Publications by authors named "William H J Norton"

30 Publications

  • Page 1 of 1

Using zebrafish (Danio rerio) models to understand the critical role of social interactions in mental health and wellbeing.

Prog Neurobiol 2021 Jan 10:101993. Epub 2021 Jan 10.

Graduate Program in Biological Sciences: Toxicological Biochemistry, Natural and Exact Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil; Laboratory of Experimental Neuropscychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil; The International Zebrafish Neuroscience Research Consortium (ZNRC), Slidell, LA, USA. Electronic address:

Social behavior represents a beneficial interaction between conspecifics that is critical for maintaining health and wellbeing. Dysfunctional or poor social interaction are associated with increased risk of physical (e.g., vascular) and psychiatric disorders (e.g., anxiety, depression, and substance abuse). Although the impact of negative and positive social interactions is well-studied, their underlying mechanisms remain poorly understood. Zebrafish have well-characterized social behavior phenotypes, high genetic homology with humans, relative experimental simplicity and the potential for high-throughput screens. Here, we discuss the use of zebrafish as a candidate model organism for studying the fundamental mechanisms underlying social interactions, as well as potential impacts of social isolation on human health and wellbeing. Overall, the growing utility of zebrafish models may improve our understanding of how the presence and absence of social interactions can differentially modulate various molecular and physiological biomarkers, as well as a wide range of other behaviors.
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http://dx.doi.org/10.1016/j.pneurobio.2021.101993DOI Listing
January 2021

Skin swabbing is a refined technique to collect DNA from model fish species.

Sci Rep 2020 10 23;10(1):18212. Epub 2020 Oct 23.

Department of Neuroscience, Psychology and Behaviour, College of Life Sciences, University of Leicester, Leicester, LE1 7RH, UK.

Model fish species such as sticklebacks and zebrafish are frequently used in studies that require DNA to be collected from live animals. This is typically achieved by fin clipping, a procedure that is simple and reliable to perform but that can harm fish. An alternative procedure to sample DNA involves swabbing the skin to collect mucus and epithelial cells. Although swabbing appears to be less invasive than fin clipping, it still requires fish to be netted, held in air and handled-procedures that can cause stress. In this study we combine behavioural and physiological analyses to investigate changes in gene expression, behaviour and welfare after fin clipping and swabbing. Swabbing led to a smaller change in cortisol release and behaviour on the first day of analysis compared to fin clipping. It also led to less variability in data suggesting that fewer animals need to be measured after using this technique. However, swabbing triggered some longer term changes in zebrafish behaviour suggesting a delayed response to sample collection. Skin swabbing does not require the use of anaesthetics and triggers fewer changes in behaviour and physiology than fin clipping. It is therefore a more refined technique for DNA collection with the potential to improve fish health and welfare.
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http://dx.doi.org/10.1038/s41598-020-75304-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584585PMC
October 2020

Chronic unpredictable early-life stress (CUELS) protocol: Early-life stress changes anxiety levels of adult zebrafish.

Prog Neuropsychopharmacol Biol Psychiatry 2020 Sep 2:110087. Epub 2020 Sep 2.

Brain and Behaviour Laboratory, School of Pharmacy and Biomedical Sciences, University of Portsmouth, UK; The International Zebrafish Neuroscience Research Consortium (ZNRC), 309 Palmer Court, Slidell, LA 70458, USA. Electronic address:

Early-life stress can lead to two different behavioral responses: (1) increased susceptibility to psychiatric disorders or (2) resilience. Here, we created a chronic unpredictable early-life stress (CUELS) protocol to assess the effects of early experiences in adult zebrafish. Animals were exposed to mild stressors twice a day and the duration was varied between groups (0, 1, 3, 7 and 14 days of stress). The stressor consisted of light/dark cycle changes; social isolation; overcrowding; water changes; water cooling; mechanical stirring; water heating; and immersion in shallow water. Behavior was assessed at young stages (21 days post-fertilization - open field analysis) and adulthood (4-months-old - novel tank diving test, light/dark task, shoaling, free movement pattern Y-maze and Pavlovian fear conditioning). Cortisol levels were assessed to evaluate the impact of CUELS in the HPI axis. Zebrafish exposed to 7 days of CUELS showed a decreased anxiety-like phenotype in two behavioral tasks, presenting increased time spent in top and decreased time spent in the dark area. Animals exposed to 14 days of CUELS showed an opposite anxious phenotype compared to 3 and 7 days of CUELS. No significant changes were observed in memory and cognition, social behavior and cortisol levels. In general, 7 days of CUELS protocol decreased anxiety in young and adult zebrafish, and could be used to understand the mechanisms underlying early-life experiences-derived alterations in neural circuits of anxiety.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110087DOI Listing
September 2020

The zebrafish histamine H3 receptor modulates aggression, neural activity and forebrain functional connectivity.

Acta Physiol (Oxf) 2020 12 12;230(4):e13543. Epub 2020 Aug 12.

Department of Neuroscience, Psychology and Behaviour, College of Life Sciences, University of Leicester, Leicester, UK.

