Dr Matt Parker

Senior Lecturer in Neuroscience and Sleep Science


Areas of specialism

neuroscience; impulsivity; animal behaviour

My qualifications

BSc Psychology (1st Class Hons)
University of Southampton
MSc Research Methods
University of Southampton
PhD Experimental Psychology
University of Southampton

Previous roles

01 September 2015 - 02 October 2022
Reader in Neuroscience and Psychopharmacology
University of Portsmouth
01 September 2014 - 30 August 2015
Lecturer Cell Biology and Developmental Genetics
Queen Mary University of London


In the media

Five ways fish are more human that you realise
The Conversation
What alcohol does to your body, unit by unit
Daily Telegraph
Why you might be drinking too much in lockdown
BBC Future


Research interests

Indicators of esteem

  • BBSRC Panel A - Member of Panel of Experts (2022 - present)

  • NC3Rs Member of 'Skills and Knowledge Transfer Grants' Panel (2022-present)

  • National Science Center (NCN; Poland) Member of NZ7 panel (Diagnostic Tools, Therapies and Public Health) (2022-present)

  • Associate Editor for the Journal of Veterinary Behavior 



Sveinsdóttir, H.S., Christensen, C., Þorsteinsson, H., Lavalou, P., Parker, M.O., Shkumatava, A., Norton, W.H.J., Andriambeloson, E., Wagner, S. & Karlsson, K.Æ. (2022). Novel non-stimulants rescue hyperactive phenotype in an adgrl3.1 mutant zebrafish model of ADHD. Neuropsychopharmacology. (Available online).

Ismail, V., Zachariassen, L., Godwin, A., Ellard, S., Stals, K.L., Brown, K.T., Foulds, N., Wheway, G., Parker, M.O., Sahakian, M, Lyngby, S.M., Pedersen, M.G., Desir, J., Bayat, A., Musgaard, M., Guille, M., Kristensen, A.S., Barelle, D. (2022). Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with intellectual disability: An emerging neurodevelopmental syndrome. American Journal of Human Genetics. (Available online).

Lewis, K., Proops, L., Parker, M.O., McBride, S.D. (2022). Risk factors for stereotypic behaviour in captive ungulates. Proceedings of the Royal Society B: Biological Sciences. (Available online).

Whitehouse, J., Milward, S.J., Parker, M.O., Kavanagh, E., Waller, B.M. (2022). Signal value of stress behaviour. Evolution and Human Behavior. (Available online).

Clay, J.M., Stafford, L.D., Parker, M.O. (2021) Associations between self-reported inhibitory control, stress, and alcohol (mis)use during the first wave of the COVID-19 pandemic in the UK: a national cross-sectional study utilising data from four birth cohorts. International Journal of Mental Health and Addiction. Available online from medRxiv https://doi.org/10.1101/2020.09.24.20197293.

Fontana, B.D., Cleal, M., McBride, S.D., Gibbon, A., Parker, M.O. (2021). The effects of two stressors on working memory and cognitive flexibility in zebrafish (Danio rerio): The protective role of D1/D5 agonist on stress responses. Neuropharmacology, 196, 108681.

Cleal, M., Fontana, B.D., Double, M., Mezabrovschi, R., Parcell, L., Redhead, E., Parker, M.O. (2021) Dopaminergic Modulation of Working Memory and Cognitive Flexibility in a Zebrafish Model of Aging-Related Cognitive Decline. Neurobiology of Aging, 102, 1-16. Available from Biorxiv: https://doi.org/10.1101/2020.06.05.136077

Clay, J.M., Parker, M.O. (2020). Alcohol use and misuse during the COVID-19 pandemic: a potential public health crisis? The Lancet Public Health, e259.

García-González, J., Brock, A.J., Parker, M.O., Riley, R., Jolliffe, D., Sudwarts, A., Teh, M-T., Busch-Nentwich, E.M., Stemple, D.L., Martineau, A.R., Kaprio, J., Palviainen, T., Kuan, V., Walton, R.T., Brennan, C.H. (2020). Identification of Slit3 as a locus affecting nicotine preference in zebrafish and human smoking behaviour. eLife, 9, e51295.

Murilo S. de Abreu, Matthew O. Parker, Allan V. Kalueff (2022)The critical impact of sex on preclinical alcohol research – Insights from zebrafish, In: Frontiers in neuroendocrinology67101014 Elsevier Inc

•Sex is an important biological variable in translational neuroscience research.•There are overt sex differences in clinical and preclinical alcohol research.•The use of zebrafish (Danio rerio) in pre-clinical alcohol research rapidly grows.•Here, we discuss zebrafish models to study sex differences in alcohol brain action. Sex is an important biological variable that is widely recognized in studies of alcohol-related effects. Complementing clinical and preclinical rodent research, the zebrafish (Danio rerio) is the second most used laboratory species, and a powerful model organism in biomedicine. Like clinical and rodent models, zebrafish demonstrate overt sex differences in alcohol-related responses. Collectively, this evidence shows that the zebrafish becomes a sensitive model species to further probe in-depth sex differences commonly reported in alcohol research.

Jamie Whitehouse, Sophie J. Milward, Matthew O. Parker, Eithne Kavanagh, Bridget M. Waller (2022)Signal value of stress behaviour, In: Evolution and human behavior43(4)pp. 325-333 Elsevier Inc

Physiological and psychological stress are accompanied by nonverbal behaviour across a wide range of species. The function of this ‘stress behaviour’ is not well understood but is often assumed to be read by others as a cue to stress. Displaying signs of weakness is, however, difficult to understand from an evolutionary perspective and therefore further investigation into why these behaviours exist is needed. Here, we test whether displacement behaviours (i.e., those known to be associated with stress) are reliable indicators of stress in humans. To do this, we presented raters (N = 133) with videos of individuals (N = 31) undergoing a stress-inducting task. Self-directed displacement behaviours and self-reported stress were both associated with stress ratings given by raters. Therefore, such behaviours can provide reliable information to others and can be considered communicative. Individuals producing more nonverbal stress behaviour were rated as more likeable by raters (perhaps presenting as more honest signallers), indicating a benefit and potential adaptive function of displaying stress. Raters also differed in their accuracy in detecting stress from nonverbal cues. Findings suggest that the accuracy with which individuals were able to detect stress was linked to the number of social connections they reported to have. However, this association was non-linear, with individuals who were most and least accurate reporting the least network connections. This could indicate that the ability to read behaviour is associated with an ability to form and maintain social networks.

Judith R Homberg, Evan J Kyzar, Adam Michael Stewart, Michael Nguyen, Manoj K Poudel, David J Echevarria, Adam D Collier, Siddharth Gaikwad, Viktor M Klimenko, William Norton, Julian Pittman, Shun Nakamura, Mamiko Koshiba, Hideo Yamanouchi, Sergey A Apryatin, Maria Luisa Scattoni, David M Diamond, Jeremy FP Ullmann, Matthew O Parker, Richard E Brown, Cai Song, Allan V Kalueff (2016)Improving treatment of neurodevelopmental disorders: recommendations based on preclinical studies, In: Expert opinion on drug discovery11(1)pp. 11-25 Taylor & Francis

Introduction: Neurodevelopmental disorders (NDDs) are common and severely debilitating. Their chronic nature and reliance on both genetic and environmental factors makes studying NDDs and their treatment a challenging task. Areas covered: Herein, the authors discuss the neurobiological mechanisms of NDDs, and present recommendations on their translational research and therapy, outlined by the International Stress and Behavior Society. Various drugs currently prescribed to treat NDDs also represent a highly diverse group. Acting on various neurotransmitter and physiological systems, these drugs often lack specificity of action, and are commonly used to treat multiple other psychiatric conditions. There has also been relatively little progress in the development of novel medications to treat NDDs. Based on clinical, preclinical and translational models of NDDs, our recommendations cover a wide range of methodological approaches and conceptual strategies. Expert opinion: To improve pharmacotherapy and drug discovery for NDDs, we need a stronger emphasis on targeting multiple endophenotypes, a better dissection of genetic/epigenetic factors or "hidden heritability," and a careful consideration of potential developmental/trophic roles of brain neurotransmitters. The validity of animal NDD models can be improved through discovery of novel (behavioral, physiological and neuroimaging) biomarkers, applying proper environmental enrichment, widening the spectrum of model organisms, targeting developmental trajectories of NDD-related behaviors and comorbid conditions beyond traditional NDDs. While these recommendations cannot be addressed all in once, our increased understanding of NDD pathobiology may trigger innovative cross-disciplinary research expanding beyond traditional methods and concepts.

Barbara D. Fontana, Talise E. Müller, Madeleine Cleal, Murilo S. de Abreu, William H.J. Norton, Konstantin A. Demin, Tamara G. Amstislavskaya, Elena V. Petersen, Allan V. Kalueff, Matthew O. Parker, Denis B. Rosemberg (2022)Using zebrafish (Danio rerio) models to understand the critical role of social interactions in mental health and wellbeing, In: Progress in neurobiology208101993 Elsevier Ltd

•Social interactions are essential for health and wellbeing across species.•Zebrafish are a prominent model to investigate the importance of social interactions.•Lack of social interaction and social isolation have negative behavioral and physiologic effects on zebrafish.•Advantages and limitations of using zebrafish to understand social behavior were discussed. 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.

Arash Omidi, Saeede Vakili, Saeed Nazifi, Matthew O. Parker (2017)Acute-phase proteins, oxidative stress, and antioxidant defense in crib-biting horses, In: Journal of veterinary behavior20pp. 31-36 Elsevier Inc

Crib biting is a common equine stereotypic behavior that has links to health problems and poor welfare. There is evidence that crib biters may be more sensitive to environmental stressors, and the aim of the present study was to test the hypothesis that crib-biting behavior in horses has a relationship with oxidative stress, antioxidant defense, or inflammatory proteins, as is observed in humans with various affective disorders such as depression and anxiety. Ten crib-biting horses and 10 age- and sex-matched healthy horses were used. Vital signs (heart rates, respiratory rates, and temperature) and blood samples were taken in 3 conditions; basal condition for crib biters (no stereotypic behavior observed for at least 30 minutes); crib biters during or directly after crib-biting periods (“acute crib biting” = crib biting for at least 15 minutes with no interruption longer than 2 minutes); non–crib-biting horses (control). Comparisons were made between crib biters and controls, and between crib-biters' basal and crib-biting values. No changes were observed in the vital signs. Total antioxidant capacity activity was significantly decreased in crib biters during the basal measurements relative to controls, and this was significantly decreased again during an episode of crib biting. Similar differences to those observed in total antioxidant capacity were also observed for the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase. Collectively, our data suggest that the antioxidant levels and antioxidant defenses against lipid peroxidation are reduced in crib biters, suggesting that oxidative stress plays a role in the pathophysiology of crib biting. In addition, our data suggest that further study on the role of oxidative stress in crib biting might be of benefit, particularly in the search for veterinary treatments or interventions for crib-biting horses.

