Volume 22, Issue 1 - Special Issue: Zebrafish in Behavioral Neuroscience

No abstract available

No abstract available

To ensure high acuity vision, eye movements have to be controlled with astonishing precision by the oculomotor system. Many human diseases can lead to abnormal eye movements, typically of the involuntary oscillatory eye movements type called nystagmus. Such nystagmus can be congenital (infantile) or acquired later in life. Although the resulting eye movements are well characterized, there is only little information about the underlying etiology. This is in part owing to the lack of appropriate animal models. In this review article, we des­cribe how the zebrafish with its quick maturing visual system can be used to model oculomotor pathologies. We compare the characteristics and assessment of human and zebrafish eye movements. We describe the oculomotor properties of the zebrafish mutant belladonna , which has non-crossing optical fibers, and is a particularly informative model for human ocu­lomotor deficits. This mutant displays a reverse optokinetic response, spontaneous oscillations that closely mimic human congenital nystagmus and abnormal motor behavior linked to circular vection.

Zebrafish have been gaining increasing popularity in behavioral neuroscience. However, the number of behavioral test paradigms specifically designed for zebrafish, and in general the amount of information available on the behavior of this species, is relatively small when compared with classical laboratory model organisms such as the mouse, the rat, and the fruit fly. A particularly typical behavioral feature of zebrafish is shoaling, i.e., group formation. Given the importance of social behavior in our own species and the fact that zebrafish possess several characteristics similar to those of other vertebrates, including humans, at many levels of biological organization (e.g., neuroanatomy, neurochemistry, biochemical processes, and amino acid sequence of proteins or nucleotide sequence of genes), the zebrafish is expected to be an excellent tool not only for basic research but perhaps also for translational research. Briefly, we propose that once social behavior of the zebrafish is better characterized and once appropriate behavioral methods have been developed, this species can be utilized for the analysis of the mechanisms of social behavior of other vertebrates including our own. In this review, we discuss general principles of shoaling and highlight what we know and what we do not know about this behavior as it pertains to zebrafish.

The function of sleep remains a central enigma of modern biology, in spite of the obvious importance of sleep for normal physiology and cognition. The zebrafish has emerged as a promising new model for studying sleep, its changes with age, and the impact of sleep alterations on cognitive function. Recent studies of this diurnal vertebrate have provided new insights into the dual role of the pineal hormone melatonin and its receptors, regulating sleep in diurnal vertebrates through both homeostatic and circadian mechanisms. Research in zebrafish has also revealed interactions between melatonin and the hypocretin/orexin system, another important sleep-wake modulator. Future investigations should benefit from the conservation in zebrafish of mechanisms that regulate normal sleep, our extensive knowledge of their molecular biology, the availability of multiple transgenic and mutant phenotypes, and the feasibility of applying sensitive in vivo imaging techniques to record sleep-related neuronal activity in these optically transparent subjects. The established sensitivity of zebrafish to many pharmacological hypnotics should also contribute to the development of new, safe and effective sleep medications.

Understanding the pathogenesis of the complex behavioural disorders that constitute psychiatric disease is a major challenge for biomedical research. Assays in rodents have contributed significantly to our understanding of the neural basis of behavioural disorders and continue to be one of the main focuses for the development of novel therapeutics. Now, owing to their genetic tractability and optical transparency (allowing in vivo imaging of circuit function) and the rapid expansion of genetic tools, zebrafish are becoming increasingly popular for behavioural genetic research. The increased development of behavioural assays in zebrafish raises the possibility of exploiting the advantages of this system to identify molecular mechanisms contributing to behavioural phenotypes associated with psychiatric disorders as well as potential therapeutics. This mini-review describes behavioural paradigms in zebrafish that can be used to address endophenotypes associated with psychiatric disease. The content reflects the interests of the author and covers tests of cognitive functions, response choice and inhibition, social interaction and executive function.

The stress response is a normal reaction to a real or perceived threat. However, stress response systems that are overwhelmed or out of balance can increase both the incidence and severity of diseases including addiction and mood and anxiety disorders. Using an animal model with both genetic diversity and large family size can help discover the specific genetic and environmental contributions to these behavioral diseases. The stress response has been studied extensively in teleosts because of their importance in food production. The zebrafish ( Danio rerio ) is a major model organism with a strong record for use in developmental biology, genetic screening, and genomic studies. More recently, the stress response of larval and adult zebrafish has been documented. High-throughput automated tracking systems make possible behavioral readouts of the stress response in zebrafish. This non-invasive measure of the stress response can be combined with mutagenesis methods to dissect the genes involved in complex stress response behaviors in vertebrates. Understanding the genetic and epigenetic basis for the stress response in vertebrates will help to develop advanced screening and therapies for stress-aggravated diseases such as addiction and mood and anxiety disorders.

This review provides an overview of the assays that are used for measuring escape and avoidance behavior in zebrafish, with a specific focus on zebrafish larvae during the first week of development. Zebrafish larvae display a startle response when exposed to tactile, acoustic, or visual stimuli and will avoid dark areas, moving objects, conspecifics, and open spaces. Emotional states such as fear and anxiety might be induced when larvae are exposed to stimuli that they would normally escape from or avoid. Although these emotional states probably differ between species and change during development, much can be learned about human fear and anxiety using zebrafish as a model system. The molecular mechanisms of fear and anxiety are highly conserved in vertebrates and are present during early zebrafish development. Larvae during the first week of development display elevated cortisol levels in response to stress and are sensitive to the same anxiolytics that are used for the management of anxiety in humans. Zebrafish larvae are well suited for high-throughput analyses of behavior, and automated systems have been developed for imaging and analyzing the behavior of zebrafish larvae in multiwell plates. These high-throughput analyses will not only provide a wealth of information on the genes and environmental factors that influence escape and avoidance behaviors and the emotional states that might accompany them but will also facilitate the discovery of novel pharmaceuticals that could be used in the management of anxiety disorders in humans.