Aim: Aggression is a behavioural trait characterized by the intention to harm others for offensive or defensive purposes. Neurotransmitters such as serotonin and dopamine are important mediators of aggression. However, the physiological role of the histaminergic system during this behaviour is currently unclear. Here, we aimed to better understand histaminergic signalling during aggression by characterizing the involvement of the histamine H3 receptor (Hrh3).

Methods: We have generated a novel zebrafish Hrh3 null mutant line using CRISPR-Cas9 genome engineering and investigated behavioural changes and alterations to neural activity using whole brain Ca imaging in zebrafish larvae and ribosomal protein S6 (rpS6) immunohistochemistry in adults.

Results: We show that genetic inactivation of the histamine H3 receptor (Hrh3) reduces aggression in zebrafish, an effect that can be reproduced by pharmacological inhibition. In addition, hrh3 zebrafish show behavioural impairments consistent with heightened anxiety. Larval in vivo whole brain Ca imaging reveals higher neuronal activity in the forebrain of mutants, but lower activity in specific hindbrain areas and changes in measures of functional connectivity between subregions. Adult hrh3 zebrafish display brain region-specific neural activity changes in response to aggression of both key regions of the social decision-making network, and the areas containing histaminergic neurons in the zebrafish brain.

Conclusion: These results highlight the importance of zebrafish Hrh3 signalling for aggression and anxiety and uncover the brain areas involved. Targeting this receptor might be a potential novel therapeutic route for human conditions characterized by heightened aggression.
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http://dx.doi.org/10.1111/apha.13543DOI Listing
December 2020

Serotonin (5-HT) neuron-specific inactivation of Cadherin-13 impacts 5-HT system formation and cognitive function.

Neuropharmacology 2020 05 28;168:108018. Epub 2020 Feb 28.

Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany; Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, the Netherlands. Electronic address:

Genome-wide screening approaches identified the cell adhesion molecule Cadherin-13 (CDH13) as a risk factor for neurodevelopmental disorders, nevertheless the contribution of CDH13 to the disease mechanism remains obscure. CDH13 is involved in neurite outgrowth and axon guidance during early brain development and we previously provided evidence that constitutive CDH13 deficiency influences the formation of the raphe serotonin (5-HT) system by modifying neuron-radial glia interaction. Here, we dissect the specific impact of CDH13 on 5-HT system development and function using a 5-HT neuron-specific Cdh13 knockout mouse model (conditional Cdh13 knockout, Cdh13 cKO). Our results show that exclusive inactivation of CDH13 in 5-HT neurons selectively increases 5-HT neuron density in the embryonic dorsal raphe, with persistence into adulthood, and serotonergic innervation of the developing prefrontal cortex. At the behavioral level, adult Cdh13 cKO mice display delayed acquisition of several learning tasks and a subtle impulsive-like phenotype, with decreased latency in a sociability paradigm alongside with deficits in visuospatial memory. Anxiety-related traits were not observed in Cdh13 cKO mice. Our findings further support the critical role of CDH13 in the development of dorsal raphe 5-HT circuitries, a mechanism that may underlie specific clinical features observed in neurodevelopmental disorders.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108018DOI Listing
May 2020

Screening for drugs to reduce zebrafish aggression identifies caffeine and sildenafil.

Eur Neuropsychopharmacol 2020 01 1;30:17-29. Epub 2019 Nov 1.

Department of Neuroscience, Psychology and Behaviour, College of Life Sciences, University of Leicester, Leicester LE1 7RH, UK. Electronic address:

Although aggression is a common symptom of psychiatric disorders the drugs available to treat it are non-specific and can have unwanted side effects. In this study we have used a behavioural platform in a phenotypic screen to identify drugs that can reduce zebrafish aggression without affecting locomotion. In a three tier screen of ninety-four drugs we discovered that caffeine and sildenafil can selectively reduce aggression. Caffeine also decreased attention and increased impulsivity in the 5-choice serial reaction time task whereas sildenafil showed the opposite effect. Imaging studies revealed that both caffeine and sildenafil are active in the zebrafish brain, with prominent activation of the thalamus and cerebellum evident. They also interact with 5-HT neurotransmitter signalling. In summary, we have demonstrated that juvenile zebrafish are a suitable model to screen for novel drugs to reduce aggression, with the potential to uncover the neural circuits and signalling pathways that mediate such behavioural effects.
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http://dx.doi.org/10.1016/j.euroneuro.2019.10.005DOI Listing
January 2020

Reelin Signaling Controls the Preference for Social Novelty in Zebrafish.

Front Behav Neurosci 2019 19;13:214. Epub 2019 Sep 19.

Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, United Kingdom.