James P. Rice, Lisa E. Suggs, Alexandra V. Lusk, Matthew O. Parker, Felicha T. Candelaria-Cook, Katherine G. Akers, Daniel D. Savage, Derek A. Hamilton (2012)Effects of exposure to moderate levels of ethanol during prenatal brain development on dendritic length, branching, and spine density in the nucleus accumbens and dorsal striatum of adult rats, In: Alcohol (Fayetteville, N.Y.)46(6)pp. 577-584 Elsevier

Reductions in measures of dendritic morphology in the agranular insular cortex have been identified as consequences of prenatal exposure to moderate levels of ethanol in the rat. Motivated by the strong connectivity between this region of frontal cortex and the striatum and a growing body of data linking specific components of the mesocortical/limbic system to effects of ethanol and ethanol self-administration, the current study investigated the effects of moderate fetal ethanol exposure on the dendritic morphology of medium spiny neurons (MSNs) in several regions of the striatum. Throughout gestation, pregnant rat dams either consumed a saccharin solution (control) or achieved average daily blood ethanol concentrations of 84 mg% via voluntary consumption of a 5% ethanol solution. The brains of adult male offspring were extracted and processed for Golgi-Cox staining. MSNs from the dorsomedial striatum, dorsolateral striatum and the nucleus accumbens core and shell were sampled for analysis. Relative to saccharin controls, robust reductions in dendritic length and branching, but not spine density, were observed in the shell of the nucleus accumbens in fetal-ethanol-exposed rats. No significant prenatal ethanol effects were found in the other regions of the striatum. These findings suggest that exposure to moderate levels of ethanol in utero can have profound effects on brain regions related to reward processing and provide possible clues relevant to understanding increased self-administration of drugs of abuse in animals exposed to ethanol during brain development. (c) 2012 Elsevier Inc. All rights reserved.

Matthew Parker, Deborah Goodwin, Edward S. Redhead (2008)Survey of breeders' management of horses in Europe, North America and Australia: Comparison of factors associated with the development of abnormal behaviour, In: Applied animal behaviour science114(1-2)pp. 206-215 Elsevier

An online survey of domestic horse breeders in the USA, UK, Australia, Canada and mainland Europe was carried out in order to examine management risk factors associated with the development of abnormal behaviour patterns. One hundred and forty breeders responded, and epidemiological results suggested that the overall number of horses showing abnormal behaviours may be declining (5.2% of the sample). However, as found in previous studies, extensive, as opposed to intensive management practices reduce the risk of foals developing abnormal behaviours. In addition, offering foals low-energy forage in higher quantities reduces the risk of abnormal behaviour (P < 0.001). Results are discussed in relation to previous surveys, and suggestions are made for breeders and owners to help reduce the risks of young horses developing abnormal behaviours associated with weaning practices. (C) 2008 Elsevier B.V. All rights reserved.

Madeleine Cleal, Matthew O. Parker (2018)Moderate developmental alcohol exposure reduces repetitive alternation in a zebrafish model of fetal alcohol spectrum disorders, In: Neurotoxicology and teratology70pp. 1-9 Elsevier

The damaging effects of alcohol on a developing fetus are well known and cause a range of conditions known as fetal alcohol spectrum disorder (FASD). High levels of alcohol exposure lead to physical deformity and severe cognitive deficits, but more moderate exposure leads to a range of subtle cognitive effects such as reduced social behavior, higher propensity to develop addictions, and reduced spatial working memory. Previous studies have demonstrated that following exposure to relatively low levels of ethanol during early brain development (equivalent in humans to moderate exposure) zebrafish display a range of social and behavioral differences. Here, our aim was to test the hypothesis that moderate developmental ethanol exposure would affect aspects of learning and memory in zebrafish. In order to do this, we exposed zebrafish embryos to 20 mM [0.12% v/v] ethanol from 2 to 9 dpf to model the effects of moderate prenatal ethanol (MPE) exposure. At 3 months old, adult fish were tested for appetitive and aversive learning, and for spatial alternation in a novel unconditioned y-maze protocol. We found that MPE did not affect appetitive or aversive learning, but exposed-fish showed a robust reduction in repetitive alternations in the y-maze when compared to age matched controls. This study confirms that moderate levels of ethanol exposure to developing embryos have subtle effects on spatial working memory in adulthood. Our data thus suggest that zebrafish may be a promising model system for studying the effects of alcohol on learning and decision-making, but also for developing treatments and interventions to reduce the negative effects of prenatal alcohol.

Kirsty Roberts, Andrew J. Hemmings, Sebastian D. McBride, Matthew O. Parker (2017)Causal factors of oral versus locomotor stereotypy in the horse, In: Journal of veterinary behavior20pp. 37-43 Elsevier Inc

Stereotypic behaviors are commonly observed in domestic equids as they are in a range of captive nondomesticated species. Estimates suggest that 19.5%-32.5% of horses perform a stereotypy. The presence of these behaviors is thought to indicate suboptimal welfare status and can result in secondary physical pathologies, such as colic, ligament strain, and incisor wear. Relatively little is understood about the etiologies of oral and locomotor stereotypies. Seemingly disparate causal factors have been proposed, including gastric pathology, neural adaptation, and genetic predisposition. In this review, we propose a model of causality that presents separate pathways to the development and continuation of oral behaviors such as crib-biting, compared with locomotor alternatives (i.e., weaving). The word stereotypy has alarmingly negative connotation among horse keepers. Stereotypic behaviors are often viewed as vices, and therefore, a number of horse owners and establishments attempt to physically prevent the behavior with harsh mechanical devices. Such interventions can result in chronic stress and be further detrimental to equine welfare. Stereotypy has been proposed to be a stress coping mechanism. However, firm evidence of coping function has proven elusive. This review will explore management options directed at both prophylaxis and remediation.

Edward S. Redhead, Derek A. Hamilton, Matthew O. Parker, Wai Chan, Craig Allison (2013)Overshadowing of geometric cues by a beacon in a spatial navigation task, In: Learning & behavior41(2)pp. 179-191 Springer Nature

In three experiments, we examined whether overshadowing of geometric cues by a discrete landmark (beacon) is due to the relative saliences of the cues. Using a virtual water maze task, human participants were required to locate a platform marked by a beacon in a distinctively shaped pool. In Experiment 1, the beacon overshadowed geometric cues in a trapezium, but not in an isosceles triangle. The longer escape latencies during acquisition in the trapezium control group with no beacon suggest that the geometric cues in the trapezium were less salient than those in the triangle. In Experiment 2, we evaluated whether generalization decrement, caused by the removal of the beacon at test, could account for overshadowing. An additional beacon was placed in an alternative corner. For the control groups, the beacons were identical; for the overshadow groups, they were visually unique. Overshadowing was again found in the trapezium. In Experiment 3, we tested whether the absence of overshadowing in the triangle was due to the geometric cues being more salient than the beacon. Following training, the beacon was relocated to a different corner. Participants approached the beacon rather than the trained platform corner, suggesting that the beacon was more salient. These results suggest that associative processes do not fully explain cue competition in the spatial domain.

Matthew Parker (2017)Modeling OCD Endophenotypes in Zebrafish, In: The rights and wrongs of zebrafish: Behavioral phenotyping of zebrafishpp. 131-143 Springer International Publishing

Obsessive compulsive disorder (OCD) is a pervasive, debilitating neuropsychiatric disorder. Despite over half a century of effort, OCD has remained remarkably resistant to treatment, partly owing to a lack of understanding of the underlying biology. Recently, there has been a growing consensus that in order to understand the basis of neuropsychiatric disorders such as OCD, we should focus on transdiagnostic, observable, measurable behavioral or neural elements, endophenotypes. Zebrafish have the well-characterized neural development and available cutting-edge genetic tools that make them the ideal species for studying psychiatric disorders. In addition, a number of endophenotypes linked to OCD have been observed, and can be objectively measured, in zebrafish. In this chapter, some key behavioral tests of relevance to OCD will be outlined. If the neural substrates underlying these behaviors are elucidated, this may represent significant progress in understanding the biological underpinnings of OCD. This will ultimately lead to increased specificity for drug discovery, as well as providing targets for personalized treatments for one of the most common neuropsychiatric disorders.

Alessia Fiorentino, Kaoru Fujinami, Gavin Arno, Anthony G. Robson, Nikolas Pontikos, Monica Arasanz Armengol, Vincent Plagnol, Takaaki Hayashi, Takeshi Iwata, Matthew Parker, Tom Fowler, Augusto Rendon, Jessica C. Gardner, Robert H. Henderson, Michael E. Cheetham, Andrew R. Webster, Michel Michaelides, Alison J. Hardcastle, (2018)Missense variants in the X‐linked gene PRPS1 cause retinal degeneration in females, In: Human mutation39(1)pp. 80-91

Retinal dystrophies are a heterogeneous group of disorders of visual function leading to partial or complete blindness. We report the genetic basis of an unusual retinal dystrophy in five families with affected females and no affected males. Heterozygous missense variants were identified in the X‐linked phosphoribosyl pyrophosphate synthetase 1 (PRPS1) gene: c.47C > T, p.(Ser16Phe); c.586C > T, p.(Arg196Trp); c.641G > C, p.(Arg214Pro); and c.640C > T, p.(Arg214Trp). Missense variants in PRPS1 are usually associated with disease in male patients, including Arts syndrome, Charcot–Marie–Tooth, and nonsyndromic sensorineural deafness. In our study families, affected females manifested a retinal dystrophy with interocular asymmetry. Three unrelated females from these families had hearing loss leading to a diagnosis of Usher syndrome. Other neurological manifestations were also observed in three individuals. Our data highlight the unexpected X‐linked inheritance of retinal degeneration in females caused by variants in PRPS1 and suggest that tissue‐specific skewed X‐inactivation or variable levels of pyrophosphate synthetase‐1 deficiency are the underlying mechanism(s). We speculate that the absence of affected males in the study families suggests that some variants may be male embryonic lethal when inherited in the hemizygous state. The unbiased nature of next‐generation sequencing enables all possible modes of inheritance to be considered for association of gene variants with novel phenotypic presentation. We report the genetic basis of an unusual retinal dystrophy with inter‐ocular asymmetry in families with only affected females. Heterozygous missense variants were identified in the X‐linked PRPS1 gene. PRPS1 missense variants are usually associated with disease in males, including Arts Syndrome and Charcot‐Marie‐Tooth. The unexpected X‐linked inheritance suggests tissue specific skewed X‐inactivation or variable levels of PRS‐I deficiency are the underlying mechanism(s). The absence of affected males in these families suggests that some PRPS1 variants may be male lethal.