Zebrafish can provide a valuable animal model to screen potential cognitive enhancing and anxiolytic drugs. They are economical and can provide a relatively quick indication of possible functional efficacy. In as much as they have a complex nervous system and elaborate behavioral repertoire, zebrafish can provide a good intermediate model between in vitro receptor and cell-based assays and classic mammalian models for drug screening. In addition, the variety of molecular tools available in zebrafish makes them outstanding models for helping to determine the neuromolecular mechanisms for psychoactive drugs. However, to use zebrafish as a translational model we must have validated, sensitive and efficient behavioral tests. In a series of studies, our lab has developed tests of cognitive function and stress response, which are sensitive to drug effects in a similar manner as rodent models and humans for cognitive enhancement and alleviating stress response. In particular, the three-chamber task for learning and memory was shown to be sensitive to the cognitive enhancing effects of nicotine and has been useful in helping to determine neural mechanisms crucial for nicotinic-induced cognitive enhancement. The novel tank diving test was shown to be a valid and efficient test of stress response. It is sensitive to the reduction in stress-related behaviors due to the amxiolytic drugs diazepam and buspirone but not chlordiazepoxide. Nicotine also causes stress alleviating effects which can be interpreted as anxiolytic effects. Zebrafish models of behavioral pharmacology can be useful to efficiently screen test compounds for drug development and can be useful in helping to determine the mechanisms crucial for new therapeutic treatments of neurobehavioral impairments.

Zebrafish are at the forefront of neurobiological research and have been gaining popularity as a viable and valid behavioral model in a variety of research applications (e.g., assessing drug induced behavioral changes). This model becomes even more attractive when considering the behavioral changes that follow exposure to compounds that are water-soluble. As such, several studies have implicated both acute and chronic ethanol exposure in the modulation of zebrafish behavior. Within this arena there appears to be a common trend across multiple studies. As with many drugs ethanol appears to influence behavior in a dose-dependent manner. In this review, we compare and contrast several studies that measure behavior as a result of alcohol exposure. Appended to this review are pilot data that report zebrafish blood alcohol concentrations as a function of acute exposure.

Mounting evidence implicates the zebrafish ( Danio rerio ) as a promising model species for reward and addiction research. Modeling drug abuse-related behavior in both adult and larval zebrafish produced a wealth of clinically translatable data, also demonstrating their sensitivity to various drugs of abuse and the ability to develop tolerance. Several studies have also applied withdrawal paradigms to model the adverse effects of drug abuse in zebrafish. In this review, we summarize recent findings of a wide spectrum of zebrafish drug abuse-related behavioral and physiological phenotypes, discuss the existing challenges, and outline potential future directions of research in this field.

Neurodevelopment depends on intrinsic and extrinsic factors that influence the overall pattern of neurogenesis and neural circuit formation, which has a direct impact on behaviour. Defects in dopamine signalling and brain morphology at a relatively early age, and mutations in neurodevelopmental genes are strongly correlated with several neuropsychiatric disorders. This evidence supports the hypothesis of a neurodevelopmental origin of at least some forms of mental illness. Zebrafish ( Danio rerio ) has emerged as an important vertebrate model system in biomedical research. The ease with which intrinsic and extrinsic factors can be altered during early development, the relatively conserved dopaminergic circuit organisation in the larval brain, and the emergence of simple sensorimotor behaviours very early in development are some of the appealing features that make this organism advantageous for developmental brain and behaviour research. Thus, examining the impact of altered dopamine signalling and disease related genetic aberrations during zebrafish development presents a unique opportunity to holistically analyse the in vivo biochemical, morphological and behavioural significance of altered dopamine signalling during a crucial period of development using a highly tractable vertebrate model organism. Ultimately, this information will shed new light on potential therapeutic targets for the treatment of schizophrenia and perhaps serve as a paradigm for investigating the neurodevelopmental origin of other psychiatric disorders.

Optogenetics has revolutionized the toolbox arsenal that neuroscientists now possess to investigate neuronal circuit function in intact and living animals. With a combination of light emitting ‘sensors’ and light activated ‘actuators’, we can monitor and control neuronal activity with minimal perturbation and unprecedented spatiotemporal resolution. Zebrafish neuronal circuits represent an ideal system to apply an optogenetic based analysis owing to its transparency, relatively small size and amenability to genetic manipulation. In this review, we describe some of the most recent advances in the development and applications of optogenetic sensors (i.e., genetically encoded calcium indicators and voltage sensors) and actuators (i.e., light activated ion channels and ion pumps). We focus mostly on the tools that have already been successfully applied in zebrafish and on those that show the greatest potential for the future. We also describe crucial technical aspects to implement optogenetics in zebrafish including strategies to drive a high level of transgene expression in defined neuronal populations, and recent optical advances that allow the precise spatiotemporal control of sample illumination.