Reelin (Reln) is an extracellular glycoprotein that is important for brain patterning. During development Reln coordinates the radial migration of postmitotic cortical neurons, cerebellar and hippocampal neurons, whereas it promotes dendrite maturation, synaptogenesis, synaptic transmission, plasticity and neurotransmitter release in the postnatal and adult brain. Genetic studies of human patients have demonstrated association between the RELN locus and autism spectrum disorder, schizophrenia, bipolar disorder, and Alzheimer's disease. In this study we have characterized the behavioral phenotype of () mutant zebrafish, as well as two canonical signaling pathway targets () and the (). Zebrafish mutants display a selective reduction in preference for social novelty that is not observed in or mutant lines. They also exhibit an increase in 5-HT signaling in the hindbrain that parallels but does not underpin the alteration in social preference. These results suggest that zebrafish mutants can be used to model some aspects of human diseases in which changes to Reln signaling alter social behavior.
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http://dx.doi.org/10.3389/fnbeh.2019.00214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761276PMC
September 2019

The Visually Mediated Social Preference Test: A Novel Technique to Measure Social Behavior and Behavioral Disturbances in Zebrafish.

Methods Mol Biol 2019 ;2011:121-132

Otto Loewi Research Centre, Medical University of Graz, Graz, Austria.

Zebrafish are an emerging model in behavioral neuroscience. They display a wide range of measurable behaviors such as locomotion, aggression, anxiety, learning and memory, and social behavior. In addition, the relative ease of genetic manipulation and the increasing availability of disease models mean that zebrafish have gained in popularity as an animal model for various neurological and psychiatric diseases including autism spectrum disorder (ASD). In order to better characterize social behavior and behavioral abnormalities in zebrafish, we have developed the visually mediated social preference (VMSP) test, a novel assay to measure social preference and social novelty in two consecutive 5-min sessions. Using recording and video tracking, the time spent in different areas of the tank, the time spent immobile, swimming speed, and distance moved can be easily measured and analyzed. Untreated experimentally naive AB WT zebrafish typically show a strong preference for spending time near and interacting with a compartment containing unfamiliar conspecifics over the empty compartments during session 1 and a stronger preference for a group of unfamiliar zebrafish over familiar conspecifics from session 1, during session 2 of the test. Research in our lab has shown that the VMSP is suitable to measure the social behavior of individual zebrafish, to uncover social phenotypes of mutant strains, and to better understand animal models of disease that include impaired sociability such as ASD. The current paper provides a step-by-step guide on how to implement and perform this test and highlights important considerations for data acquisition, analysis, and interpretation.
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http://dx.doi.org/10.1007/978-1-4939-9554-7_8DOI Listing
March 2020

Correction: The three-spined stickleback as a model for behavioural neuroscience.

PLoS One 2019 1;14(5):e0216518. Epub 2019 May 1.

[This corrects the article DOI: 10.1371/journal.pone.0213320.].
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216518PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493743PMC
May 2019

The three-spined stickleback as a model for behavioural neuroscience.

PLoS One 2019 26;14(3):e0213320. Epub 2019 Mar 26.

Department of Neuroscience, Psychology and Behaviour, College of Life Sciences, University of Leicester, Leicester, United Kingdom.

The three-spined stickleback (Gasterosteus aculeatus) is a small teleost fish that is ubiquitous across the Northern Hemisphere. Among the behaviours that have been characterised in this species is ritualized courtship, aggressiveness and parental behaviour. Whereas three-spined sticklebacks have been used for ecological, evolutionary, parasitological and toxicological research, its complex behavioural repertoire and experimental advantages have not been exploited for basic neuroscience research. The aim of the present study is to describe some innate behaviours of laboratory bred three-spined sticklebacks by using a battery of tests that have been developed and validated to model some aspects of human psychiatric disorders in zebrafish. We recorded mirror induced aggression, novel object boldness, shoaling, and anxiety-like behaviour using both the novel tank diving and the black-white preference tests. We show that behaviour of three-spined sticklebacks in these standard tests is remarkably similar to that of zebrafish and other species and can be altered by fluoxetine and buspirone. These findings highlight the potential of using three-spined sticklebacks for cross-species and translational studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213320PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435232PMC
December 2019

Endothelin neurotransmitter signalling controls zebrafish social behaviour.

Sci Rep 2019 02 28;9(1):3040. Epub 2019 Feb 28.

Department of Neuroscience, Psychology and Behaviour, College of Life Sciences, University of Leicester, Leicester, LE1 7RH, UK.

The formation of social groups is an adaptive behaviour that can provide protection from predators, improve foraging and facilitate social learning. However, the costs of proximity can include competition for resources, aggression and kleptoparasitism meaning that the decision whether to interact represents a trade-off. Here we show that zebrafish harbouring a mutation in endothelin receptor aa (ednraa) form less cohesive shoals than wild-types. ednraa mutants exhibit heightened aggression and decreased whole-body cortisol levels suggesting that they are dominant. These behavioural changes correlate with a reduction of parvocellular arginine vasopressin (AVP)-positive neurons in the preoptic area, an increase in the size of magnocellular AVP neurons and a higher concentration of 5-HT and dopamine in the brain. Manipulation of AVP or 5-HT signalling can rescue the shoaling phenotype of ednraa providing an insight into how the brain controls social interactions.
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http://dx.doi.org/10.1038/s41598-019-39907-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395658PMC
February 2019

Zebrafish models for attention deficit hyperactivity disorder (ADHD).

