nIII/nIV motor neuron specification: phox2a. Loss of sim1a impaired the vestibulo-ocular reflex without change to nIII/nIV motor neuron number. Our data suggest that constitutive disruptions to sim1a can impair nIII/nIV-dependent eye movements. More broadly, our work illuminates considerable transcriptomic diversity among extraocular motor neuron subpopulations, and establishes a pipeline to identify genes relevant to ocular motor disease etiology.

neuroscience↗

bioRxiv2025

Lighting and circadian cues shape locomotor strategies for balance and navigation in larval zebrafish

Most fish are inherently unstable and must swim to stabilize posture. How diurnal fish reduce activity at night while maintaining postural control remains unclear. We defined distinct locomotor strategies that larval zebrafish (Danio rerio) use to control posture and navigate the water column in response to light and circadian cues. In the dark, larvae maintain balance by swimming in long bouts with large nose-up rotations, compensating for nose-down drift accrued during prolonged inactivity. Effective postural compensation requires vestibular sensation from the utricle. By contrast, in the light, larvae navigate with short, frequent, and variable bouts. While lighting exerts a dominant, masking effect on the locomotor strategies, circadian rhythms modulate swim kinematics. Our results reveal distinct light-dark locomotor strategies and disentangle how ambient light and the internal clock jointly shape balance control and navigation. This work lays the foundation for understanding how external and internal cues interact to govern locomotor activity in freely moving diurnal animals.

animal behavior and cognition↗

bioRxiv2025

Oligodendrocytes support functional development of subcortical premotor neurons and navigation

Oligodendrocytes and the myelin they produce are required for proper balance behaviors in adult vertebrates. If, when, and how they shape the functional development of vestibular (balance) circuits and associated behaviors is unclear. We first adopted a pharmacological approach to investigate the contribution of oligodendrocytes across early development of larval zebrafish (Danio rerio). Disruption of oligodendrogenesis reduces the number of oligodendrocytes near vestibular neurons across development, but only impacts vertical navigation -- a behavior requiring vestibular function -- in older larvae. Correspondingly, we found that midbrain premotor neurons in the vertical navigation circuit only decreased their responses to tilts at later ages. In contrast, we found that the vestibulo-ocular reflex was unaffected by drug treatment, and that body-tilt responses in the underlying hindbrain vestibular neurons and their target extraocular motor neurons were unchanged. Targeted photoablation of oligodendrocytes in the anterior hindbrain replicated our pharmacological findings, selectively disrupting vertical navigation in older animals. By dissociating where and when developmentally-disrupted oligodendrogenesis impacts neuronal function and behavior, our work takes a major step towards understanding how oligodendrocytes enable the maturation of sensorimotor behaviors.

neuroscience↗

bioRxiv2024

Birthdate aligns vestibular sensory neurons with central and motor partners across a sensorimotor reflex circuit for gaze stabilization

Developing populations of connected neurons often share spatial and/or temporal features that anticipate their assembly. A unifying spatiotemporal motif might link sensory, central, and motor populations that comprise an entire circuit. In the sensorimotor reflex circuit that stabilizes vertebrate gaze, central and motor partners are paired in time (birthdate) and space (dorso-ventral). To determine if birthdate and/or dorso-ventral organiza-tion could align the entire circuit, we measured the spatial and temporal development of the sensory circuit node: the vestibular ganglion neurons. We discovered that progressive dorsal-to-ventral organization closely predicts vestibular ganglion development, with additional organization along its functional (rostrocaudal) axis. With an acute optical lesion and calcium imaging paradigm, we found that this common spatiotemporal axis anticipated functional sensory-to-central partner matching. We propose a "first-come, first-served" model in which birth-date organizes and assembles the sensory, central, and motor populations that comprise the gaze stabilization circuit, a general strategy for poly-synaptic circuit assembly across embryonically-diverse neural populations. SUMMARY STATEMENTCircuit nodes often develop along common axes. We find that a "first-come, first-served" temporal rule underscores the organization of a canonical sensorimotor circuit for gaze stabilization, simplifying poly-synaptic assembly.

