Peripheral Glia Have a Pivotal Role in the Initial Response to Axon Degeneration of Peripheral Sensory Neurons in Zebrafish

Pope, Holly M.; Voigt, Mark M.

doi:10.1371/journal.pone.0103283

Cited by 13 publications

(14 citation statements)

References 73 publications

(108 reference statements)

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“…In NTR-expressing cells, the prodrug metronidazole (Mtz) is converted into cytotoxic metabolites leading to cell death within 24-48 hours of treatment (Drabek et al, 1997). NTR-mediated cell ablation has been successfully employed in zebrafish, and demonstrated to be both effective and specific, resulting in the ablation of NTR-expressing cells while leaving neighboring cells unharmed (Curado et al, 2008; Godoy et al, 2015; Pisharath et al, 2007; Pope and Voigt, 2014). …”

Section: Resultsmentioning

confidence: 99%

Role of branchiomotor neurons in controlling food intake of zebrafish larvae

Allen

Bhattacharyya

Asante

et al. 2017

Journal of Neurogenetics

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The physical act of eating or feeding involves the coordinated action of several organs like eyes and jaws, and associated neural networks. Moreover, the activity of the neural networks controlling jaw movements (branchiomotor circuits) is regulated by the visual, olfactory, gustatory and hypothalamic systems, which are largely well characterized at the physiological level. By contrast, the behavioral output of the branchiomotor circuits, and the functional consequences of disruption of these circuits by abnormal neural development are poorly understood. To begin to address these questions, we sought to evaluate the feeding ability of zebrafish larvae, a direct output of the branchiomotor circuits, and developed a qualitative assay for measuring food intake in zebrafish larvae at 7 days post fertilization. We validated the assay by examining the effects of ablating the branchiomotor neurons. Metronidazole-mediated ablation of nitroreductase-expressing branchiomotor neurons resulted in a predictable reduction in food intake without significantly affecting swimming ability, indicating that the assay is robust. Laser-mediated ablation of trigeminal motor neurons resulted in a significant decrease in food intake, indicating that the assay is sensitive. Importantly, in larvae of a genetic mutant with severe loss of branchiomotor neurons, food intake was abolished. These studies establish a foundation for dissecting the neural circuits driving a motor behavior essential for survival.

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Section: Resultsmentioning

confidence: 99%

Role of branchiomotor neurons in controlling food intake of zebrafish larvae

Allen

Bhattacharyya

Asante

et al. 2017

Journal of Neurogenetics

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“…Control fish were treated with fish water alone. Verification of neuron ablation was carried out using epifluorescent imaging as described in [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

“…Thus the ensheathing glia of these circuits are non-myelinating Schwann cells. In a recent report, we described a zebrafish line that allows for the selective ablation of these unmyelinated cranial nerves using the metronidazole (MET)- nsfB cell-death system [ 29 ]. Upon exposure to MET, the cranial neurons selectively expressing the nsfB transgene quickly died, with the affected cell bodies and axons degenerating over the course of 18 hours of treatment.…”

Section: Introductionmentioning

confidence: 99%

“…The second phase, occurring between 5–18 hours of treatment, comprised phagocytosis of the cell body/axonal debris and recruitment of macrophages to the areas of degeneration. Further analysis using foxd3 zd10 mutants, which lack peripheral glia, demonstrated that both phagocytosis of axonal/neuronal debris and recruitment of immune cells were dependent on the presence of the non-myelinating glia ensheathing the neuronal somas and axons [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

“…Significant changes in gene expression reflected alterations in a select number of cellular pathways: e.g., membrane transport, anti-inflammatory pathways, oxidative stress, metabolism and cytokine signaling. Analyses were also carried out using RNA isolated from mutant larvae ( foxd3 zd10 nulls) that lack all peripheral glia [ 29 – 31 ]. In those experiments, no significant effect was seen on pathways involved in cytokine signaling, response to stress and oxidoreductase activities.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptome Analysis of Chemically-Induced Sensory Neuron Ablation in Zebrafish