Neurosci Biobehav Rev 2019 05 16;100:9-18. Epub 2019 Feb 16.

Brain and Behaviour Laboratory, School of Pharmacy and Biomedical Sciences, University of Portsmouth, UK; The International Zebrafish Neuroscience Research Consortium (ZNRC), 309 Palmer Court, Slidell, LA 70458, USA. Electronic address:

Attention deficit hyperactivity disorder (ADHD) is a common, debilitating neurodevelopmental disorder associated with inattentiveness, pathological hyperactivity and impulsivity. Despite the mounting human and animal evidence, the neurological pathways underlying ADHD remain poorly understood. Novel translational model organisms, such as the zebrafish (Danio rerio), are becoming important tools to investigate genetic and pathophysiological mechanisms of various neuropsychiatric disorders. Here, we discuss ADHD etiology, existing animal models and their limitations, and emphasize the advantages of using zebrafish to model ADHD. Overall, the growing utility of zebrafish models may improve our understanding of ADHD and facilitate drug discovery to prevent or treat this disorder.
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http://dx.doi.org/10.1016/j.neubiorev.2019.02.009DOI Listing
May 2019

Cross-species models of attention-deficit/hyperactivity disorder and autism spectrum disorder: lessons from CNTNAP2, ADGRL3, and PARK2.

Psychiatr Genet 2019 02;29(1):1-17

Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK.

Animal and cellular models are essential tools for all areas of biological research including neuroscience. Model systems can also be used to investigate the pathophysiology of psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In this review, we provide a summary of animal and cellular models for three genes linked to ADHD and ASD in human patients - CNTNAP2, ADGRL3, and PARK2. We also highlight the strengths and weaknesses of each model system. By bringing together behavioral and neurobiological data, we demonstrate how a cross-species approach can provide integrated insights into gene function and the pathogenesis of ADHD and ASD. The knowledge gained from transgenic models will be essential to discover and validate new treatment targets for these disorders.
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http://dx.doi.org/10.1097/YPG.0000000000000211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654943PMC
February 2019

Screening for drugs to reduce aggression in zebrafish.

Neuropharmacology 2019 09 16;156:107394. Epub 2018 Oct 16.

Department of Neuroscience, Psychology and Behaviour, College of Life Sciences, University of Leicester, Leicester, LE1 7RH, UK. Electronic address:

Aggression is a common symptom of several human psychiatric disorders. However, the drugs available to treat aggression are non-specific and can have unwanted side effects. The zebrafish is an ideal model for behavioural pharmacology. They are small, aggression can be measured reliably, and drugs can be applied by immersion in the tank water. The ability to visualise and manipulate circuits in the intact brain represents an excellent opportunity to understand how chemical compounds modify the signalling pathways that control this behaviour. This review discusses protocols to measure zebrafish aggression, the neural circuits that control this behaviour and how pharmacological studies can inform us about environmental toxicology and the development of therapeutic drugs for humans. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.
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http://dx.doi.org/10.1016/j.neuropharm.2018.10.023DOI Listing
September 2019

Pharmacological analysis of zebrafish lphn3.1 morphant larvae suggests that saturated dopaminergic signaling could underlie the ADHD-like locomotor hyperactivity.

Prog Neuropsychopharmacol Biol Psychiatry 2018 06 26;84(Pt A):181-189. Epub 2018 Feb 26.

Paris-Saclay Institute for Neuroscience (Neuro-PSI), UMR 9197, CNRS - Université Paris-Sud, Team Zebrafish Neurogenetics, Avenue de la Terrasse, F-91190 Gif-sur-Yvette, France; Unit Zebrafish Neurogenetics, Department of Developmental and Stem Cell Biology, Institut Pasteur and CNRS UMR3738, 25 rue du Dr Roux, 75015 Paris, France. Electronic address:

Polymorphisms in the gene coding for the adhesion G-protein coupled receptor LPHN3 are a risk factor for attention-deficit/hyperactivity disorder (ADHD). Transient down-regulation of latrophilin3.1 (lphn3.1), the zebrafish LPHN3 homologue, causes hyperactivity. Zebrafish injected with a lphn3.1-specific morpholino are hyperactive and display an impairment in dopaminergic neuron development. In the present study we used lphn3.1 morphants to further characterize the changes to dopaminergic signaling that trigger hyperactivity. We applied dopamine agonists (Apomorphine, Quinpirole, SKF-38393) and antagonists (Haloperidol, Eticlopride, SCH-23390) to Lphn3.1 morpholino-injected or control-injected animals. The percentage of change in locomotor activity was then determined at three different time periods (10-20 min, 30-40 min and 60-70 min). Our results show that drugs targeting dopamine receptors appear to elicit similar effects on locomotion in zebrafish larvae and mammals. In addition, we observed that lphn3.1 morphants have an overall hyposensitivity to dopamine agonists and antagonists compared to control fish. These results are compatible with a model whereby dopaminergic neurotransmission is saturated in lphn3.1 morphants.
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http://dx.doi.org/10.1016/j.pnpbp.2018.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912797PMC
June 2018

MicroRNA degradation by a conserved target RNA regulates animal behavior.

