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Multi-parameter Behavioral Phenotyping of the MPP+ Model of Parkinson’s Disease in Zebrafish

Parkinson’s disease (PD) has been modeled in several animal species using the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its oxidized product 1-methyl-4-phenylpyridinium (MPP+). MPP+ selectively kills dopaminergic neurons in pars compacta of the substantia nigra, inducing pa...

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Autores principales: Christensen, Christian, Þorsteinsson, Haraldur, Maier, Valerie Helene, Karlsson, Karl Ægir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775599/
https://www.ncbi.nlm.nih.gov/pubmed/33390914
http://dx.doi.org/10.3389/fnbeh.2020.623924
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author Christensen, Christian
Þorsteinsson, Haraldur
Maier, Valerie Helene
Karlsson, Karl Ægir
author_facet Christensen, Christian
Þorsteinsson, Haraldur
Maier, Valerie Helene
Karlsson, Karl Ægir
author_sort Christensen, Christian
collection PubMed
description Parkinson’s disease (PD) has been modeled in several animal species using the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its oxidized product 1-methyl-4-phenylpyridinium (MPP+). MPP+ selectively kills dopaminergic neurons in pars compacta of the substantia nigra, inducing parkinsonian symptoms in animals. Typically, neurotoxicity models of PD in zebrafish assess acute drug effects on locomotion. In the present study, we examined the lasting effects of MPP+ exposure and drug treatment in zebrafish larvae. Larvae were incubated in 500 μM MPP+, from 1 to 5 days post fertilization (dpf), followed by 24 h drug-free acclimation. At 6 dpf, the behavior was analyzed for locomotion, thigmotaxis, and sleep. Next, in separate assays we assessed the drug effects of brain injected glial cell-derived neurotrophic factor (GDNF) and 4-phenylbutyrate (PBA), co-incubated with MPP+. We show that MPP+ exposure consistently reduces swim distance, movement frequency, and cumulative time of movement; thus mimicking a parkinsonian phenotype of reduced movement. In contrast, MPP+ exposed larvae demonstrate reduced anxiety-like behavior and exhibit a sleep phenotype inconsistent with human PD: the larvae display longer sleep bouts, less sleep fragmentation, and more sleep. Previously reported rescuing effects of PBA were not replicated in this study. Moreover, whereas GDNF attenuated the sleep phenotype induced by MPP+, PBA augmented it. The current data suggest that MPP+ exposure generates a multifaceted phenotype in zebrafish and highlights that analyzing a narrow window of data can reveal effects that may be inconsistent with longer multi-parameter approaches. It further indicates that the model generally captures motor symptoms more faithfully than non-motor symptoms.
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spelling pubmed-77755992021-01-02 Multi-parameter Behavioral Phenotyping of the MPP+ Model of Parkinson’s Disease in Zebrafish Christensen, Christian Þorsteinsson, Haraldur Maier, Valerie Helene Karlsson, Karl Ægir Front Behav Neurosci Behavioral Neuroscience Parkinson’s disease (PD) has been modeled in several animal species using the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its oxidized product 1-methyl-4-phenylpyridinium (MPP+). MPP+ selectively kills dopaminergic neurons in pars compacta of the substantia nigra, inducing parkinsonian symptoms in animals. Typically, neurotoxicity models of PD in zebrafish assess acute drug effects on locomotion. In the present study, we examined the lasting effects of MPP+ exposure and drug treatment in zebrafish larvae. Larvae were incubated in 500 μM MPP+, from 1 to 5 days post fertilization (dpf), followed by 24 h drug-free acclimation. At 6 dpf, the behavior was analyzed for locomotion, thigmotaxis, and sleep. Next, in separate assays we assessed the drug effects of brain injected glial cell-derived neurotrophic factor (GDNF) and 4-phenylbutyrate (PBA), co-incubated with MPP+. We show that MPP+ exposure consistently reduces swim distance, movement frequency, and cumulative time of movement; thus mimicking a parkinsonian phenotype of reduced movement. In contrast, MPP+ exposed larvae demonstrate reduced anxiety-like behavior and exhibit a sleep phenotype inconsistent with human PD: the larvae display longer sleep bouts, less sleep fragmentation, and more sleep. Previously reported rescuing effects of PBA were not replicated in this study. Moreover, whereas GDNF attenuated the sleep phenotype induced by MPP+, PBA augmented it. The current data suggest that MPP+ exposure generates a multifaceted phenotype in zebrafish and highlights that analyzing a narrow window of data can reveal effects that may be inconsistent with longer multi-parameter approaches. It further indicates that the model generally captures motor symptoms more faithfully than non-motor symptoms. Frontiers Media S.A. 2020-12-18 /pmc/articles/PMC7775599/ /pubmed/33390914 http://dx.doi.org/10.3389/fnbeh.2020.623924 Text en Copyright © 2020 Christensen, Þorsteinsson, Maier and Karlsson. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Behavioral Neuroscience
Christensen, Christian
Þorsteinsson, Haraldur
Maier, Valerie Helene
Karlsson, Karl Ægir
Multi-parameter Behavioral Phenotyping of the MPP+ Model of Parkinson’s Disease in Zebrafish
title Multi-parameter Behavioral Phenotyping of the MPP+ Model of Parkinson’s Disease in Zebrafish
title_full Multi-parameter Behavioral Phenotyping of the MPP+ Model of Parkinson’s Disease in Zebrafish
title_fullStr Multi-parameter Behavioral Phenotyping of the MPP+ Model of Parkinson’s Disease in Zebrafish
title_full_unstemmed Multi-parameter Behavioral Phenotyping of the MPP+ Model of Parkinson’s Disease in Zebrafish
title_short Multi-parameter Behavioral Phenotyping of the MPP+ Model of Parkinson’s Disease in Zebrafish
title_sort multi-parameter behavioral phenotyping of the mpp+ model of parkinson’s disease in zebrafish
topic Behavioral Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775599/
https://www.ncbi.nlm.nih.gov/pubmed/33390914
http://dx.doi.org/10.3389/fnbeh.2020.623924
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