et al. 2016

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Peripheral glia are known to have a critical role in the initial response to axon damage and degeneration. However, little is known about the cellular responses of non-myelinating glia to nerve injury. In this study, we analyzed the transcriptomes of wild-type and mutant (lacking peripheral glia) zebrafish larvae that were treated with metronidazole. This treatment allowed us to conditionally and selectively ablate cranial sensory neurons whose axons are ensheathed only by non-myelinating glia. While transcripts representing over 27,000 genes were detected by RNAseq, only a small fraction (~1% of genes) were found to be differentially expressed in response to neuronal degeneration in either line at either 2 hrs or 5 hrs of metronidazole treatment. Analysis revealed that most expression changes (332 out of the total of 458 differentially expressed genes) occurred over a continuous period (from 2 to 5 hrs of metronidazole exposure), with a small number of genes showing changes limited to only the 2 hr (55 genes) or 5 hr (71 genes) time points. For genes with continuous alterations in expression, some of the most meaningful sets of enriched categories in the wild-type line were those involving the inflammatory TNF-alpha and IL6 signaling pathways, oxidoreductase activities and response to stress. Intriguingly, these changes were not observed in the mutant line. Indeed, cluster analysis indicated that the effects of metronidazole treatment on gene expression was heavily influenced by the presence or absence of glia, indicating that the peripheral non-myelinating glia play a significant role in the transcriptional response to sensory neuron degeneration. This is the first transcriptome study of metronidazole-induced neuronal death in zebrafish and the response of non-myelinating glia to sensory neuron degeneration. We believe this study provides important insight into the mechanisms by which non-myelinating glia react to neuronal death and degeneration in sensory circuits.

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Immune cell dynamics in the CNS: Learning from the zebrafish

Oosterhof

Boddeke

Ham

2014

Glia

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A major question in research on immune responses in the brain is how the timing and nature of these responses influence physiology, pathogenesis or recovery from pathogenic processes. Proper understanding of the immune regulation of the human brain requires a detailed description of the function and activities of the immune cells in the brain. Zebrafish larvae allow long-term, noninvasive imaging inside the brain at high-spatiotemporal resolution using fluorescent transgenic reporters labeling specific cell populations. Together with recent additional technical advances this allows an unprecedented versatility and scope of future studies. Modeling of human physiology and pathology in zebrafish has already yielded relevant insights into cellular dynamics and function that can be translated to the human clinical situation. For instance, in vivo studies in the zebrafish have provided new insight into immune cell dynamics in granuloma formation in tuberculosis and the mechanisms involving treatment resistance. In this review, we highlight recent findings and novel tools paving the way for basic neuroimmunology research in the zebrafish. GLIA 2015;63:719-735 Key words: microglia, brain disease, neurodegeneration, neuroinflammation, live imaging, immune cell behavior Introduction I t is well established that the immune system plays an important role in brain homeostasis and most conditions affecting the brain, including neurodegenerative diseases, psychiatric diseases and neurodevelopmental disorders (Lucin and Wyss-Coray, 2009;Prinz and Priller, 2014;Schwartz et al., 2013). Our current understanding of neuroimmunology, the complex interactions of the immune system with the central nervous system (CNS), however, is limited and many fundamental questions are still unanswered. Basic questions concerning the ontogeny of the brain's immune cells and glia, their functional phenotypes, the life-span of brain immune cells and the effect of aging remain to be answered and are essential for a better understanding of the role of the immune system in CNS health and disease (Streit, 2006;Ginhoux et al., 2013;Biber et al., 2014).A prerequisite for a more comprehensive description of immunological processes in the brain is a thorough characterization of the function of the different types of immune cells involved. This can be achieved in animal model systems by long-term visualization and mapping of neuroimmune cellular dynamic interactions in the living brain.In the last decade, the zebrafish has gained substantial popularity as a model for basic research as well as translational biomedical research. Also in neuroscience research, the use of zebrafish as a model is now quickly gaining momentum. Recent technical advances including genome editing (Hwang et al., 2013; Sander et al., 2011;, optogenetics (Teh et al., 2010;Weber and Koster, 2013), fluorescent imaging tools (Giepmans et al., 2006;Mickoleit et al., 2014), and high-throughput behavioral screens have highlighted the use of zebrafish in understanding brain development and...

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Peripheral Glia Have a Pivotal Role in the Initial Response to Axon Degeneration of Peripheral Sensory Neurons in Zebrafish

Cited by 13 publications

References 73 publications

Role of branchiomotor neurons in controlling food intake of zebrafish larvae

Role of branchiomotor neurons in controlling food intake of zebrafish larvae

Transcriptome Analysis of Chemically-Induced Sensory Neuron Ablation in Zebrafish

Immune cell dynamics in the CNS: Learning from the zebrafish

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