neuroscience↗

bioRxiv2024

Tau load in select brainstem neurons predicts the severity and nature of balance deficits in the absence of cell death

Patients with tauopathies present with profoundly different clinical symptoms1, even within the same disorder2. A central hypothesis in the field, well-supported by biomarker studies3,4 and post-mortem pathology5-7, is that clinical heterogeneity reflects differential degeneration of vulnerable neuronal populations responsible for specific neurological functions. Recent work has revealed mechanisms underlying susceptibility of particular cell types8-10, but relating tau load to disrupted behavior -- es- pecially before cell death -- requires a targeted circuit-level approach. Here we studied two distinct balance behaviors in larval zebrafish11 expressing a human 0N/4R-tau allele12 in select populations of evolutionarily-conserved and well-characterized brainstem vestibular circuits13,14. We observed that human tau load predicted the severity of circuit-specific deficits in posture and navigation in the ab- sence of cell death. Targeting expression to either mid- or hindbrain balance neurons recapitulated these particular deficits in posture and navigation. By parametrically linking tau load in specific neu- rons to early behavioral deficits, our work moves beyond cell type to close the gap between pathological and neurological conceptions of tauopathy.

neuroscience↗

bioRxiv2024

Development of the Motor Periphery is the Rate-Limiting Step in the Ontogeny of the Vestibulo-ocular Reflex

Vertebrates stabilize gaze using a neural circuit that transforms sensed instability into compensatory counter-rotation of the eyes. Sensory feedback tunes this vestibulo-ocular reflex throughout life. Gaze stabilization matures progressively, either due to similar tuning, or to a slowly developing circuit component. Here we studied the functional development of vestibulo-ocular reflex circuit components in the larval zebrafish, with and without sensation. Blind fish stabilize gaze normally, and neural responses to body tilts mature before behavior. Instead, synapses between motor neurons and the eye muscles mature with a timecourse similar to behavioral maturation. Larvae without vestibular sensory experience, but whose neuromuscular junction was mature, had a strong vestibulo-ocular reflex. Development of the neuromuscular junction, and not sensory experience, determines the rate of maturation of an ancient behavior.

neuroscience↗

bioRxiv2024

A brainstem circuit for gravity-guided vertical navigation

The sensation of gravity anchors our perception of the environment and is crucial for navigation. However, the neural circuits that transform gravity into commands for navigation are undefined. We first determined that larval zebrafish (Danio rerio) navigate vertically by maintaining a consistent heading across a series of upward climb or downward dive bouts. Gravity-blind mutant fish swim with more variable heading and excessive veering, leading to inefficient vertical navigation. After targeted photoablation of ascending vestibular neurons and spinal projecting midbrain neurons, but not vestibulospinal neurons, vertical navigation was impaired. These data define a sensorimotor circuit that uses evolutionarily-conserved brainstem architecture to transform gravitational signals into persistent heading for vertical navigation. The work lays a foundation to understand how vestibular inputs allow animals to move efficiently through their environment.

neuroscience↗

bioRxiv2024

Motor neurons are dispensable for the assembly of a sensorimotor circuit for gaze stabilization

Sensorimotor reflex circuits engage distinct neuronal subtypes, defined by precise connectivity, to transform sensation into compensatory behavior. Whether and how motor neuron populations specify the subtype fate and/or sensory connectivity of their pre-motor partners remains controversial. Here, we discovered that motor neurons are dispensable for proper connectivity in the vestibular reflex circuit that stabilizes gaze. We first measured activity following vestibular sensation in premotor projection neurons after constitutive loss of their extraocular motor neuron partners. We observed normal responses and topography indicative of unchanged functional connectivity between sensory neurons and projection neurons. Next, we show that projection neurons remain anatomically and molecularly poised to connect appropriately with their down-stream partners. Lastly, we show that the transcriptional signatures that typify projection neurons develop independently of motor partners. Our findings comprehensively overturn a long-standing model: that connectivity in the circuit for gaze stabilization is retrogradely determined by motor partner-derived signals. By defining the contribution of motor neurons to specification of an archetypal sensorimotor circuit, our work speaks to comparable processes in the spinal cord and advances our understanding of principles of neural development.