Judith R. Homberg, Evan J. Kyzar, Maria Luisa Scattoni, William H. Norton, Julian Pittman, Siddharth Gaikwad, Michael Nguyen, Manoj K. Poudel, Jeremy F.P. Ullmann, David M. Diamond, Aleksandra A. Kaluyeva, Matthew O. Parker, Richard E. Brown, Cai Song, Raul R. Gainetdinov, Irving I. Gottesman, Allan V. Kalueff (2016)Genetic and environmental modulation of neurodevelopmental disorders: Translational insights from labs to beds, In: Brain research bulletin125pp. 79-91 Elsevier Inc

•Neurodevelopmental disorders (NDDs) are severely debilitating neuropsychiatric illnesses.•NDDs are caused by aberrant brain development, and have strong genetic causes and risk factors.•NDDs are also modulated by various environmental factors, and can be modeled experimentally.•Animal models are a valuable tool to mimic a wide spectrum of NDDs and related conditions.•Here, we discuss the neurobiological mechanisms of selected NDDs and their experimental models. Neurodevelopmental disorders (NDDs) are a heterogeneous group of prevalent neuropsychiatric illnesses with various degrees of social, cognitive, motor, language and affective deficits. NDDs are caused by aberrant brain development due to genetic and environmental perturbations. Common NDDs include autism spectrum disorder (ASD), intellectual disability, communication/speech disorders, motor/tic disorders and attention deficit hyperactivity disorder. Genetic and epigenetic/environmental factors play a key role in these NDDs with significant societal impact. Given the lack of their efficient therapies, it is important to gain further translational insights into the pathobiology of NDDs. To address these challenges, the International Stress and Behavior Society (ISBS) has established the Strategic Task Force on NDDs. Summarizing the Panel’s findings, here we discuss the neurobiological mechanisms of selected common NDDs and a wider NDD+ spectrum of associated neuropsychiatric disorders with developmental trajectories. We also outline the utility of existing preclinical (animal) models for building translational and cross-diagnostic bridges to improve our understanding of various NDDs.

Jen Jamieson, Michael J. Reiss, David Allen, Lucy Asher, Matthew O. Parker, Christopher M. Wathes, Siobhan M. Abeyesinghe (2015)Adolescents Care but Don't Feel Responsible for Farm Animal Welfare, In: Society & animals23(3)pp. 269-297 Brill

Adolescents are the next generation of consumers with the potential to raise standards of farm animal welfare to their satisfaction if their preferences and concerns are translated into accurate market drivers and signals. There are no published data about adolescent views of farm animal welfare to allow meaningful design, implementation, and evaluation of educational strategies to improve consideration of and behavior toward farm animals. Knowledge of farm animal welfare, as well as beliefs and attitudes about farm animal welfare and behavioral intention relevant to it were determined in a sample of UK adolescents, using a survey incorporating an extended version of the theory of planned behavior and novel assessment tools. Our results indicate that adolescents have only a limited knowledge of welfare problems for farm animals and welfare-relevant product labels. Intentions to identify welfare standards for the animals from whom their food was derived were weak. Although they cared about farm animal welfare and agreed with fundamental principles for example, the provision of space and the absence of pain and suffering like adults they held limited belief in the power and responsibility that they possess through their choices as consumers; responsibility was often shifted to others, such as the government and farmers.

Kirsty Roberts, Andrew J. Hemmings, Sebastian D. McBride, Matthew O. Parker (2017)Developing a 3-choice serial reaction time task for examining neural and cognitive function in an equine model, In: Journal of neuroscience methods292pp. 45-52 Elsevier

Background: Large animal models of human neurological disorders are advantageous compared to rodent models due to their neuroanatomical complexity, longevity and their ability to be maintained in naturalised environments. Some large animal models spontaneously develop behaviours that closely resemble the symptoms of neural and psychiatric disorders. The horse is an example of this; the domestic form of this species consistently develops spontaneous stereotypic behaviours akin to the compulsive and impulsive behaviours observed in human neurological disorders such as Tourette's syndrome. The ability to non-invasively probe normal and abnormal equine brain function through cognitive testing may provide an extremely useful methodological tool to assess brain changes associated with certain human neurological and psychiatric conditions. New method: An automated operant system with the ability to present visual and auditory stimuli as well as dispense salient food reward was developed. To validate the system, ten horses were trained and tested using a standard cognitive task (three choice serial reaction time task (3-CSRTT)). Results: All animals achieved total learning criterion and performed six probe sessions. Learning criterion was met within 16.30 +/- 0.79 sessions over a three day period. During six probe sessions, level of performance was maintained at 80.67 +/- 0.57% (mean +/- SEM) accuracy. Comparison with existing method(s): This is the first mobile fully automated system developed to examine cognitive function in the horse. Conclusions: A fully-automated operant system for mobile cognitive function of a large animal model has been designed and validated. Horses pose an interesting complementary model to rodents for the examination of human neurological dysfunction. 2017 Elsevier B.V. All rights reserved.

Lorenzo D Stafford, Kit Damant, Sophie Ashurst, Matthew O Parker (2020)Higher olfactory sensitivity to coffee odour in habitual caffeine users, In: Experimental and clinical psychopharmacology28(2)pp. 245-250

The present two studies aimed to look at alternative methods of assaying the changes underpinning drug consumption and dependence. Here, we focus on whether olfactory differences exist in habitual consumers in the form of recognition and sensitivity tasks to a caffeine-related odor. In Experiment 1, high ( = 18), moderate ( = 23), and non-consumers ( = 21) of caffeine completed a threshold test for a coffee odor, followed by a recognition test for both a coffee and a neutral odor and, finally, a measure of caffeine craving. In Experiment 2, 16 consumers and 16 non-consumers completed threshold tests for two odors, coffee and control (n-butanol), followed by a caffeine-related implicit association test. In Experiment 1, recognition of the coffee odor was faster for caffeine consumers versus non-consumers. We also found that high-caffeine consumers had greater olfactory sensitivity for the coffee odor compared to the other groups, which was related to craving. In Experiment 2, we again found greater sensitivity for the coffee odor in consumers but no differences between groups for the control odor. Additionally, craving was greater in consumers who had just been exposed to the coffee odor. These findings provide evidence for the first time that regular consumers of coffee have enhanced sensitivity to an odor associated with caffeine. They further suggest that drug-associated odors could be a useful tool in furthering theory in drug dependence. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Konstantin A. Demin, Maxim Sysoev, Maria V. Chernysh, Anna K. Savva, Mamiko Koshiba, Edina A. Wappler-Guzzetta, Cai Song, Murilo S. De Abreu, Brian Leonard, Matthew O. Parker, Brian H. Harvey, Li Tian, Eero Vasar, Tatyana Strekalova, Tamara G. Amstislavskaya, Andrey D. Volgin, Erik T. Alpyshov, Dongmei Wang, Allan V. Kalueff (2019)Animal models of major depressive disorder and the implications for drug discovery and development, In: Expert opinion on drug discovery14(4)pp. 365-378 Taylor & Francis

Introduction: Depression is a highly debilitating psychiatric disorder that affects the global population and causes severe disabilities and suicide. Depression pathogenesis remains poorly understood, and the disorder is often treatment-resistant and recurrent, necessitating the development of novel therapies, models and concepts in this field. Areas covered: Animal models are indispensable for translational biological psychiatry, and markedly advance the study of depression. Novel approaches continuously emerge that may help untangle the disorder heterogeneity and unclear categories of disease classification systems. Some of these approaches include widening the spectrum of model species used for translational research, using a broader range of test paradigms, exploring new pathogenic pathways and biomarkers, and focusing more closely on processes beyond neural cells (e.g. glial, inflammatory and metabolic deficits). Expert opinion: Dividing the core symptoms into easily translatable, evolutionarily conserved phenotypes is an effective way to reevaluate current depression modeling. Conceptually novel approaches based on the endophenotype paradigm, cross-species trait genetics and 'domain interplay concept', as well as using a wider spectrum of model organisms and target systems will enhance experimental modeling of depression and antidepressant drug discovery.

Arash Omidi, Reza Jafari, Saeed Nazifi, Matthew O. Parker (2018)Potential role for selenium in the pathophysiology of crib-biting behavior in horses, In: Journal of veterinary behavior23pp. 10-14 Elsevier Inc

Crib-biting is a repetitive and compulsive behavior that is characterized by “grasping a fixed object with incisor teeth and aspirating air with an audible grunt.” Little is known about etiology and pathophysiology of crib-biting behavior in horses. Previously, we have shown that oxidative stress is linked to crib-biting, with crib-biters showing lower antioxidant capacity than non–crib-biting horses. The aim of the present study was to extend our understanding of oxidative stress in crib-biting to determine the serum contents of some mineral trace elements (manganese [Mn], magnesium [Mg], selenium [Se], copper [Cu], and zinc [Zn]), and electrolytes (sodium [Na], potassium [K], calcium [Ca], and phosphorus [P]). Also, the activity of enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma glutamyl transferase), some hormones (cortisol, ghrelin, β-endorphin, and serotonin) and blood biochemistry values of various parameters was measured to evaluate their possible association with crib-biting behavior in horses. Blood samples were taken from all horses under the following conditions: basal conditions of crib-biting horses, during or immediately after crib-biting periods, and from non–crib-biting, healthy horses (control group). Serum Se concentration was significantly lower (P ≤ 0.001) in crib-biting horses than in controls, with the lowest levels seen during crib-biting behavior. Other measured parameters did not differ between acute crib-biting horses and healthy controls. These observations suggest that alterations in serum Se, an important component of the antioxidant system, may play a role in the pathophysiology of crib-biting behavior in horses, adding further evidence to the theory that crib-biting may be related to increased oxidative stress and alterations in essential trace elements.

Matthew Parker, Edward S. Redhead, Deborah Goodwin, Sebastian D. McBride (2008)Impaired instrumental choice in crib-biting horses (Equus caballus), In: Behavioural brain research191(1)pp. 137-140 Elsevier

Horses displaying an oral stereotypy were tested on an instrumental choice paradigm to examine differences in learning from non-stereotypic counterparts. Stereotypic horses are known to have dysfunction of the dorsomedial striatum, and lesion studies have shown that this region may mediate response-outcome learning. The paradigm was specifically applied in order to examine learning that requires maintenance of response-outcome judgements. The non-stereotypic horses learned, over three sessions, to choose a more immediate reinforcer, whereas the stereotypic horses failed to do so. This suggests an initial behavioural correlate for dorsomedial striatum dysregulation in the stereotypy phenotype. (C) 2008 Elsevier B.V. All rights reserved.

Judith R Homberg, Evan J Kyzar, Michael Nguyen, William H Norton, Julian Pittman, Manoj K Poudel, Siddharth Gaikwad, Shun Nakamura, Mamiko Koshiba, Hideo Yamanouchi, Maria Luisa Scattoni, Jeremy F P Ullman, David M Diamond, Aleksandra A Kaluyeva, Matthew O Parker, Victor M Klimenko, Sergey A Apryatin, Richard E Brown, Cai Song, Raul R Gainetdinov, Irving I Gottesman, Allan V Kalueff (2016)Understanding autism and other neurodevelopmental disorders through experimental translational neurobehavioral models, In: Neuroscience and biobehavioral reviews65pp. 292-312

Neurodevelopmental disorders (NDDs) are highly prevalent and severely debilitating brain illnesses caused by aberrant brain growth and development. Resulting in cognitive, social, motor, language and affective disabilities, common NDDs include autism spectrum disorder (ASD), intellectual disability, communication/speech disorders, motor/tic disorders and attention deficit hyperactivity disorder. Affecting neurogenesis, glia/neuronal proliferation and migration, synapse formation and myelination, aberrant neural development occurs over a substantial period of time. Genetic, epigenetic, and environmental factors play a key role in NDD pathogenesis. Animal models are an indispensable tool to study NDDs. Paralleling clinical findings, we comprehensively evaluate various preclinical tests and models which target key (social, cognitive, motor) neurobehavioral domains of ASD and other common NDDs. Covering both traditional (rodent) and alternative NDD models, we outline the emerging areas of research and emphasize how preclinical models play a key role in gaining translational and mechanistic insights into NDDs and their therapy.

