Zebrafish Larvae Behavior Models As a Tool for Drug Screenings and Pre-Clinical Trials: A Review

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Jun 24

PMID 35743088

Authors

Joao Gabriel Santos Rosa

Carla Lima

Monica Lopes-Ferreira

Affiliations

Soon will be listed here.

Abstract

To discover new molecules or review the biological activity and toxicity of therapeutic substances, drug development, and research relies on robust biological systems to obtain reliable results. Phenotype-based screenings can transpose the organism's compensatory pathways by adopting multi-target strategies for treating complex diseases, and zebrafish emerged as an important model for biomedical research and drug screenings. Zebrafish's clear correlation between neuro-anatomical and physiological features and behavior is very similar to that verified in mammals, enabling the construction of reliable and relevant experimental models for neurological disorders research. Zebrafish presents highly conserved physiological pathways that are found in higher vertebrates, including mammals, along with a robust behavioral repertoire. Moreover, it is very sensitive to pharmacological/environmental manipulations, and these behavioral phenotypes are detected in both larvae and adults. These advantages align with the 3Rs concept and qualify the zebrafish as a powerful tool for drug screenings and pre-clinical trials. This review highlights important behavioral domains studied in zebrafish larvae and their neurotransmitter systems and summarizes currently used techniques to evaluate and quantify zebrafish larvae behavior in laboratory studies.

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References

Schnorr S, Steenbergen P, Richardson M, Champagne D . Measuring thigmotaxis in larval zebrafish. Behav Brain Res. 2011; 228(2):367-74. DOI: 10.1016/j.bbr.2011.12.016. View

Tay T, Ronneberger O, Ryu S, Nitschke R, Driever W . Comprehensive catecholaminergic projectome analysis reveals single-neuron integration of zebrafish ascending and descending dopaminergic systems. Nat Commun. 2011; 2:171. PMC: 3105308. DOI: 10.1038/ncomms1171. View

Han S, Zhang D, Dong Q, Wang X, Wang L . Overexpression of neuroserpin in larval and adult zebrafish shows different behavioral phenotypes. Neurosci Lett. 2021; 762:136175. DOI: 10.1016/j.neulet.2021.136175. View

Bollmann J . The Zebrafish Visual System: From Circuits to Behavior. Annu Rev Vis Sci. 2019; 5:269-293. DOI: 10.1146/annurev-vision-091718-014723. View

Agetsuma M, Aizawa H, Aoki T, Nakayama R, Takahoko M, Goto M . The habenula is crucial for experience-dependent modification of fear responses in zebrafish. Nat Neurosci. 2010; 13(11):1354-6. DOI: 10.1038/nn.2654. View

Jeong J, Kwon H, Ahn J, Kang D, Kwon S, Park J . Functional and developmental analysis of the blood-brain barrier in zebrafish. Brain Res Bull. 2008; 75(5):619-28. DOI: 10.1016/j.brainresbull.2007.10.043. View

Orger M, de Polavieja G . Zebrafish Behavior: Opportunities and Challenges. Annu Rev Neurosci. 2017; 40:125-147. DOI: 10.1146/annurev-neuro-071714-033857. View

Vaz R, Outeiro T, Ferreira J . Zebrafish as an Animal Model for Drug Discovery in Parkinson's Disease and Other Movement Disorders: A Systematic Review. Front Neurol. 2018; 9:347. PMC: 5992294. DOI: 10.3389/fneur.2018.00347. View

Faria M, Prats E, Bellot M, Gomez-Canela C, Raldua D . Pharmacological Modulation of Serotonin Levels in Zebrafish Larvae: Lessons for Identifying Environmental Neurotoxicants Targeting the Serotonergic System. Toxics. 2021; 9(6). PMC: 8227033. DOI: 10.3390/toxics9060118. View

10.

Blaser R, Chadwick L, McGinnis G . Behavioral measures of anxiety in zebrafish (Danio rerio). Behav Brain Res. 2009; 208(1):56-62. DOI: 10.1016/j.bbr.2009.11.009. View

11.

Parker M, Gaviria J, Haigh A, Millington M, Brown V, Combe F . Discrimination reversal and attentional sets in zebrafish (Danio rerio). Behav Brain Res. 2012; 232(1):264-8. PMC: 4167590. DOI: 10.1016/j.bbr.2012.04.035. View

12.

Cassar S, Adatto I, Freeman J, Gamse J, Iturria I, Lawrence C . Use of Zebrafish in Drug Discovery Toxicology. Chem Res Toxicol. 2019; 33(1):95-118. PMC: 7162671. DOI: 10.1021/acs.chemrestox.9b00335. View

13.

Kawashima T, Zwart M, Yang C, Mensh B, Ahrens M . The Serotonergic System Tracks the Outcomes of Actions to Mediate Short-Term Motor Learning. Cell. 2016; 167(4):933-946.e20. DOI: 10.1016/j.cell.2016.09.055. View

14.

Lovett-Barron M, Andalman A, Allen W, Vesuna S, Kauvar I, Burns V . Ancestral Circuits for the Coordinated Modulation of Brain State. Cell. 2017; 171(6):1411-1423.e17. PMC: 5725395. DOI: 10.1016/j.cell.2017.10.021. View

15.

Liu Y, Carmer R, Zhang G, Venkatraman P, Brown S, Pang C . Statistical Analysis of Zebrafish Locomotor Response. PLoS One. 2015; 10(10):e0139521. PMC: 4593604. DOI: 10.1371/journal.pone.0139521. View

16.

Scott C, Marsden A, Slusarski D . Automated, high-throughput, in vivo analysis of visual function using the zebrafish. Dev Dyn. 2016; 245(5):605-13. PMC: 4844763. DOI: 10.1002/dvdy.24398. View

17.

McLean D, Fetcho J . Ontogeny and innervation patterns of dopaminergic, noradrenergic, and serotonergic neurons in larval zebrafish. J Comp Neurol. 2004; 480(1):38-56. DOI: 10.1002/cne.20280. View

18.

Braida D, Ponzoni L, Martucci R, Sala M . A new model to study visual attention in zebrafish. Prog Neuropsychopharmacol Biol Psychiatry. 2014; 55:80-6. DOI: 10.1016/j.pnpbp.2014.03.010. View

19.

Mirat O, Sternberg J, Severi K, Wyart C . ZebraZoom: an automated program for high-throughput behavioral analysis and categorization. Front Neural Circuits. 2013; 7:107. PMC: 3679480. DOI: 10.3389/fncir.2013.00107. View

20.

Maximino C, Herculano A . A review of monoaminergic neuropsychopharmacology in zebrafish. Zebrafish. 2010; 7(4):359-78. DOI: 10.1089/zeb.2010.0669. View