neuroscience↗

bioRxiv2024

Multisensory strategies for postural compensation after lateral line loss

Fish actively control posture in the pitch axis (nose-up/nose-down) to counter instability and regulate their elevation in the water column. To test the hypothesis that environmental cues shape strategies fish use to control posture, we leveraged a serendipitous finding: larval zebrafish (Danio rerio) lose swim bladder volume and sink mildly after acute loss of lateral line hair cells. Using long-term (48 h) recordings of unrestrained swimming, we discovered that sinking larvae compensated differently depending on light conditions. In the dark, they swim more frequently with an increased nose-up posture. In contrast, larvae in the light do not swim more frequently, but do climb more often. Finally, after lateral line regeneration, larvae returned to normal buoyancy and swam comparably to control siblings. We conclude that larvae can switch postural control strategies depending on the availability of visual information. Our findings complement and extend morphological and kinematic analyses of locomotion. More broadly, by quantifying the variation in strategies our work speaks to the evolutionary substrate for different balance behaviors.

neuroscience↗

bioRxiv2023

The vestibulospinal nucleus is a locus of balance development

Mature vertebrates maintain posture using vestibulospinal neurons that transform sensed instability into reflexive commands to spinal motor circuits. Postural stability improves across development. However, due to the complexity of terrestrial locomotion, vestibulospinal contributions to postural refinement in early life remain unexplored. Here we leveraged the relative simplicity of underwater locomotion to quantify the postural consequences of losing vestibulospinal neurons during development in larval zebrafish of undifferentiated sex. By comparing posture at two timepoints, we discovered that later lesions of vestibulospinal neurons led to greater instability. Analysis of thousands of individual swim bouts revealed that lesions disrupted movement timing and corrective reflexes without impacting swim kinematics, and that this effect was particularly strong in older larvae. Using a generative model of swimming, we showed how these disruptions could account for the increased postural variability at both timepoints. Finally, late lesions disrupted the fin/trunk coordination observed in older larvae, linking vestibulospinal neurons to postural control schemes used to navigate in depth. Since later lesions were considerably more disruptive to postural stability, we conclude that vestibulospinal contributions to balance increase as larvae mature. Vestibulospinal neurons are highly conserved across vertebrates; we therefore propose that they are a substrate for developmental improvements to postural control. SIGNIFICANCE STATEMENTMany animals experience balance improvements during early life. Mature vertebrates use vestibulospinal neurons to transform sensed instability into postural corrections. To understand if/how these neurons shape postural development, we ablated them at two developmentally important timepoints in larval zebrafish. Loss of vestibulospinal neurons disrupted specific stabilizing behaviors (swim timing, tilt correction, and fin/body coordination) more profoundly in older fish. We conclude that postural development happens in part by changes to vestibulospinal neurons -- a significant step towards understanding how developing brains gain the ability to balance.

neuroscience↗

bioRxiv2023

Purkinje Cells Control Posture in Larval Zebrafish (Danio rerio)

Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells -- the output neurons of the cerebellar cortex -- as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically-tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.

neuroscience↗

bioRxiv2023

The nature and origin of synaptic inputs to vestibulospinal neurons in the larval zebrafish