Nat Struct Mol Biol 2018 03 26;25(3):244-251. Epub 2018 Feb 26.

Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, Paris, France.

microRNAs (miRNAs) repress target transcripts through partial complementarity. By contrast, highly complementary miRNA-binding sites within viral and artificially engineered transcripts induce miRNA degradation in vitro and in cell lines. Here, we show that a genome-encoded transcript harboring a near-perfect and deeply conserved miRNA-binding site for miR-29 controls zebrafish and mouse behavior. This transcript originated in basal vertebrates as a long noncoding RNA (lncRNA) and evolved to the protein-coding gene NREP in mammals, where the miR-29-binding site is located within the 3' UTR. We show that the near-perfect miRNA site selectively triggers miR-29b destabilization through 3' trimming and restricts its spatial expression in the cerebellum. Genetic disruption of the miR-29 site within mouse Nrep results in ectopic expression of cerebellar miR-29b and impaired coordination and motor learning. Thus, we demonstrate an endogenous target-RNA-directed miRNA degradation event and its requirement for animal behavior.
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http://dx.doi.org/10.1038/s41594-018-0032-xDOI Listing
March 2018

Automatic quantification of juvenile zebrafish aggression.

J Neurosci Methods 2018 02 21;296:23-31. Epub 2017 Dec 21.

Department of Neuroscience, Psychology and Behaviour, College of Medicine, Biological Sciences and Psychology, University of Leicester, Leicester, LE1 7RH, UK. Electronic address:

Background: Although aggression is a common symptom of psychiatric disorders the drugs available to treat it are non-specific and can have unwanted side effects. The zebrafish is an ideal model for aggression research. Zebrafish are small, amenable to genetic and pharmacological manipulation, and agonistic behaviour can be measured reliably.

New Method: In this study we have established a novel setup to automatically quantify aggression and locomotion in one-month old juvenile zebrafish, a stage at which fish exhibit adult-like behaviour but are small so that one camera can film several animals.

Results: We have validated our novel software by comparison to manual quantification of behaviour, characterised the aggression of one-month old fish, and demonstrated that we can detect alterations to aggression caused by mutation or drug application.

Comparison With Other Methods: The ability to record up to 12 juvenile fish allows us to speed up and standardise data acquisition compared to studies of single fish.

Conclusions: This setup appears to be suitable to screen for drugs that decrease zebrafish aggression as a first step toward developing novel treatments for this behaviour.
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http://dx.doi.org/10.1016/j.jneumeth.2017.12.012DOI Listing
February 2018

Nitric oxide interacts with monoamine oxidase to modulate aggression and anxiety-like behaviour.

Eur Neuropsychopharmacol 2020 01 23;30:30-43. Epub 2017 Sep 23.

Department of Neuroscience, Psychology and Behaviour, University of Leicester, University Rd, Leicester, LE1 7RH, UK. Electronic address:

Nitric oxide (NO) is a gaseous neurotransmitter that has important behavioural functions in the vertebrate brain. In this study we compare the impact of decreased nitric NO signalling upon behaviour and neurobiology using both zebrafish and mouse. nitric oxide synthase mutant (nos1) zebrafish show significantly reduced aggression and an increase in anxiety-like behaviour without altered production of the stress hormone cortisol. Nos1 mice also exhibit decreased aggression and are hyperactive in an open field test. Upon reduction of NO signalling, monoamine neurotransmitter metabolism is reduced as a consequence of decreased Monoamine oxidase activity. Treatment of nos1 zebrafish with the 5-HT receptor 1A agonist 8-OH-DPAT rescues aggression and some aspects of anxiety-like behaviour. Taken together, the interplay between NO and 5-HT appears to be critical to control behaviour. Our cross-species approach challenges the previous notion that reduced neuronal NOS leads to increased aggression. Rather, Nos1 knock-out can also lead to decreased aggression in some situations, a finding that may have implications for future translational research.
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http://dx.doi.org/10.1016/j.euroneuro.2017.09.004DOI Listing
January 2020

A Low-Cost Method of Skin Swabbing for the Collection of DNA Samples from Small Laboratory Fish.

Zebrafish 2017 02 27;14(1):35-41. Epub 2016 Oct 27.

Department of Neuroscience, Psychology and Behaviour, College of Medicine, Biological Sciences and Psychology, University of Leicester , Leicester, United Kingdom .

