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

Goldblatt, Dena; Huang, Stephanie; Greaney, Marie R; Hamling, Kyla R; Voleti, Venkatakaushik; Perez-Campos, Citlali; Patel, Kripa B; Li, Wenze; Hillman, Elizabeth M C; Bagnall, Martha W; Schoppik, David
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. Finally, 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.
PMID: 36924768
ISSN: 1879-0445
CID: 5462542

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

Hamling, Kyla R; Zhu, Yunlu; Auer, Franziska; Schoppik, David
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 TIPM's utility to study the neural basis of balance, especially in developing animals.Significance Statement:Vestibular sensation influences everything from navigation to interoception. Here we detail a straightforward, 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 brain's response to destabilization, particularly across development.
PMID: 36517242
ISSN: 1529-2401
CID: 5382242

Linking molecular abnormalities to balance deficits using a zebrafish model for tauopathies

Zhu, Yunlu; Leary, Paige; Bai, Qing; Burton, Edward A.; Schoppik, David
Background: The ability to maintain balance is an evolutionarily-conserved behavior that is frequently disrupted found in patients with neurodegenerative diseases. One of the most prominent balance disorders is found in patients with progressive supranuclear palsy (PSP), a primary tauopathy pathologically characterized by tau over-representation in the brainstem vestibulospinal (VS) nucleus, where they frequently exhibit accidental-backward falls starting from the early stage of the disease. Although pathological features of PSP correlate well with its clinical phenotype, how tau aggregation affects neuronal and circuit functions, which eventually leads to behavioral deficits, remains unclear. Method: To dissect disease mechanisms across molecular, cellular, circuitry, and behavioral levels, we generated tau fish by expressing human 0N/4R-Tau in zebrafish VS nucleus. Tau expression and phosphorylation were validated using immunohistochemistry staining with PHF-1 antibody. To examine the effect of tau on balance behavior, we measured postural control of free-swimming tau fish and compared to that of tau-negative siblings. Moreover, we tested response of VS neurons to nose-down and nose-up tilt stimulus using 2-photon calcium imaging. Result: Ttau-expressing zebrafish exhibit impaired balance control while maintaining normal locomotor ability. Interestingly, we did not observe any neuronal death in the VS nucleus. Functional imaging of the VS nucleus shows impaired directional tuning in tau-expressing neurons in response to tilt stimulus. We also found ectopic accumulation of acidic organelles in the cell bodies of tau-positive neurons, suggesting abnormal lysosomal function. Conclusion: Our results demonstrate how molecular abnormalities disrupt specific behavior in tauopathies before neurodegeneration appeared.
ISSN: 1552-5260
CID: 5393922

Efference copies: Side-eyeing across species

Leary, Paige; Schoppik, David
Efference copies of movement-inducing neural signals have been proposed to serve a role in gaze stabilization. Prior work has demonstrated a spino-extraocular motor circuit in the tadpole that relays copies of spinal commands to extraocular motor neurons. A recent study demonstrates the presence of this circuitry in mice, suggesting a unique method of gaze stabilization in the locomoting mouse.
PMID: 35077698
ISSN: 1879-0445
CID: 5154412

The Larval Zebrafish Vestibular System Is a Promising Model to Understand the Role of Myelin in Neural Circuits

Auer, Franziska; Schoppik, David
Myelin is classically known for its role in facilitating nerve conduction. However, recent work casts myelin as a key player in both proper neuronal circuit development and function. With this expanding role comes a demand for new approaches to characterize and perturb myelin in the context of tractable neural circuits as they mature. Here we argue that the simplicity, strong conservation, and clinical relevance of the vestibular system offer a way forward. Further, the tractability of the larval zebrafish affords a uniquely powerful means to test open hypotheses of myelin's role in normal development and disordered vestibular circuits. We end by identifying key open questions in myelin neurobiology that the zebrafish vestibular system is particularly well-suited to address.
PMID: 35600621
ISSN: 1662-4548
CID: 5283722

Efference Copies: Hair Cells Are the Link

Goldblatt, Dena S; Schoppik, David
Animals must distinguish external stimuli from self-generated sensory input to guide appropriate behaviors. A recent study elucidates a cellular mechanism by which zebrafish perform this distinction while maintaining sensitivity to external environmental signals.
PMID: 31910366
ISSN: 1879-0445
CID: 4257212