Vestibulospinal neurons integrate sensed imbalance to regulate postural reflexes. As an evolutionarily-conserved neural population, understanding their synaptic and circuit-level properties can offer insight into vertebrate antigravity reflexes. Motivated by recent work, we set out to verify and extend the characterization of vestibulospinal neurons in the larval zebrafish. Using current clamp recordings together with stimulation, we observed that larval zebrafish vestibulospinal neurons are silent at rest, yet capable of sustained spiking following depolarization. Neurons responded systematically to a vestibular stimulus (translation in the dark); responses were abolished after chronic or acute loss of the utricular otolith. Voltage clamp recordings at rest revealed strong excitatory inputs with a characteristic multimodal distribution of amplitudes, as well as strong inhibitory inputs. Excitatory inputs within a particular mode (amplitude range) routinely violated refractory period criteria and exhibited complex sensory tuning, suggesting a non-unitary origin. Next, using a unilateral loss-of-function approach, we characterized the source of vestibular inputs to vestibulospinal neurons from each ear. We observed systematic loss of high-amplitude excitatory inputs after utricular lesions ipsilateral, but not contralateral to the recorded vestibulospinal neuron. In contrast, while some neurons had decreased inhibitory inputs after either ipsilateral or contralateral lesions, there were no systematic changes across the population of recorded neurons. We conclude that imbalance sensed by the utricular otolith shapes the responses of larval zebrafish vestibulospinal neurons through both excitatory and inhibitory inputs. Our findings expand our understanding of how a vertebrate model, the larval zebrafish, might use vestibulospinal input to stabilize posture. More broadly, when compared to recordings in other vertebrates, our data speak to conserved origins of vestibulospinal synaptic input.

neuroscience↗

bioRxiv2023

Scalable Apparatus to Measure Posture and Locomotion (SAMPL): a high-throughput solution to study unconstrained vertical behavior in small animals

Balance and movement are impaired in a wide variety of neurological disorders. Recent advances in behavioral monitoring provide unprecedented access to posture and loco-motor kinematics, but without the throughput and scalability necessary to screen candidate genes / potential therapeutics. We present a powerful solution: a Scalable Apparatus to Measure Posture and Locomotion (SAMPL). SAMPL includes extensible imaging hardware and low-cost open-source acquisition software with real-time processing. We first demonstrate that SAMPLs hardware and acquisition software can acquire data from D. melanogaster, C.elegans, and D. rerio as they move vertically. Next, we leverage SAMPLs throughput to rapidly (two weeks) gather a new zebrafish dataset. We use SAMPLs analysis and visualization tools to replicate and extend our current understanding of how zebrafish balance as they navigate through a vertical environment. Next, we discover (1) that key kinematic parameters vary systematically with genetic background, and (2) that such background variation is small relative to the changes that accompany early development. Finally, we simulate SAMPLs ability to resolve differences in posture or vertical navigation as a function of effect size and data gathered - key data for screens. Taken together, our apparatus, data, and analysis provide a powerful solution for laboratories using small animals to investigate balance and locomotor disorders at scale. More broadly, SAMPL is both an adaptable resource for laboratories looking process video-graphic measures of behavior in real-time, and an exemplar of how to scale hardware to enable the throughput necessary for screening.

neuroscience↗

bioRxiv2022

Determinants of Motor Neuron Functional Subtypes Important for Locomotor Speed

Locomotion requires precise control of the strength and speed of muscle contraction and is achieved by recruiting functionally-distinct subtypes of motor neurons (MNs). MNs are essential to movement and differentially susceptible in disease, but little is known about how MNs acquire functional subtype-specific features during development. Using single-cell RNA profiling in embryonic and larval zebrafish, we identify novel and conserved molecular signatures for MN functional subtypes, and identify genes expressed in both early post-mitotic and mature MNs. Assessing MN development in genetic mutants, we define a molecular program essential for MN functional subtype specification. Two evolutionarily-conserved transcription factors, Prdm16 and Mecom, are both functional subtype-specific determinants integral for fast MN development. Loss of prdm16 or mecom causes fast MNs to develop transcriptional profiles and innervation similar to slow MNs. These results reveal the molecular diversity of vertebrate axial MNs and demonstrate that functional subtypes are specified through intrinsic transcriptional codes.

neuroscience↗

bioRxiv2022

Neuronal birthdate reveals topography in a vestibular brainstem circuit for gaze stabilization