Fin clipping of live fish under anesthesia is widely used to collect samples for DNA extraction. An alternative, potentially less invasive, approach involves obtaining samples by swabbing the skin of nonanesthetized fish. However, this method has yet to be widely adopted for use in laboratory studies in the biological and biomedical sciences. Here, we compare DNA samples from zebrafish Danio rerio and three-spined sticklebacks Gasterosteus aculeatus collected via fin clipping and skin swabbing techniques, and test a range of DNA extraction methods, including commercially available kits and a lower-cost, in-house method. We verify the method for polymerase chain reaction analysis, and examine the potential risk of cross contamination between individual fish that are netted together. We show that swabbing, which may not require the use of anesthesia or analgesics, offers a reliable alternative to fin clipping. Further work is now required to determine the relative effects of fin clipping and swabbing on the stress responses and subsequent health of fish, and hence the potential of swabbing as a refinement to existing DNA sampling procedures.
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http://dx.doi.org/10.1089/zeb.2016.1348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312459PMC
February 2017

Neurochemical measurements in the zebrafish brain.

Front Behav Neurosci 2015 8;9:246. Epub 2015 Sep 8.

Department of Neuroscience, Psychology and Behaviour, University of Leicester Leicester, UK.

The zebrafish is an ideal model organism for behavioral genetics and neuroscience. The high conservation of genes and neurotransmitter pathways between zebrafish and other vertebrates permits the translation of research between species. Zebrafish behavior can be studied at both larval and adult stages and recent research has begun to establish zebrafish models for human disease. Fast scan cyclic voltammetry (FSCV) is an electrochemical technique that permits the detection of neurotransmitter release and reuptake. In this study we have used in vitro FSCV to measure the release of analytes in the adult zebrafish telencephalon. We compare different stimulation methods and present a characterization of neurochemical changes in the wild-type zebrafish brain. This study represents the first FSCV recordings in zebrafish, thus paving the way for neurochemical analysis of the fish brain.
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http://dx.doi.org/10.3389/fnbeh.2015.00246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561813PMC
October 2015

Aggression in non-human vertebrates: Genetic mechanisms and molecular pathways.

Am J Med Genet B Neuropsychiatr Genet 2016 07 18;171(5):603-40. Epub 2015 Aug 18.

Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK.

Aggression is an adaptive behavioral trait that is important for the establishment of social hierarchies and competition for mating partners, food, and territories. While a certain level of aggression can be beneficial for the survival of an individual or species, abnormal aggression levels can be detrimental. Abnormal aggression is commonly found in human patients with psychiatric disorders. The predisposition to aggression is influenced by a combination of environmental and genetic factors and a large number of genes have been associated with aggression in both human and animal studies. In this review, we compare and contrast aggression studies in zebrafish and mouse. We present gene ontology and pathway analyses of genes linked to aggression and discuss the molecular pathways that underpin agonistic behavior in these species. © 2015 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.b.32358DOI Listing
July 2016

Using zebrafish to uncover the genetic and neural basis of aggression, a frequent comorbid symptom of psychiatric disorders.

Behav Brain Res 2015 Jan 2;276:171-80. Epub 2014 Jun 2.

University of Leicester, Department of Biology, College of Medicine, Biological Sciences and Psychiatry, Adrian Building, University Rd, Leicester LE1 7RH, UK. Electronic address:

Aggression is an important adaptive behavior that can be used to monopolize resources such as mates or food, acquire and defend territory and establish dominant hierarchies in social groups. It is also a symptom of several psychiatric disorders including attention-deficit/hyperactivity disorder and schizophrenia. The frequent comorbidity of aggression and psychiatric diseases suggests that common genes and neural circuits may link these disorders. Research using animal models has the potential to uncover these genes and neural circuits despite the difficulty of fully modeling human behavioral disorders. In this review we propose that zebrafish may be a suitable model organism for aggression research with the potential to shed light upon the aggressive symptoms of human diseases.
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http://dx.doi.org/10.1016/j.bbr.2014.05.055DOI Listing
January 2015

Inter-individual and inter-strain variations in zebrafish locomotor ontogeny.

PLoS One 2013 9;8(8):e70172. Epub 2013 Aug 9.

Zebrafish Neurogenetics, Neurobiologie et Développement, Insitut de Neurobiologie Albert Fessard, Centre National de la Recherche Scientifique, Gif-sur-Yvette, Essonne, France.

Zebrafish exhibit remarkable alterations in behaviour and morphology as they develop from early larval stages to mature adults. In this study we compare the locomotion parameters of six common zebrafish strains from two different laboratories to determine the stability and repeatability of these behaviours. Our results demonstrate large variability in locomotion and fast swim events between strains and between laboratories across time. These data highlight the necessity for careful, strain-specific controls when analysing locomotor phenotypes and open up the possibility of standardising the quantification of zebrafish behaviour at multiple life stages.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070172PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739779PMC
March 2014

Toward developmental models of psychiatric disorders in zebrafish.

Front Neural Circuits 2013 26;7:79. Epub 2013 Apr 26.

Department of Biology, College of Medicine, Biological Sciences and Psychiatry, University of Leicester Leicester, UK.

