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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

Sensory Gating: Cellular Substrates of Surprise

Hamling, Kyla R; Schoppik, David
Context modulates the brain's response to sensory input. Recent work has identified the neurons that implement contextual gating of a startle behavior in zebrafish and suggests a synaptic mechanism for this modulation.
PMID: 30130505
ISSN: 1879-0445
CID: 3246112

Expansion microscopy of zebrafish for neuroscience and developmental biology studies

Freifeld, Limor; Odstrcil, Iris; Forster, Dominique; Ramirez, Alyson; Gagnon, James A; Randlett, Owen; Costa, Emma K; Asano, Shoh; Celiker, Orhan T; Gao, Ruixuan; Martin-Alarcon, Daniel A; Reginato, Paul; Dick, Cortni; Chen, Linlin; Schoppik, David; Engert, Florian; Baier, Herwig; Boyden, Edward S
Expansion microscopy (ExM) allows scalable imaging of preserved 3D biological specimens with nanoscale resolution on fast diffraction-limited microscopes. Here, we explore the utility of ExM in the larval and embryonic zebrafish, an important model organism for the study of neuroscience and development. Regarding neuroscience, we found that ExM enabled the tracing of fine processes of radial glia, which are not resolvable with diffraction-limited microscopy. ExM further resolved putative synaptic connections, as well as molecular differences between densely packed synapses. Finally, ExM could resolve subsynaptic protein organization, such as ring-like structures composed of glycine receptors. Regarding development, we used ExM to characterize the shapes of nuclear invaginations and channels, and to visualize cytoskeletal proteins nearby. We detected nuclear invagination channels at late prophase and telophase, potentially suggesting roles for such channels in cell division. Thus, ExM of the larval and embryonic zebrafish may enable systematic studies of how molecular components are configured in multiple contexts of interest to neuroscience and developmental biology.
PMID: 29162696
ISSN: 1091-6490
CID: 2792332