Across the nervous system, neurons with similar attributes are topographically organized. This topography reflects developmental pressures. Oddly, vestibular (balance) nuclei are thought to be disorganized. By measuring activity in birthdated neurons, we revealed a functional map within the central vestibular projection nucleus that stabilizes gaze in the larval zebrafish. We first discovered that both somatic position and stimulus selectivity follow projection neuron birthdate. Next, with electron microscopy and loss-of-function assays, we found that patterns of peripheral innervation to projection neurons were similarly organized by birthdate. Lastly, birthdate revealed spatial patterns of axonal arborization and synapse formation to projection neuron outputs. Collectively, we find that development reveals previously hidden organization to the input, processing, and output layers of a highly-conserved vertebrate sensorimotor circuit. The spatial and temporal attributes we uncover constrain the developmental mechanisms that may specify the fate, function, and organization of vestibulo-ocular reflex neurons. More broadly, our data suggest that, like invertebrates, temporal mechanisms may assemble vertebrate sensorimotor architecture.

neuroscience↗

bioRxiv2022

Tilt In Place Microscopy (TIPM): a simple, low-cost solution to image neural responses to body rotations

Animals use information about gravity and other destabilizing forces to balance and navigate through their environment. Measuring how brains respond to these forces requires considerable technical knowledge and/or financial resources. We present a simple alternative: Tilt In Place Microscopy (TIPM). TIPM is a low-cost and non-invasive way to measure neural activity following rapid changes in body orientation. Here we used TIPM to study vestibulospinal neurons in larval zebrafish during and immediately after roll tilts. Vestibulospinal neurons responded with reliable increases in activity that varied as a function of ipsilateral tilt amplitude. TIPM differentiated tonic (i.e. sustained tilt) from phasic responses, revealing coarse topography of stimulus sensitivity in the lateral vestibular nucleus. Neuronal variability across repeated sessions was minor relative to trial-to-trial variability, allowing us to use TIPM for longitudinal studies of the same neurons across two developmental timepoints. There, we observed global increases in response strength, and systematic changes in the neural representation of stimulus direction. Our data extend classical characterization of the body tilt representation by vestibulospinal neurons and establish TIPMs utility to study the neural basis of balance, especially in developing animals. Significance StatementVestibular sensation influences everything from navigation to interoception. Here we detail a straight-forward, validated and nearly-universal approach to image how the nervous system senses and responds to body tilts. We use our new method to replicate and expand upon past findings of tilt sensing by a conserved population of spinal-projecting vestibular neurons. The simplicity and broad compatibility of our approach will democratize the study of the brains response to destabilization, particularly across development.

neuroscience↗

bioRxiv2021

Synaptic Encoding of Vestibular Sensation Regulates Movement Timing and Coordination

Vertebrate vestibular circuits use sensory signals derived from the inner ear to guide both corrective and volitional movements. A major challenge in the neuroscience of balance is to link the synaptic and cellular substrates that encode body tilts to specific behaviors that stabilize posture and enable efficient locomotion. Here we address this problem by measuring the development, synaptic architecture, and behavioral contributions of vestibulospinal neurons in the larval zebrafish. First, we find that vestibulospinal neurons are born and are functionally mature before larvae swim freely, allowing them to act as a substrate for postural regulation. Next, we map the synaptic inputs to vestibulospinal neurons that allow them to encode posture. Further, we find that this synaptic architecture allows them to respond to linear acceleration in a directionally-tuned and utricle-dependent manner; they are thus poised to guide corrective movements. After loss of vestibulospinal neurons, larvae adopted eccentric postures with disrupted movement timing and weaker corrective kinematics. We used a generative model of swimming to demonstrate that together these disruptions can account for the increased postural variability. Finally, we observed that lesions disrupt vestibular-dependent coordination between the fins and trunk during vertical swimming, linking vestibulospinal neurons to navigation. We conclude that vestibulospinal neurons turn synaptic representations of body tilt into defined corrective behaviors and coordinated movements. As the need for stable locomotion is common and the vestibulospinal circuit is highly conserved our findings reveal general mechanisms for neuronal control of balance.

neuroscience↗