Vardha Ismail, Linda G. Zachariassen, Annie Godwin, Mane Sahakian, Sian Ellard, Karen L. Stals, Emma Baple, Kate Tatton Brown, Nicola Foulds, Gabrielle Wheway, Matthew O. Parker, Signe M. Lyngby, Miriam G. Pedersen, Julie Desir, Allan Bayat, Maria Musgaard, Matthew Guille, Anders S. Kristensen, Diana Baralle (2022)Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome, In: American journal of human genetics109(7)pp. 1217-1241 Elsevier

GRIA1 encodes the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, which are ligand-gated ion channels that act as excitatory receptors for the neurotransmitter L -glutamate (Glu). AMPA receptors (AMPARs) are homo- or heteromeric protein complexes with four subunits, each encoded by different genes, GRIA1 to GRIA4 . Although GluA1-containing AMPARs have a crucial role in brain function, the human phenotype associated with deleterious GRIA1 sequence variants has not been established. Subjects with de novo missense and nonsense GRIA1 variants were identified through international collaboration. Detailed phenotypic and genetic assessments of the subjects were carried out and the pathogenicity of the variants was evaluated in vitro to characterize changes in AMPAR function and expression. In addition, two Xenopus gria1 CRISPR-Cas9 F 0 models were established to characterize the in vivo consequences. Seven unrelated individuals with rare GRIA1 variants were identified. One individual carried a homozygous nonsense variant (p.Arg377Ter), and six had heterozygous missense variations (p.Arg345Gln, p.Ala636Thr, p.Ile627Thr, and p.Gly745Asp), of which the p.Ala636Thr variant was recurrent in three individuals. The cohort revealed subjects to have a recurrent neurodevelopmental disorder mostly affecting cognition and speech. Functional evaluation of major GluA1-containing AMPAR subtypes carrying the GRIA1 variant mutations showed that three of the four missense variants profoundly perturb receptor function. The homozygous stop-gain variant completely destroys the expression of GluA1-containing AMPARs. The Xenopus gria1 models show transient motor deficits, an intermittent seizure phenotype, and a significant impairment to working memory in mutants. These data support a developmental disorder caused by both heterozygous and homozygous variants in GRIA1 affecting AMPAR function.

James M. Clay, Matthew O. Parker (2018)The role of stress-reactivity, stress-recovery and risky decision-making in psychosocial stress-induced alcohol consumption in social drinkers, In: PSYCHOPHARMACOLOGY235(11)pp. 3243-3257 Springer Nature

RationaleChronic alcohol misuse can escalate into alcohol use disorder (AUD). The causal mechanisms through which recreational social drinking develops into compulsive uncontrolled alcohol misuse are multifaceted. For example, stress is an important risk factor that influences alcohol craving in both healthy and addicted individuals. In addition, those that are high in impulsivity/risk taking drink more and are at greater risk of developing addiction. At present, however, it is not possible accurately to predict those at risk of escalation in alcohol use, or of developing AUD.ObjectivesThe aim of this study was to investigate how underlying physiological and personality traits affect stress-induced craving for, and consumption of, alcohol, in a sample of social drinkers. The primary hypothesis was that impulsivity/risk-taking would modulate stress-induced alcohol craving and consumption.MethodsThirty-nine participants (22 male and 17 female; mean age=23.92years [SD=4.90]) were randomly allocated to stress' and no-stress' groups; in the stress group, participants took part in the Trier Social Stress Test (TSST). Participants completed several questionnaires and computer tasks in order to assess prior alcohol use, impulsivity/risk-taking, stress-reactivity, craving and physiological biomarkers of stress. Finally, participants completed a voluntary drinking task, in which increasing numbers of presses on a computer keyboard were reinforced with 5-ml shots of 37% ABV vodka (plus mixer).ResultsParticipants exposed to the TSST showed an increase in craving following the stressor. Several factors predicted voluntary drinking, including risky decision making, slow HR recovery from stress, poor vagal tone during recovery from stress and greater stress reactivity. Surprisingly, we found no correlation between craving and consumption.ConclusionsOur data suggest that variation in physiological stress parameters and poor decision-making abilities increase risk of stress-induced alcohol consumption. This may provide a useful translational framework through which we can further study early predictive markers for the shift between controlled recreational drinking to uncontrolled alcohol misuse, including AUD.

James M. Clay, Matthew O. Parker (2020)Alcohol use and misuse during the COVID-19 pandemic: a potential public health crisis?, In: The Lancet. Public health5(5)pp. E259-E259 Elsevier
James M. Clay, Barbara D. Fontana, Cristina Proserpio, Eduardo J. Fernandez, Ella Pagliarini, Fernando Lopes, Jose Antonio Lopez-Moreno, Juan J. Canales, Louise Loyant, Ravid Doron, Lorenzo D. Stafford, Matthew O. Parker (2022)Drinking during social isolation: investigating associations between stress, inhibitory control, boredom, drinking motives, and alcohol use, In: Addiction research & theory Taylor & Francis

Background: We aimed to assess whether stress, boredom, drinking motives, and/or inhibitory control were related to alcohol use during a period of social isolation. Method: Analyses were carried out on questionnaire data (N = 337) collected during the first wave of the COVID-19 pandemic (7 April-3 May 2020). We first assessed changes in drinking behavior, stress and boredom. We then regressed drinking behavior on drinking motives, inhibitory control, stress, and boredom. We also investigated interactions between change in stress/boredom and inhibitory control. Results: A minority of respondents reported increased alcohol use (units = 23.52%, drinking days = 20.73%, heavy days = 7.06%), alcohol-related problems (9.67%), and stress (36.63%). Meanwhile, most respondents reported increased boredom (67.42%). Similarly, boredom significantly increased (B = 21.22, p < .001), on average, while alcohol-related problems decreased (B = -1.43 p < .001). Regarding drinking motives, decreased alcohol-related problems were associated with social drinking motives (B = -0.09, p = .005). Surprisingly, risk-taking was associated with decreased alcohol-related problems (B = -0.02, p = .008) and neither stress nor boredom independently predicted changes in alcohol use. Finally, several significant interactions suggested that those who were more impulsive and less bored were more likely to report increased alcohol use and vice versa. Conclusions: These data provide a nuanced overview of changes in drinking-related behavior during the COVID-19-induced period of social isolation. While most people reduced their drinking, there was evidence of complex interactions between impulsivity and boredom that may be explored in future studies.

James M. Clay, Cameron Adams, Peter Archer, Mark English, Abbey Hyde, Lorenzo D. Stafford, Matthew O. Parker (2018)Psychosocial stress increases craving for alcohol in social drinkers: Effects of risk-taking, In: Drug and alcohol dependence185pp. 192-197 Elsevier

Background: Exposure to stress and trait impulsivity are independent predictors of relapse in recovering alcoholics, but potential mechanisms that link these two risk-factors in terms of their putative additive or interactive contributions to relapse are not known. The aim of this study was to use a model of stress-induced relapse to test the hypothesis that acute psychosocial stress increases craving for alcohol in social drinkers. We also tested the hypothesis that change in craving could be explained by variability in impulsivity and risk-taking. Methods: Participants completed questionnaires to assess drinking behaviour (Alcohol Dependence Questionnaire [ADQ]; and an Alcohol Use Disorders Identification Test [AUDIT]), craving (Desires for Alcohol Questionnaire [DAQ] and impulsivity (Barrett Impulsiveness Scale [BIS]). Participants also completed two computer tasks to assess risk-taking and impulsivity, the Balloon Analogue Risk Test (BART) and a continuous performance task (CPT). Participants then underwent the Trier Social Stress Test (TSST), and completed a final DAQ to assess post-stress craving. Results: Participants showed an increase in craving following exposure to the TSST. In addition, risk-taking was positively correlated with change in craving. Conclusions: Our data suggests that acute psychosocial stress increases subjective craving in social drinkers, but that the effects may be trait-dependent, with stress-induced increases in craving correlated with risk-taking.

We explored (1) self-reported changes in alcohol use during the pandemic in the UK and (2) the extent to which self-reported inhibitory control and/or stress were associated with any change in drinking behaviour. We used a UK-based cross-sectional online survey administered to four nationally representative birth cohorts (N = 13,453). A significant minority of 30- (29.08%) and 50-year-olds (26.67%) reported drinking more, and between 32.23 and 45.02% of respondents reported feeling more stressed depending on the cohort. Stress was associated with hazardous drinking among 30-year-olds (OR = 3.77, 95% CI 1.15 to 12.28). Impatience was associated with both increased alcohol use (1.14, 95% CI 1.06, 1.24) and hazardous drinking (1.20, 95% CI 1.05, 1.38) among 19-year-olds. Risk-taking was associated with hazardous drinking for 30-year-olds (OR = 1.18, 95% CI 1.05, 1.32). These data highlight concerns for those at risk of alcohol misuse and alcohol-related harm during COVID-19 lockdowns.

Barbara D. Fontana, Nancy Alnassar, Matthew O. Parker (2021)Tricaine Methanesulfonate (MS222) Has Short-Term Effects on Young Adult Zebrafish (Danio rerio) Working Memory and Cognitive Flexibility, but Not on Aging Fish, In: Frontiers in behavioral neuroscience15686102 Frontiers Media Sa

Exposure to anesthetic drugs is common in biomedical sciences being part of routine procedures in different translational species, however its impacts on memory and cognition are still debated, having different impacts depending on drug and age. The zebrafish (Danio rerio) is a translational species widely used in behavioral neuroscience, where tricaine methanesulfonate (MS222) is the most acceptable and used drug when conducting routine procedures. Based on this, we investigated the effects of MS222 (100 mg/l) in young adults and aging zebrafish 1, 2, 3, and 7 days after exposure. Animals' were submitted to the anesthetic procedure until loss of body posture, slowing of opercular movements and lack of response to tail touch with a plastic pipette were achieved, then further left in the drug for 3 min. After that, animals (6 mpf vs. 24 mpf) were transferred to a recovery tank until fully recovered and transferred back to their housing system until further testing in the free movement pattern (FMP) Y-maze, which assesses zebrafish working memory and cognitive lexibility. Young animals had significant impairment in their working memory and cognitive flexibility 1 and 2 days after the exposure to MS222, being fully recovered by day 3 and with no effects 7 days post drug exposure. Increased repetitions were also observed for animals exposed to MS222 which could indicate increased stress-related response in animals up to 2 days after drug exposure. No drug effect was observed in aging animals besides their natural decreased alternations and working memory. Overall, behavioral experiments after routine procedures using MS222 should be performed with caution and need to be delayed, at least 3 days after exposure where working memory, cognitive flexibility, and repetitive behavior are back to normal.

Triangulation of approaches (i.e., using several tests of the same construct) can be extremely useful for increasing the robustness of the findings being widely used when working with behavioral testing, especially when using rodents as a translational model. Although zebrafish are widely used in neuropharmacology research due to their high-throughput screening potential for new therapeutic drugs, behavioral test battery effects following pharmacological manipulations are still unknown. Here, we tested the effects of an anxiety test battery and test time following pharmacological manipulations in zebrafish by using two behavioral tasks: the novel tank diving task (NTT) and the light-dark test (LDT). Fluoxetine and conspecific alarm substance (CAS) were chosen to induce anxiolytic and anxiogenic-like behavior, respectively. For non-drug-treated animals, no differences were observed for testing order (NTT → LDT or LDT → NTT) and there was a strong correlation between performances on the two behavioral tasks. However, we found that during drug treatment, NTT/LDT responses are affected by the tested order depending on the test time being fluoxetine effects higher at the second behavioral task (6 min later) and CAS effects lower across time. Overall, our data supports the use of baseline behavior assessment using this anxiety test battery. However, when working with drug exposure, data analysis must carefully consider time-drug-response and data variability across behavioral tasks.