Zebrafish dscaml1 Deficiency Impairs Retinal Patterning and Oculomotor Function

Ma 马漫修, Manxiu; Ramirez, Alexandro D; Wang 王彤, Tong; Roberts, Rachel L; Harmon, Katherine E; Schoppik, David; Sharma, Avirale; Kuang, Christopher; Goei, Stephanie L; Gagnon, James A; Zimmerman, Steve; Tsai, Shengdar Q; Reyon, Deepak; Joung, J Keith; Aksay, Emre R F; Schier, Alexander F; Pan 潘於勤, Y Albert
Down Syndrome Cell Adhesion Molecules (dscam and dscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the functional consequences of dscaml1 deficiency in the larval zebrafish (sexually undifferentiated) oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Genetic perturbation of dscaml1 resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses revealed specific deficits related to the dscaml1 mutation, including severe fatigue during gaze stabilization, reduced saccade amplitude and velocity in the light, greater disconjugacy, and impaired fixation. Two-photon calcium imaging of abducens neurons in control and dscaml1 mutant animals confirmed deficits in saccade-command signals (indicative of an impairment in the saccadic premotor pathway), while abducens activation by the pretectum-vestibular pathway was not affected. Together, we show that loss of dscaml1 resulted in impairments in specific oculomotor circuits, providing a new animal model to investigate the development of oculomotor premotor pathways and their associated human ocular disorders.SIGNIFICANCE STATEMENTDscaml1 is a neural developmental gene with unknown behavioral significance. Using the zebrafish model, this study shows that dscaml1 mutants have a host of oculomotor (eye movement) deficits. Notably, the oculomotor phenotypes in dscaml1 mutants are reminiscent of human ocular motor apraxia, a neurodevelopmental disorder characterized by reduced saccade amplitude and gaze stabilization deficits. Population-level recording of neuronal activity further revealed potential subcircuit-specific requirements for dscaml1 during oculomotor behavior. These findings underscore the importance of dscaml1 in the development of visuomotor function and characterize a new model to investigate potential circuit deficits underlying human oculomotor disorders.
PMID: 31685652
ISSN: 1529-2401
CID: 4172342

A primal role for the vestibular sense in the development of coordinated locomotion

Ehrlich, David E; Schoppik, David
Mature locomotion requires that animal nervous systems coordinate distinct groups of muscles. The pressures that guide the development of coordination are not well understood. To understand how and why coordination might emerge, we measured the kinematics of spontaneous vertical locomotion across early development in zebrafish (Danio rerio) . We found that zebrafish used their pectoral fins and bodies synergistically during upwards swims. As larvae developed, they changed the way they coordinated fin and body movements, allowing them to climb with increasingly stable postures. This fin-body synergy was absent in vestibular mutants, suggesting sensed imbalance promotes coordinated movements. Similarly, synergies were systematically altered following cerebellar lesions, identifying a neural substrate regulating fin-body coordination. Together these findings link the vestibular sense to the maturation of coordinated locomotion. Developing zebrafish improve postural stability by changing fin-body coordination. We therefore propose that the development of coordinated locomotion is regulated by vestibular sensation.
PMID: 31591962
ISSN: 2050-084x
CID: 4130532

Encoding of Wind Direction by Central Neurons in Drosophila

Suver, Marie P; Matheson, Andrew M M; Sarkar, Sinekdha; Damiata, Matthew; Schoppik, David; Nagel, Katherine I
Wind is a major navigational cue for insects, but how wind direction is decoded by central neurons in the insect brain is unknown. Here we find that walking flies combine signals from both antennae to orient to wind during olfactory search behavior. Movements of single antennae are ambiguous with respect to wind direction, but the difference between left and right antennal displacements yields a linear code for wind direction in azimuth. Second-order mechanosensory neurons share the ambiguous responses of a single antenna and receive input primarily from the ipsilateral antenna. Finally, we identify novel "wedge projection neurons" that integrate signals across the two antennae and receive input from at least three classes of second-order neurons to produce a more linear representation of wind direction. This study establishes how a feature of the sensory environment-wind direction-is decoded by neurons that compare information across two sensors.
PMID: 30948249
ISSN: 1097-4199
CID: 3900752

Balance Sense: Response Motifs that Pervade the Brain

Ehrlich, David E; Schoppik, David
Measuring how the brain encodes and processes an animal's own motion presents major technical challenges. New approaches demonstrate the viability and merit of measuring vestibular responses throughout the entire brain.
PMID: 30513329
ISSN: 1879-0445
CID: 3520302