Psychiatric disorders are a diverse set of diseases that affect all aspects of mental function including social interaction, thinking, feeling, and mood. Although psychiatric disorders place a large economic burden on society, the drugs available to treat them are often palliative with variable efficacy and intolerable side-effects. The development of novel drugs has been hindered by a lack of knowledge about the etiology of these diseases. It is thus necessary to further investigate psychiatric disorders using a combination of human molecular genetics, gene-by-environment studies, in vitro pharmacological and biochemistry experiments, animal models, and investigation of the non-biological basis of these diseases, such as environmental effects. Many psychiatric disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, mental retardation, and schizophrenia can be triggered by alterations to neural development. The zebrafish is a popular model for developmental biology that is increasingly used to study human disease. Recent work has extended this approach to examine psychiatric disorders as well. However, since psychiatric disorders affect complex mental functions that might be human specific, it is not possible to fully model them in fish. In this review, I will propose that the suitability of zebrafish for developmental studies, and the genetic tools available to manipulate them, provide a powerful model to study the roles of genes that are linked to psychiatric disorders during neural development. The relative speed and ease of conducting experiments in zebrafish can be used to address two areas of future research: the contribution of environmental factors to disease onset, and screening for novel therapeutic compounds.
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http://dx.doi.org/10.3389/fncir.2013.00079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636468PMC
May 2014

Homeodomain protein otp and activity-dependent splicing modulate neuronal adaptation to stress.

Neuron 2012 Jan;73(2):279-91

Department of Molecular Cell Biology, Weizmann Institute of Science, P.O. Box 26, Rehovot 76100, Israel.

Regulation of corticotropin-releasing hormone (CRH) activity is critical for the animal's adaptation to stressful challenges, and its dysregulation is associated with psychiatric disorders in humans. However, the molecular mechanism underlying this transcriptional response to stress is not well understood. Using various stress paradigms in mouse and zebrafish, we show that the hypothalamic transcription factor Orthopedia modulates the expression of CRH as well as the splicing factor Ataxin 2-Binding Protein-1 (A2BP1/Rbfox-1). We further show that the G protein coupled receptor PAC1, which is a known A2BP1/Rbfox-1 splicing target and an important mediator of CRH activity, is alternatively spliced in response to a stressful challenge. The generation of PAC1-hop messenger RNA isoform by alternative splicing is required for termination of CRH transcription, normal activation of the hypothalamic-pituitary-adrenal axis and adaptive anxiety-like behavior. Our study identifies an evolutionarily conserved biochemical pathway that modulates the neuronal adaptation to stress through transcriptional activation and alternative splicing.
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http://dx.doi.org/10.1016/j.neuron.2011.11.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387198PMC
January 2012

Modulation of Fgfr1a signaling in zebrafish reveals a genetic basis for the aggression-boldness syndrome.

J Neurosci 2011 Sep;31(39):13796-807

Zebrafish Neurogenetics, Laboratory of Neurobiology and Development, Institut de Neurobiologie Alfred Fessard, Unité Propre de Recherche 3294, CNRS, Avenue de la Terrasse, Gif-sur-Yvette, 91190, France.

Behavioral syndromes are suites of two or more behaviors that correlate across environmental contexts. The aggression-boldness syndrome links aggression, boldness, and exploratory activity in a novel environment. Although aggression-boldness has been described in many animals, the mechanism linking its behavioral components is not known. Here we show that mutation of the gene encoding fibroblast growth factor receptor 1a (fgfr1a) simultaneously increases aggression, boldness, and exploration in adult zebrafish. We demonstrate that altered Fgf signaling also results in reduced brain histamine levels in mutants. Pharmacological increase of histamine signaling is sufficient to rescue the behavioral phenotype of fgfr1a mutants. Together, we show that a single genetic locus can underlie the aggression-boldness behavioral syndrome. We also identify one of the neurotransmitter pathways that may mediate clustering of these behaviors.
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http://dx.doi.org/10.1523/JNEUROSCI.2892-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633160PMC
September 2011

Comparative analysis of serotonin receptor (HTR1A/HTR1B families) and transporter (slc6a4a/b) gene expression in the zebrafish brain.

J Comp Neurol 2008 Dec;511(4):521-42

Zebrafish Neurogenetics, Institute of Developmental Genetics, HelmholtzZentrum muenchen, 85764, Neuherberg, Germany.