Madeleine Cleal, Alistair Gibbon, Barbara D Fontana, Matthew O Parker (2020)The importance of pH: How aquarium water is affecting behavioural responses to drug exposure in larval zebrafish, In: Pharmacology, biochemistry and behavior199173066

There has been rapid growth in the use of larval zebrafish as a complementary vertebrate model for drug discovery, abuse liability and pharmacological toxicology, resulting in a huge increase in zebrafish facilities worldwide. However, many research groups working with zebrafish do not typically report the pH of husbandry conditions in methodologies, nor are the pH of drug treatments reported in many research articles. This unknown factor can be a major contributor in the differential effects of drug treatments. Therefore, as a case study, we tested the impact of altering pH of several drugs of abuse and assessed locomotor changes associated with a single drug concentration delivered at different pHs. We found that a change of a single pH unit, within the pH ranges commonly used in zebrafish husbandry, was enough to alter locomotor activity at a fixed drug concentration. Many pharmacological agents are dependent on environmental factors, such as pH, to determine bioavailability. Efficaciousness for many classes of drug is dependent on their ionization state in which shifts towards uncharged species can influence the easy of a drug crossing biological membranes. Thus, we urge users to report pH in husbandry methods and drug treatments to improve replicability and inter-study comparisons.

Madeleine Cleal, Barbara D Fontana, Matthew O Parker (2021)The cognitive and behavioral effects of D-amphetamine and nicotine sensitization in adult zebrafish, In: Psychopharmacology (Berlin, Germany)238(8)pp. 2191-2200

Zebrafish are growing in use as a model for understanding drug dependence and addiction. Sensitization paradigms have been a useful tool in identifying mechanisms involved in drug-induced behavioral and neurological changes, but in zebrafish have tended to focus on locomotor, rather than cognitive, endpoints. Here, we used a novel method, the FMP Y-maze, which measures continuous performance through a series of repeated binary choices (L vs R), to establish a model for assessing parameters associated with psychostimulant-induced behavioral and cognitive sensitization in adult zebrafish. Repeat, intermittent exposure to d-amphetamine (AMPH) for 14 days increased alternations (LRLR) in the maze, suggesting improved working memory, which was enhanced further following drug challenge after a short withdrawal period, suggesting behavioral sensitization. However, this cognitive enhancement coincided with a reduction in the use of other exploration strategies, hypolocomotion, and inhibition of cognitive flexibility. Like AMPH, exposure to nicotine (NIC) increased alternations following drug challenge after chronic treatment. Repeat NIC exposure appeared to induce both cognitive and psychomotor sensitization, as evidenced by increased working memory performance (alternations) and locomotor activity, without negatively impacting other search strategies or cognitive flexibility. Chronic treatment with AMPH or NIC boosts cognitive performance in adult zebrafish. Cognitive sensitization occurred with both drugs, resulting in enhanced working memory; however, repeat AMPH exposure, following a withdrawal period, resulted in inhibited cognitive flexibility, an effect not evident with repeat NIC exposure. Cognitive and behavioral sensitization paradigms in zebrafish could serve as a useful tool for assessing cognitive states which result in cognitive enhancing or impairing effects of drugs.

Barbara D. Fontana, Nancy Alnassar, Matthew O. Parker (2021)The impact of water changes on stress and subject variation in a zebrafish (Danio rerio) anxiety-related task, In: Journal of neuroscience methods363109347 Elsevier

Background: Zebrafish have been widely used to study anxiety-related phenotypes using the novel tank test (NTT). Although the NTT is well-characterized and commonly used by researchers, there is still a lack of information regarding how different experimental variables such as water quality can influence NTT performance. Zebrafish use different chemical cues and olfactory stimuli to communicate in water, so we predicted that water change frequency would affect cortisol, locomotion and anxiety-related parameters in the NTT. New methods: After extensive literature research, we found that only about 18% of papers using NTT report partial or complete water changes between subjects. Here, we tested multiple zebrafish in the NTT using the same water up to 9 consecutive times (with no water change) and analyzed cortisol levels, as a stressrelated marker. Results: We found that when using the same water for more than 4 trials, data variability is increased and a higher number of extreme values is observed for the time spent in the top zone and immobility. Moreover, after 4 trials with no water change, increased cortisol levels are observed, indicating that animals show increased stressrelated responses with the lack of water changes. Conclusions: This study shows that lack of water change can significantly influence zebrafish stress-responses in the NTT. Altogether, behavioral experiments should avoid using the same water when testing multiple fish in the task, especially when looking at anxiety in the NTT.

Barbara D. Fontana, Tamie Duarte, Talise E. Müller, Julia Canzian, Paola R. Ziani, Nathana J. Mezzomo, Matthew O. Parker, Denis B. Rosemberg (2019)Concomitant taurine exposure counteracts ethanol-induced changes in locomotor and anxiety-like responses in zebrafish, In: Psychopharmacology237(3)pp. 735-743 Springer Berlin Heidelberg

Taurine (TAU) is a β-amino sulfonic acid with pleiotropic roles in the brain, including the neuromodulatory activity via GABAergic and glycinergic agonism. This molecule is found at high concentrations in energy drinks and is often mixed with alcohol in beverages. Although TAU has a neuroprotective role in the brain, the putative risks of mixing TAU and EtOH are not fully understood. Here, we investigated whether TAU modulates locomotor and anxiety-like behavior in adult zebrafish by using the novel tank and light-dark tests following acute EtOH exposure at anxiogenic and anxiolytic concentrations. Zebrafish were individually exposed to water (control), TAU (42, 150, and 400 mg/L), and EtOH (0.25% (v/v) and 1% (v/v)) both independently and cotreated for 1 h. EtOH 0.25% and TAU produced U-shape anxiolytic-like behavior in the light-dark test, TAU 42 and 400 positively modulated EtOH effects, and TAU 150 exerted a protective effect. All TAU concentrations counteracted EtOH 1%-induced locomotion impairment, as well as the anxiogenic-like behavior. Finally, all TAU concentrations when given independently or cotreated with EtOH 0.25% and 1% decreased the risk assessment of the lit compartment. Principal component analyses revealed that exploration and anxiety-like responses were the main behaviors that contribute to the effects of TAU and EtOH. Overall, we demonstrate that TAU differently modulates EtOH-induced anxiolytic- and anxiogenic-like behaviors depending on the concentration, suggesting a complex mechanism underlying TAU and EtOH interactions.

Background: Zebrafish are used in anxiety research as the species' naturalistic diving response to a new envi-ronment is a reliable and validated marker for anxiety-like behavior. One of the benefits of using zebrafish is the potential for high throughput drug screens in fish at the larval stage. However, at present, tests of anxiety in larvae and adults often measure different endpoints.New method: Here, for the first time, we have adapted the novel tank diving response test for examining diving behavior in zebrafish larvae to assess anxiety-like behaviors at very early-stages (7 days-post-fertilization [dpf]).Comparison with existing methods: Current methods to examine anxiety in larvae can show low reliability, and measure different endpoints as in adults, thus calling into question their translational relevance. Results: We found that 7dpf zebrafish spent more time at the bottom of a small novel tank. We validated this as anxiety-like behaviors with diazepam reducing, and caffeine increasing the time spent in the bottom of the novel environment.Conclusions: This new automated and high-throughput screening tool has the potential use for screening of anxiogenic and anxiolytic compounds, and for studies aiming to better understand anxiety-like behaviors.

Barbara D. Fontana, Alistair J. Gibbon, Madeleine Cleal, William H.J. Norton, Matthew O. Parker (2021)Chronic unpredictable early-life stress (CUELS) protocol: Early-life stress changes anxiety levels of adult zebrafish, In: Progress in neuro-psychopharmacology & biological psychiatry108110087 Elsevier Inc

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. •An early-life stress protocol was developed and successfully affects zebrafish behavior without decreasing survival rate.•Chronic unpredictable early-life stress (CUELS) affects adult zebrafish anxiety-like phenotypes.•7 days of CUELS decreases anxiety in two different behavioral tasks.•CUELS neither affects social behavior nor memory and cognition.•Cortisol levels are not changed in animals exposed to CUELS protocol.

Barbara D. Fontana, Madeleine Cleal, William H.J. Norton, Matthew O. Parker (2021)The impact of chronic unpredictable early-life stress (CUELS) on boldness and stress-reactivity: Differential effects of stress duration and context of testing, In: Physiology & behavior240113526 Elsevier Inc

•Chronic unpredictable early-life stress (CUELS) is a reliable protocol for altering boldness/anxiety-like behavior in the novel tank test.•Boldness towards a new object is not affected by CUELS.•Increased cortisol induced by CAS are normal in adult animals exposed to CUELS.•7 and 14 days of CUELS show abnormal behavioral responses when exposed to CAS in the novel tank. Early-life stress (ELS) has been shown to result in a diverse array of long-lasting impacts; for example, increasing vulnerability to disease or building ‘resilience’ in adulthood. Previously, zebrafish (Danio rerio) have been used to understand the mechanisms by which ELS induces different behavioral phenotypes in adults, with alterations in both learning and anxiety observed in exposed individuals. Here, we subjected zebrafish larvae to chronic unpredictable early-life stress (CUELS) for 7 or 14 days, to investigate the impact on boldness towards a new environment and novel object, and stress-reactivity. We observed that 7 days of CUELS resulted in increased time spent in the top of a novel tank (indicating boldness) but did not alter approach to a novel object. Although CUELS did not affect stress-reactivity in terms of cortisol levels, decreased anxiety-like response to conspecific alarm substance (CAS) was observed in both ELS groups (7 and 14 days of CUELS). Therefore, for the first time, we observe a potential negative effect of CUELS by dampening the behavioral stress response following exposure to CAS. Overall, these data support the use of zebrafish as a translational model to study the broad range of ELS-induced permanent changes in behavior. It could also be used to investigate the mechanisms underlying both the positive and the negative effects of early-life adversity.

Barbara D. Fontana, Madeleine Cleal, Alistair J. Gibbon, Sebastian D. McBride, Matthew O. Parker (2021)The effects of two stressors on working memory and cognitive flexibility in zebrafish (Danio rerio): The protective role of D1/D5 agonist on stress responses, In: Neuropharmacology196108681 Elsevier Ltd

Acute stressors are recurrent in multiple species' lives and can facilitate or impair cognition. The use of zebrafish (Danio rerio) as a translational species to understand the mechanisms by which stress induces different behavioral phenotypes has been widely studied. Two acute stressors are recognized when using this species: (1) conspecific alarm substance (CAS); and (2) net chasing. Here, we tested if CAS or net chasing would affect working memory and cognitive flexibility by testing performance in the FMP Y-maze after exposure to stress. We observed that CAS altered zebrafish behavioral phenotypes by increasing repetitive behavior; meanwhile, animals showed different patterns of repetitive behavior when exposed to net chasing, depending on the chasing direction. Because D1 receptors were previously studied as a potential mechanism underlying stress responses in different species, here, we pretreated fish with a D1/D5 agonist (SKF-38393) to assess whether this system plays a role in repetitive behavior in the FMP Y-maze. The pretreatment with D1/D5 agonist significantly decreased repetitive behavior in CAS exposed animals, and cortisol levels for both stressed groups, suggesting that the dopaminergic system plays an important role in zebrafish stress-related responses. •Net chasing differently affects animals' repetitive behavior depending on the chasing direction.•CAS increases ARBs in the FMP Y-maze which is partially reversed by a D1/D5 agonist.•CAS and net chasing affect zebrafish cognitive flexibility.•D1/D5 agonist pretreatment attenuates the effects of stress increasing cortisol levels.

Konstantin N. Zabegalov, Sergey L. Khatsko, Anton M. Lakstygal, Konstantin A. Demin, Madeleine Cleal, Barbara D. Fontana, Sebastian D. McBride, Brian H. Harvey, Murilo S. de Abreu, Matthew O. Parker, Allan V. Kalueff (2019)Abnormal repetitive behaviors in zebrafish and their relevance to human brain disorders, In: Behavioural brain research367pp. 101-110 Elsevier B.V

Abnormal repetitive behaviors (ARBs) are a prominent symptom of numerous human brain disorders and are commonly seen in rodent models as well. While rodent studies of ARBs continue to dominate the field, mounting evidence suggests that zebrafish (Danio rerio) also display ARB-like phenotypes and may therefore be a novel model organism for ARB research. In addition to clear practical research advantages as a model species, zebrafish share high genetic and physiological homology to humans and rodents, including multiple ARB-related genes and robust behaviors relevant to ARB. Here, we discuss a wide spectrum of stereotypic repetitive behaviors in zebrafish, data on their genetic and pharmacological modulation, and the overall translational relevance of fish ARBs to modeling human brain disorders. Overall, the zebrafish is rapidly emerging as a new promising model to study ARBs and their underlying mechanisms.

Barbara D. Fontana, Flavia V. Stefanello, Nathana J. Mezzomo, Talise E. Müller, Vanessa A. Quadros, Matthew O. Parker, Eduardo P. Rico, Denis B. Rosemberg (2018)Taurine modulates acute ethanol-induced social behavioral deficits and fear responses in adult zebrafish, In: Journal of psychiatric research104pp. 176-182 Elsevier Ltd

Ethanol (EtOH) is a central nervous system (CNS) depressant drug that modifies various behavioral domains (i.e., sociability, aggressiveness, and memory) by promoting disinhibition of punished operant behavior and neurochemical changes. Taurine (TAU) is a β-amino sulfonic acid with pleiotropic roles in the brain. Although exogenous TAU is found in energy drinks and often mixed with alcohol in beverages, the putative risks of mixing TAU and EtOH are poorly explored. Here, we investigated whether TAU modulates social and fear responses by assessing shoaling behavior, preference for conspecifics, and antipredatory behavior of adult zebrafish acutely exposed to EtOH. Zebrafish shoals (4 fish per shoal) were exposed to water (control), TAU (42, 150, and 400 mg/L), 0.25% (v/v) EtOH alone or in association with TAU for 1 h, and their behaviors were analyzed at different time intervals (0–5 min, 30–35 min, and 55–60 min). The effects of TAU and EtOH were further tested in a social preference test and during exposure to a predator. Both EtOH and TAU co-treated fish showed a higher shoal dispersion, while TAU 400/EtOH group shoal area had a similar profile when compared to control. However, in the social preference test, TAU 400/EtOH impaired the seeking for conspecifics. Regarding fear-like behaviors, TAU-cotreated fish showed a prominent reduction in risk assessments when compared to EtOH alone. Overall, we demonstrate that TAU modulates EtOH-induced changes in different behavioral domains, suggesting a complex relationship between social and fear-like responses. •Taurine affects shoaling behavior in adult zebrafish.•Taurine and ethanol display a temporal effect on zebrafish shoal cohesion.•Ethanol associated with high taurine concentrations decreases social preference.•Taurine potentiates ethanol-induced reduction in risk assessments.

Barbara D Fontana, William H J Norton, Matthew O Parker (2022)Modelling ADHD-Like Phenotypes in Zebrafish, In: Current topics in behavioral neurosciences57pp. 395-414

The use of multiple species to model complex human psychiatric disorders, such as ADHD, can give important insights into conserved evolutionary patterns underlying multidomain behaviors (e.g., locomotion, attention, and impulsivity). Here we discuss the advantages and challenges in modelling ADHD-like phenotypes in zebrafish (Danio rerio), a vertebrate species that has been widely used in neuroscience and behavior research. Moreover, multiple behavioral tasks can be used to model the core symptoms of ADHD and its comorbidities. We present a critical review of current ADHD studies in zebrafish, and how this species might be used to accelerate the discovery of new drug treatments for this disorder.

Barbara D. Fontana, Madeleine Cleal, James M. Clay, Matthew O. Parker (2019)Zebrafish (Danio rerio) behavioral laterality predicts increased short-term avoidance memory but not stress-reactivity responses, In: Animal cognition22pp. 1051-1061 Springer Nature

Once considered a uniquely human attribute, behavioral laterality has proven to be ubiquitous among non-human animals, and is associated with several neurophenotypes in rodents and fishes. Zebrafish (Danio rerio) is a versatile vertebrate model system widely used in translational neuropsychiatric research owing to their highly conserved genetic homology, well-characterized physiological responses, and extensive behavioral repertoire. Although spontaneous left- and right-biased responses, and associated behavioral domains (e.g., stress reactivity, aggression, and learning), have previously been observed in other teleost species, no information relating to whether spontaneous motor left-right-bias responses of zebrafish predicts other behavioral domains has been described. Thus, we aimed to investigate the existence and incidence of natural left-right bias in adult zebrafish, exploiting an unconditioned continuous free movement pattern (FMP) Y-maze task, and to explore the relationship of biasedness on performance within different behavioral domains. This included learning about threat cues in a Pavlovian fear conditioning test, and locomotion and anxiety-related behavior in the novel tank diving test. Although laterality did not change locomotion or anxiety-related behaviors, we found that biased animals displayed a different search strategy in the Y-maze, making them easily discernable from their unbiased counterparts, and increased learning associated to fear cues. In conclusion, we showed, for the first time, that zebrafish exhibit a natural manifestation of motor behavioral lateralization which can influence aversive learning responses.

Talise E. Mueller, Barbara D. Fontana, Kanandra T. Bertoncello, Francini Franscescon, Nathana J. Mezzomo, Julia Canzian, Flavia V. Stefanello, Matthew O. Parker, Robert Gerlai, Denis B. Rosemberg (2020)Understanding the neurobiological effects of drug abuse: Lessons from zebrafish models, In: Progress in neuro-psychopharmacology & biological psychiatry100109873 Elsevier

Drug abuse and brain disorders related to drug comsumption are public health problems with harmful individual and social consequences. The identification of therapeutic targets and precise pharmacological treatments to these neuropsychiatric conditions associated with drug abuse are urgently needed. Understanding the link between neurobiological mechanisms and behavior is a key aspect of elucidating drug abuse-related targets. Due to various molecular, biochemical, pharmacological, and physiological features, the zebrafish (Danio rerio) has been considered a suitable vertebrate for modeling complex processes involved in drug abuse responses. In this review, we discuss how the zebrafish has been successfully used for modeling neurobehavioral phenotypes related to drug abuse and review the effects of opioids, cannabinoids, alcohol, nicotine, and psychedelic drugs on the central nervous system (CNS). Moreover, we summarize recent advances in zebrafish-based studies and outline potential advantages and limitations of the existing zebrafish models to explore the neurochemical bases of drug abuse and addiction. Finally, we discuss how the use of zebrafish models may present fruitful approaches to provide valuable clinically translatable data.

Dongmei Wang, Jiantao Wang, Dongni Yan, Mengyao Wang, LongEn Yang, Guojun Hu, Maksim Bytov, Konstantin N. Zabegalov, Aleksander Zhdanov, Brian H. Harvey, Fabiano Costa, Denis B. Rosemberg, Brian E. Leonard, Konstantin A. Demin, Barbara D. Fontana, Anton M. Lakstygal, Madeleine Cleal, Andrey D. Volgin, Matthew O. Parker, Jiajia Wang, Murilo S. de Abreu, Cai Song, Rafael Genario, Tamara G. Amstislavskaya, Erik T. Alpyshov, Nazar Serikuly, Allan Kalueff (2020)Cross-species Analyses of Intra-species Behavioral Differences in Mammals and Fish, In: Neuroscience429pp. 33-45 Elsevier

Multiple species display robust behavioral variance among individuals due to different genetic, genomic, epigenetic, neuroplasticity and environmental factors. Behavioral individuality has been extensively studied in various animal models, including rodents and other mammals. Fish, such as zebrafish (Danio rerio), have recently emerged as powerful aquatic model organisms with overt individual differences in behavioral, nociceptive and other CNS traits. Here, we evaluate individual behavioral differences in mammals and fish, emphasizing the importance of cross-species analyses of intraspecies variance in experimental models of normal and pathological CNS functions. (C) 2019 IBRO. Published by Elsevier Ltd. All rights reserved.

Adam Michael Stewart, Jeremy F.P. Ullmann, William H.J. Norton, Caroline H. Brennan, Matthew O. Parker, Robert Gerlai, Allan V. Kalueff (2014)Molecular psychiatry of zebrafish, In: Molecular psychiatry20pp. 2-17

Due to their well-characterized neural development and high genetic homology to mammals, zebrafish ( Danio rerio ) have emerged as a powerful model organism in the field of biological psychiatry. Here, we discuss the molecular psychiatry of zebrafish, and its implications for translational neuroscience research and modeling CNS disorders. In particular, we outline recent genetic and technological developments allowing for in-vivo examinations, high-throughput screening and whole-brain analyses in larval and adult zebrafish. We also summarize the application of these molecular techniques to the understanding of neuropsychiatric disease, outlining the potential of zebrafish for modeling complex brain disorders, including attention-deficit/hyperactivity disorder (ADHD), aggression, post-traumatic stress and substance abuse. Critically evaluating the advantages and limitations of larval and adult fish tests, we suggest that zebrafish models become a rapidly emerging new field in modern biological psychiatry research.

Judit García-González, Alistair J Brock, Matthew O Parker, Riva J Riley, David Joliffe, Ari Sudwarts, Muy-Teck Teh, Elisabeth M Busch-Nentwich, Derek L Stemple, Adrian R Martineau, Jaakko Kaprio, Teemu Palviainen, Valerie Kuan, Robert T Walton, Caroline H Brennan (2020)Identification of slit3 as a locus affecting nicotine preference in zebrafish and human smoking behaviour, In: eLife9

To facilitate smoking genetics research we determined whether a screen of mutagenized zebrafish for nicotine preference could predict loci affecting smoking behaviour. From 30 screened F sibling groups, where each was derived from an individual ethyl-nitrosurea mutagenized F fish, two showed increased or decreased nicotine preference. Out of 25 inactivating mutations carried by the F fish, one in the gene segregated with increased nicotine preference in heterozygous individuals. Focussed SNP analysis of the human locus in cohorts from UK (n=863) and Finland (n=1715) identified two variants associated with cigarette consumption and likelihood of cessation. Characterisation of mutant larvae and adult fish revealed decreased sensitivity to the dopaminergic and serotonergic antagonist amisulpride, known to affect startle reflex that is correlated with addiction in humans, and increased mRNA expression in mutant larvae. No effect on neuronal pathfinding was detected. These findings reveal a role for SLIT3 in development of pathways affecting responses to nicotine in zebrafish and smoking in humans.