In this study we analyze 5-hydroxytryptamine [5-HT]; serotonin) signaling in zebrafish, an increasingly popular vertebrate disease model. We compare and contrast expression of the 5-HT transporter genes slc6a4a and slc6a4b, which identify 5-HT-producing neurons and three novel 5-HT receptors, htr1aa, htr1ab, and htr1bd. slc6a4a and slc6a4b are expressed in the raphe nuclei, retina, medulla oblongata, paraventricular organ, pretectal diencephalic complex, and caudal zone of the periventricular hypothalamus, in line with the expression profiles of homologues from other vertebrates. Our analysis of serotonin transporter (SERT)-encoding genes also identifies parallel genetic pathways used to build the 5-HT system in zebrafish. In cells in which 5-HT is synthesized by tph1, slc6a4b is used for re-uptake, whereas tph2-positive cells utilize slc6a4a. The receptors htr1aa, htr1ab, and htr1bd also show widespread expression in both the larval and adult brain. Receptor expression is seen in the superior raphe nucleus, retina, ventral telencephalon, optic tectum, thalamus, posterior tuberculum, cerebellum, hypothalamus, and reticular formation, thus implicating 5-HT signaling in several neural circuits. We also examine larval brains double-labeled with 5-HTergic and dopaminergic pathway-specific antibodies, to uncover the identity of some 5-HTergic target neurons. Furthermore, comparison of the expression of transporter and receptor genes also allows us to map sites of autoreceptor activity within the brain. We detect autoreceptor activity in the pretectal diencephalic cluster (htr1aa-, htr1ab-, htr1bd-, and slc6a4a-positive), superior raphe nucleus (htr1aa-, htr1ab-, and slc6a4a-positive), paraventricular organ (htr1aa-, htr1ab-, htr1bd-, and slc6a4b-positive), and the caudal zone of the periventricular hypothalamus (htr1ab- and slc6a4b-positive).
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http://dx.doi.org/10.1002/cne.21831DOI Listing
December 2008

Dynamic Fgf signaling couples morphogenesis and migration in the zebrafish lateral line primordium.

Development 2008 Aug 3;135(16):2695-705. Epub 2008 Jul 3.

European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, Germany.

The collective migration of cells in the form of cohesive tissues is a hallmark of both morphogenesis and repair. The extrinsic cues that direct these complex migrations usually act by regulating the dynamics of a specific subset of cells, those at the leading edge. Given that normally the function of tissue migration is to lay down multicellular structures, such as branched epithelial networks or sensory organs, it is surprising how little is known about the mechanisms that organize cells behind the leading edge. Cells of the zebrafish lateral line primordium switch from mesenchyme-like leader cells to epithelial rosettes that develop into mechanosensory organs. Here, we show that this transition is regulated by an Fgf signaling circuit that is active within the migrating primordium. Point sources of Fgf ligand drive surrounding cells towards a ;non-leader' fate by increasing their epithelial character, a prerequisite for rosette formation. We demonstrate that the dynamic expression of Fgf ligands determines the spatiotemporal pattern of epithelialization underlying sensory organ formation in the lateral line. Furthermore, this work uncovers a surprising link between internal tissue organization and collective migration.
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http://dx.doi.org/10.1242/dev.025981DOI Listing
August 2008

HSPG synthesis by zebrafish Ext2 and Extl3 is required for Fgf10 signalling during limb development.

Development 2005 Nov 12;132(22):4963-73. Epub 2005 Oct 12.

European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

Heparan sulphate proteoglycans (HSPGs) are known to be crucial for signalling by the secreted Wnt, Hedgehog, Bmp and Fgf proteins during invertebrate development. However, relatively little is known about their effect on developmental signalling in vertebrates. Here, we report the analysis of daedalus, a novel zebrafish pectoral fin mutant. Positional cloning identified fgf10 as the gene disrupted in daedalus. We find that fgf10 mutants strongly resemble zebrafish ext2 and extl3 mutants, which encode glycosyltransferases required for heparan sulphate biosynthesis. This suggests that HSPGs are crucial for Fgf10 signalling during limb development. Consistent with this proposal, we observe a strong genetic interaction between fgf10 and extl3 mutants. Furthermore, application of Fgf10 protein can rescue target gene activation in fgf10, but not in ext2 or extl3 mutants. By contrast, application of Fgf4 protein can activate target genes in both ext2 and extl3 mutants, indicating that ext2 and extl3 are differentially required for Fgf10, but not Fgf4, signalling during limb development. This reveals an unexpected specificity of HSPGs in regulating distinct vertebrate Fgfs.
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http://dx.doi.org/10.1242/dev.02084DOI Listing
November 2005

Histone deacetylase 1 is required for cell cycle exit and differentiation in the zebrafish retina.

Dev Dyn 2005 Jul;233(3):883-9

European Molecular Biology Laboratory, Heidelberg, Germany.

Histone acetylation is an important epigenetic mechanism for the control of eukaryotic transcription. The histone deacetylase 1 (HDAC1) gene has been implicated in controlling the transcription of core cell cycle regulators, but the in vivo role of HDACs in cell cycle regulation is still poorly understood. Loss of HDAC1 activity causes underproliferation in several contexts during vertebrate development. In contrast, we show here that HDAC1 has the opposite effect in the zebrafish visual system, where loss of HDAC1 activity leads to failure of cells to exit the cell cycle in the retina and in the optic stalk. The effect of HDAC1 on cell cycle exit is cell-autonomous, and loss of HDAC1 in the retina leads to up-regulation of cyclin D and E transcripts. These results demonstrate that the in vivo role of HDAC1 in regulating cell cycle progression is region-specific, as HDAC1 promotes cell cycle exit in the retina but stimulates proliferation in other cellular contexts.
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http://dx.doi.org/10.1002/dvdy.20427DOI Listing
July 2005