Michael J Proulx, Matthew O Parker, Yasser Tahir, Caroline H Brennan (2014)Parallel mechanisms for visual search in zebrafish, In: PloS one9(10)e111540

Parallel visual search mechanisms have been reported previously only in mammals and birds, and not animals lacking an expanded telencephalon such as bees. Here we report the first evidence for parallel visual search in fish using a choice task where the fish had to find a target amongst an increasing number of distractors. Following two-choice discrimination training, zebrafish were presented with the original stimulus within an increasing array of distractor stimuli. We found that zebrafish exhibit no significant change in accuracy and approach latency as the number of distractors increased, providing evidence of parallel processing. This evidence challenges theories of vertebrate neural architecture and the importance of an expanded telencephalon for the evolution of executive function.

Matthew O. Parker, Alexandra M-D. Evans, Alistair J. Brock, Fraser J. Combe, Muy-Teck Teh, Caroline H. Brennan (2016)Moderate alcohol exposure during early brain development increases stimulus-response habits in adulthood, In: Addiction biology21(1)pp. 49-60 Wiley

Exposure to alcohol during early central nervous system development has been shown variously to affect aspects of physiological and behavioural development. In extreme cases, this can extend to craniofacial defects, severe developmental delay and mental retardation. At more moderate levels, subtle differences in brain morphology and behaviour have been observed. One clear effect of developmental alcohol exposure is an increase in the propensity to develop alcoholism and other addictions. The mechanisms by which this occurs, however, are not currently understood. In this study, we tested the hypothesis that adult zebrafish chronically exposed to moderate levels of ethanol during early brain ontogenesis would show an increase in conditioned place preference for alcohol and an increased propensity towards habit formation, a key component of drug addiction in humans. We found support for both of these hypotheses and found that the exposed fish had changes in mRNA expression patterns for dopamine receptor, nicotinic acetylcholine receptor and -opioid receptor encoding genes. Collectively, these data show an explicit link between the increased proclivity for addiction and addiction-related behaviour following exposure to ethanol during early brain development and alterations in the neural circuits underlying habit learning.

Matthew O. Parker, Jessica Gaviria, Alastair Haigh, Mollie E. Millington, Verity J. Brown, Fraser J. Combe, Caroline H. Brennan (2012)Discrimination reversal and attentional sets in zebrafish (Danio rerio), In: Behavioural brain research232(1)pp. 264-268 Elsevier

The potential of zebrafish as a comparative model in behavioural neuroscience is currently hampered only by the lack of reliable and validated behavioural assays available to researchers. In the present experiment, we describe the performance of zebrafish in a test of attentional set formation. The fish were initially trained on a two-choice colour discrimination. Upon reaching acquisition criterion, the reinforced alternative was switched to the previously unreinforced alternative. Again, upon reaching criterion, the cues were replaced with a novel pair of colours (intra-dimensional shift) and reversed again on reaching criteria. We found that zebrafish show a steady decrease in trials-to-criteria over the four phases of the experiment, suggesting that they are forming and maintaining an attentional set, as has previously been demonstrated with mammals. Reversal learning deficits have been implicated in a variety of human psychological disorders (e.g., disorders of impulse control) and as such, we propose that performance of zebrafish in this procedure may represent a useful comparative model to complement existing rodent models. (C) 2012 Elsevier B.V. All rights reserved.

Matthew O. Parker, Leonette V. Annan, Alexandros H. Kanellopoulos, Alistair J. Brock, Fraser J. Combe, Matteo Baiamonte, Muy-Teck Teh, Caroline H. Brennan (2014)The utility of zebrafish to study the mechanisms by which ethanol affects social behavior and anxiety during early brain development, In: Progress in neuro-psychopharmacology & biological psychiatry55pp. 94-100 Elsevier

Exposure to moderate levels of ethanol during brain development has a number of effects on social behavior but the molecular mechanisms that mediate this are not well understood. Gaining a better understanding of these factors may help to develop therapeutic interventions in the future. Zebrafish offer a potentially useful model in this regard. Here, we introduce a zebrafish model of moderate prenatal ethanol exposure. Embryos were exposed to 20 mM ethanol for seven days (48hpf-9dpf) and tested as adults for individual social behavior and shoaling. We also tested their basal anxiety with the novel tank diving test. We found that the ethanol-exposed fish displayed reductions in social approach and shoaling, and an increase in anxiety in the novel tank test. These behavioral differences corresponded to differences in hrt1aa, slc6a4 and oxtr expression. Namely, acute ethanol caused a spike in oxtr and ht1aa mRNA expression, which was followed by down-regulation at 7dpf, and an up-regulation in slc6a4 at 72hpf. This study confirms the utility of zebrafish as a model system for studying the molecular basis of developmental ethanol exposure. Furthermore, it proposes a putative developmental mechanism characterized by ethanol-induced OT inhibition leading to suppression of 5-HT and up-regulation of 5-HT1A, which leads, in turn, to possible homeostatic up-regulation of 5-HTT at 72hpf and subsequent imbalance of the 5-HT system. (C) 2014 Elsevier Inc. All rights reserved.

Barbara D. Fontana, Alistair J. Gibbon, Madeleine Cleal, Ari Sudwarts, David Pritchett, Maria Elena Miletto Petrazzini, Caroline H. Brennan, Matthew O. Parker (2021)Moderate early life stress improves adult zebrafish (Danio rerio) working memory but does not affect social and anxiety-like responses, In: Developmental psychobiology63(1)pp. 54-64 Wiley

Early life stress (ELS) is defined as a short or chronic period of trauma, environmental or social deprivation, which can affect different neurochemical and behavioral patterns during adulthood. Zebrafish (Danio rerio) have been widely used as a model system to understand human neurodevelopmental disorders and display translationally relevant behavioral and stress-regulating systems. In this study, we aimed to investigate the effects of moderate ELS by exposing young animals (6-weeks postfertilization), for 3 consecutive days, to three stressors, and analyzing the impact of this on adult zebrafish behavior (16-week postfertilization). The ELS impact in adults was assessed through analysis of performance on tests of unconditioned memory (free movement pattern Y-maze test), exploratory and anxiety-related task (novel tank diving test), and social cohesion (shoaling test). Here, we show for the first time that moderate ELS increases the number of alternations in turn-direction compared to repetitions in the unconditioned Y-maze task, suggesting increased working memory, but has no effect on shoal cohesion, locomotor profile, or anxiety-like behavior. Overall, our data suggest that moderate ELS may be linked to adaptive flexibility which contributes to build "resilience" in adult zebrafish by improving working memory performance.

Matthew O. Parker, Alistair J. Brock, Mollie E. Millington, Caroline H. Brennan (2013)Behavioural Phenotyping of Casper Mutant and 1-Pheny-2-Thiourea Treated Adult Zebrafish, In: Zebrafish10(4)pp. 466-471 Mary Ann Liebert, Inc

The ability to visualise neural circuits in zebrafish in vivo is one of the most useful aspects of this model organism in neuroscience. To maintain the transparency of embryos, however, drugs, such as 1-pheyl-2-thiourea (PTU) must be added, or researchers can use mutants that do not develop pigment (e.g., the casper). The behavioural characteristics of such strains, however, have not been documented. Here, we tested adult zebrafish from the casper line, as well as wild-type (Tubingen, TU) and wild-types treated as embryos with PTU on three commonly used behavioural endpoints in neuroscience: novel tank test (similar to open-field in rodents), conditioned place preference for nicotine, and social cohesion (using a new method of cluster analysis). We found no differences between the casper and the TU, but the adult TU treated with PTU as embryos showed a marked increase in anxiety during the novel tank test. These data suggest that where possible, labs interested in analysis of developmental processes involved in adult phenotypes should avoid the use of PTU in favour of transparent mutants, such as casper.

Caroline H. Brennan, Matthew O. Parker (2012)Zebrafish (Danio rerio) models of substance abuse: Harnessing the capabilities, In: Behaviour149(10-12)pp. 1037-1062 Brill

Zebrafish are fast becoming one of the most widely used animal models in systems biology and developmental genetics, but their potential as models for behavioural neuroscience is only just beginning to be realised. This progress is dependent upon the rate at which behavioural assays for adult zebrafish are designed, reported and validated. As models for drug abuse and addiction, this species has been shown thus far to show high face validity, in that they show robust place preference for drug-related cues, as well as evidence for withdrawal, relapse and compulsive drug seeking. This review will outline the case for using zebrafish as models to study endophenotypes relating to drug addiction.

Matthew O. Parker, Mollie E. Millington, Fraser J. Combe, Caroline H. Brennan (2012)Development and implementation of a three-choice serial reaction time task for zebrafish (Danio rerio), In: Behavioural brain research227(1)pp. 73-80 Elsevier

Zebrafish are an established and widely utilized developmental genetic model system, but limitations in developed behavioral assays have meant that their potential as a model in behavioral neuroscience has yet to be fully realized. Here, we describe the development of a novel operant behavioral assay to examine a variety of aspects of stimulus control in zebrafish using a 3 choice serial reaction time task (3 CSRTT). Fish were briefly exposed to three spatially distinct, but perceptually identical stimuli, presented in a random order after a fixed-time inter-trial interval (ITI). Entries to the correct response aperture either during the stimulus presentation, or within a brief limited hold period following presentation, were reinforced with illumination of the magazine light and delivery of a small food reward. Following training, premature responding was probed with a long-ITI session three times; once at baseline, once following a saline injection and once following an injection of a low dose of amphetamine (AMPH; 0.025 mg/kg). We predicted that if premature responding was related to impulsivity (as in rodents) it would be reduced following the AMPH injection. Results confirmed that zebrafish could learn to perform a complex operant task similar to tasks developed for rodents which are used to probe sustained attention and impulsivity, but the results from the AMPH trials were inconclusive. This study provides the foundations for development and further validation of this species as a model for some aspects of human attentional and impulse control disorders, such as substance abuse disorder. (C) 2011 Elsevier B.V. All rights reserved.

Matteo Baiamonte, Matthew O. Parker, Gavin P. Vinson, Caroline H. Brennan (2016)Sustained Effects of Developmental Exposure to Ethanol on Zebrafish Anxiety-Like Behaviour, In: PloS one11(2)e0148425 Public Library Science

In zebrafish developmentally exposed to ambient ethanol (20mM-50mM) 1-9 days post fertilization (dpf), the cortisol response to stress has been shown to be significantly attenuated in larvae, juveniles and 6 month old adults. These data are somewhat at variance with similar studies in mammals, which often show heightened stress responses. To test whether these cortisol data correlate with behavioural changes in treated animals, anxiety-like behaviour of zebrafish larvae (9dpf and 10dpf) and juveniles (23dpf) was tested in locomotor assays designed to this end. In open field tests treated animals were more exploratory, spending significantly less time at the periphery of the arena. Behavioural effects of developmental exposure to ethanol were sustained in 6-month-old adults, as judged by assessment of thigmotaxis, novel tank diving and scototaxis. Like larvae and juveniles, developmentally treated adults were generally more exploratory, and spent less time at the periphery of the arena in thigmotaxis tests, less time at the bottom of the tank in the novel tank diving tests, and less time in the dark area in scototaxis tests. The conclusion that ethanol- exposed animals showed less anxiety-like behaviour was validated by comparison with the effects of diazepam treatment, which in thigmotaxis and novel tank diving tests had similar effects to ethanol pretreatment. There is thus a possible link between the hypophysealpituitary- interrenal axis and the behavioural actions of developmental ethanol exposure. The mechanisms require further elucidation.

Matthew O. Parker, Dennis Lfe, Jun Ma, Mahesh Pancholi, Fabrizio Smeraldi, Chris Straw, Caroline H. Brennan (2013)Development and automation of a test of impulse control in zebrafish, In: Frontiers in systems neuroscience765 Frontiers Media Sa

Deficits in impulse control (difficulties in inhibition of a pre-potent response) are fundamental to a number of psychiatric disorders, but the molecular and cellular basis is poorly understood. Zebrafish offer a very useful model for exploring these mechanisms, but there is currently a lack of validated procedures for measuring impulsivity in fish. In mammals, impulsivity can be measured by examining rates of anticipatory responding in the 5-choice serial reaction time task (5-CSRTT), a continuous performance task where the subject is reinforced upon accurate detection of a briefly presented light in one of five distinct spatial locations. This paper describes the development of a fully-integrated automated system for testing impulsivity in adult zebrafish. We outline the development of our image analysis software and its integration with National Instruments drivers and actuators to produce the system. We also describe an initial validation of the system through a one-generation screen of chemically mutagenized zebrafish, where the testing parameters were optimized.

Matthew O. Parker, Alistair J. Brock, Ari Sudwarts, Muy-Teck Teh, Fraser J. Combe, Caroline H. Brennan (2015)Developmental role of acetylcholinesterase in impulse control in zebrafish, In: Frontiers in behavioral neuroscience9271 Frontiers Media Sa

Cellular and molecular processes that mediate individual variability in impulsivity, a key behavioral component of many neuropsychiatric disorders, are poorly understood. Zebrafish heterozygous for a nonsense mutation in ache (ache(sb55/+)) showed lower levels of impulsivity in a 5-choice serial reaction time task (5-CSRTT) than wild type and ache(+/+). Assessment of expression of cholinergic (nAChR), serotonergic (5-HT), and dopamine (DR) receptor mRNA in both adult and larval (9dpf) ache(sb55/+) revealed significant downregulation of chrna2, chrna5, and drd2 mRNA in ache(sb55/+) larvae, but no differences in adults. Acute exposure to cholinergic agonist/antagonists had no effect on impulsivity, supporting the hypothesis that behavioral effects observed in adults were due to lasting impact of developmental alterations in cholinergic and dopaminergic signaling. This shows the cross-species role of cholinergic signaling during brain development in impulsivity, and suggests zebrafish may be a useful model for the role of cholinergic pathways as a target for therapeutic advances in addiction medicine.

Matthew O. Parker, Alistair J. Brock, Ari Sudwarts, Caroline H. Brennan (2014)Atomoxetine reduces anticipatory responding in a 5-choice serial reaction time task for adult zebrafish, In: PSYCHOPHARMACOLOGY231(13)pp. 2671-2679 Springer Nature

Deficits in impulse control are related to a number of psychiatric diagnoses, including attention deficit hyperactivity disorder, addiction, and pathological gambling. Despite increases in our knowledge about the underlying neurochemical and neuroanatomical correlates, understanding of the molecular and cellular mechanisms is less well established. Understanding these mechanisms is essential in order to move towards individualized treatment programs and increase efficacy of interventions. Zebrafish are a very useful vertebrate model for exploring molecular processes underlying disease owing to their small size and genetic tractability. Their utility in terms of behavioral neuroscience, however, hinges on the validation and publication of reliable assays with adequate translational relevance. Here, we report an initial pharmacological validation of a fully automated zebrafish version of the commonly used five-choice serial reaction time task using a variable interval pre-stimulus interval. We found that atomoxetine reduced anticipatory responses (0.6 mg/kg), whereas a high-dose (4 mg/kg) methylphenidate increased anticipatory responses and the number of trials completed in a session. On the basis of these results, we argue that similar neurochemical processes in fish as in mammals may control impulsivity, as operationally defined by anticipatory responses on a continuous performance task such as this, making zebrafish potentially a good model for exploring the molecular basis of impulse control disorders and for first-round drug screening.

Alistair J. Brock, Ari Sudwarts, Matthew O. Parker, Caroline H. Brennan (2017)Zebrafish Behavioral Models of Ageing, In: The rights and wrongs of zebrafish: Behavioral phenotyping of zebrafishpp. 241-258 Springer International Publishing

With lifespans rapidly increasing worldwide there has been a marked increase in age-related diseases—particularly those affecting cognition—that place a major socioeconomic burden on society. Despite this, much of what occurs during the aging process at a molecular level is poorly understood, facilitating the need for a greater understanding of the processes involved. In recent years, zebrafish have proved a useful model for the identification of genetic and cellular mechanisms affecting a variety of disease processes. Here we review the potential of zebrafish as a model for the study of cognitive ageing.

Matthew O. Parker, Mollie E. Millington, Fraser J. Combe, Caroline H. Brennan (2012)Housing Conditions Differentially Affect Physiological and Behavioural Stress Responses of Zebrafish, as well as the Response to Anxiolytics, In: PloS one7(4)e34992 Public Library Science

Zebrafish are a widely utilised animal model in developmental genetics, and owing to recent advances in our understanding of zebrafish behaviour, their utility as a comparative model in behavioural neuroscience is beginning to be realised. One widely reported behavioural measure is the novel tank-diving assay, which has been often cited as a test of anxiety and stress reactivity. Despite its wide utilisation, and various validations against anxiolytic drugs, reporting of pre-test housing has been sparse in the literature. As zebrafish are a shoaling species, we predicted that housing environment would affect their stress reactivity and, as such, their response in the tank-diving procedure. In our first experiment, we tested various aspects of housing (large groups, large groups with no contact, paired, visual contact only, olfactory contact only) and found that the tank diving response was mediated by visual contact with conspecifics. We also tested the basal cortisol levels of group and individually housed fish, and found that individually housed individuals have lower basal cortisol levels. In our second experiment we found ethanol appeared to have an anxiolytic effect with individually housed fish but not those that were group housed. In our final experiment, we examined the effects of changing the fishes' water prior to tank diving as an additional acclimation procedure. We found that this had no effect on individually housed fish, but appeared to affect the typical tank diving responses of the group housed individuals. In conclusion, we demonstrate that housing represents an important factor in obtaining reliable data from this methodology, and should be considered by researchers interested in comparative models of anxiety in zebrafish in order to refine their approach and to increase the power in their experiments.

Matthew O. Parker, Alistair J. Brock, Robert T. Walton, Caroline H. Brennan (2013)The role of zebrafish (Danio rerio) in dissecting the genetics and neural circuits of executive function, In: Frontiers in neural circuits763 Frontiers Media Sa

Zebrafish have great potential to contribute to our understanding of behavioral genetics and thus to contribute to our understanding of the etiology of psychiatric disease. However, progress is dependent upon the rate at which behavioural assays addressing complex behavioral phenotypes are designed, reported and validated. Here we critically review existing behavioral assays with particular focus on the use of adult zebrafish to explore executive process and phenotypes associated with human psychiatric disease. We outline the case for using zebrafish as models to study impulse control and attention, discussing the validity of applying extant rodent assays to zebrafish and evidence for the conservation of relevant neural circuits.

Barbara D. Fontana, Francini Franscescon, Denis B. Rosemberg, William H.J. Norton, Allan V. Kalueff, Matthew O. Parker (2019)Zebrafish models for attention deficit hyperactivity disorder (ADHD), In: Neuroscience and biobehavioral reviews100pp. 9-18 Elsevier Ltd

•ADHD is a neurodevelopmental disorder that affects an increasing number of people worldwide.•Zebrafish is a prominent model to assess the underlying mechanisms of ADHD and it comorbidities.•Advantages and disadvantages of using zebrafish to model ADHD were discussed.•Current zebrafish ADHD models and future directions are highlighted. 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.

Matthew Parker, Sebastian D. McBride, Edward S. Redhead, Deborah Goodwin (2009)Differential place and response learning in horses displaying an oral stereotypy, In: Behavioural brain research200(1)pp. 100-105 Elsevier B.V

Significant similarities exist between the neural and behavioural features of environmentally and drug-induced stereotypy. For example, exposure to dopamine agonists, such as amphetamine, induces stereotypy and causes alterations in midbrain neurophysiology similar to those observed following chronic stress. An additional behavioural feature of these neural changes in the drug-induced phenotype is an enhanced rate of switching from response-outcome (R-O) to stimulus-response (S-R) learning. The aim of the current experiment was to examine R-O and S-R learning in horses displaying environmentally induced oral stereotypies. This was achieved by employing variations of the place/response paradigm. In Experiment 1, we found that crib-biting horses displayed ‘response’ learning after 20 learning trials, whereas non-crib-biting controls tended to display ‘place’ learning throughout the experiment. In Experiment 2, we used a modified version of the procedure, in which the subjects were introduced to the maze from different start points and forced always to turn the same way. We found that the crib-biters acquired the task at a faster rate suggesting again that this group was displaying ‘response’ learning. Finally, in Experiment 3, we carried out an arena test to ensure that crib-biters were capable of ‘place’ learning. These results are the first to show that horses displaying an oral stereotypy, a behavioural phenotype previously associated with stress-induced perturbations of the basal ganglia, preferentially use ‘response’ learning. The findings are discussed in relation to the search for an aetiological model of stereotypy.

Matthew Parker, Deborah Goodwin, Rachael A Eager, Edward S Redhead, David J Marlin (2009)Comparison of Polar® heart rate interval data with simultaneously recorded ECG signals in horses, In: Comparative exercise physiology6(4)pp. 137-142 Cambridge University Press

Human heart rate monitors (HRMs) are frequently used in equine studies to measure heart rate (HR) and interbeat intervals (IBIs). However, to date, the most commonly used HRM (the Polar® system) in horses has not been validated against simultaneously recorded electrocardiogram (ECG) signals during a range of ambulatory conditions. Polar® S810i and ECG IBIs were simultaneously recorded from six horses under three conditions commonly included in behavioural observation: standing at rest, loose in the stable and at liberty in a field. Following recording, Polar® IBI data were corrected for error processing in cardiac data. Corrected and uncorrected Polar® data were then compared with simultaneously recorded ECG data using a variety of commonly measured time and frequency domain parameters (e.g. HR variability (HRV)). Polar® data collected while horses were stabled or in the field were significantly different from ECG data, even following correction of the data, and therefore, it may not be possible for the two systems to be used interchangeably. This study indicates the need for caution while using Polar® S810i for collecting HRV data, unless horses are stationary, and even when the IBI data are corrected for measurement error.