Darya A. Meshalkina

Zebrafish models in neuropsychopharmacology and CNS drug discovery

Despite the high prevalence of neuropsychiatric disorders, their aetiology and molecular mechanisms remain poorly understood. The zebrafish (Danio rerio) is increasingly utilized as a powerful animal model in neuropharmacology research and in vivo drug screening. Collectively, this makes zebrafish a useful tool for drug discovery and the identification of disordered molecular pathways. Here, we discuss zebrafish models of selected human neuropsychiatric disorders and drug‐induced phenotypes. As well as covering a broad range of brain disorders (from anxiety and psychoses to neurodegeneration), we also summarize recent developments in zebrafish genetics and small molecule screening, which markedly enhance the disease modelling and the discovery of novel drug targets.

Modeling consequences of prolonged strong unpredictable stress in zebrafish: Complex effects on behavior and physiology

&NA; Chronic stress is the major pathogenetic factor of human anxiety and depression. Zebrafish (Danio rerio) have become a novel popular model species for neuroscience research and CNS drug discovery. The utility of zebrafish for mimicking human affective disorders is also rapidly growing. Here, we present a new zebrafish model of clinically relevant, prolonged unpredictable strong chronic stress (PUCS). The 5‐week PUCS induced overt anxiety‐like and motor retardation‐like behaviors in adult zebrafish, also elevating whole‐body cortisol and proinflammatory cytokines ‐ interleukins IL‐1&bgr; and IL‐6. PUCS also elevated whole‐body levels of the anti‐inflammatory cytokine IL‐10 and increased the density of dendritic spines in zebrafish telencephalic neurons. Chronic treatment of fish with an antidepressant fluoxetine (0.1 mg/L for 8 days) normalized their behavioral and endocrine phenotypes, as well as corrected stress‐elevated IL‐1&bgr; and IL‐6 levels, similar to clinical and rodent data. The CNS expression of the bdnf gene, the two genes of its receptors (trkB, p75), and the gfap gene of glia biomarker, the glial fibrillary acidic protein, was unaltered in all three groups. However, PUCS elevated whole‐body BDNF levels and the telencephalic dendritic spine density (which were corrected by fluoxetine), thereby somewhat differing from the effects of chronic stress in rodents. Together, these findings support zebrafish as a useful in‐vivo model of chronic stress, also calling for further cross‐species studies of both shared/overlapping and distinct neurobiological responses to chronic stress. HighlightsHere, we report a zebrafish model of prolonged unpredictable chronic stress (PUCS).The 5‐week PUCS induced overt anxiety‐like and motor retardation‐like behaviorsPUCS elevated whole‐body cortisol and proinflammatory cytokines IL‐1&bgr; and IL‐6.PUCS also elevated the anti‐inflammatory cytokine IL‐10 and increased the density of dendritic spines in telencephalic neurons.Chronic treatment with an antidepressant fluoxetine corrected these behavioral and physiological responses.

Animal inflammation-based models of depression and their application to drug discovery

ABSTRACT Introduction: Depression, anxiety and other affective disorders are globally widespread and severely debilitating human brain diseases. Despite their high prevalence and mental health impact, affective pathogenesis is poorly understood, and often remains recurrent and resistant to treatment. The lack of efficient antidepressants and presently limited conceptual innovation necessitate novel approaches and new drug targets in the field of antidepressant therapy. Areas covered: Herein, the authors discuss the emerging role of neuro-immune interactions in affective pathogenesis, which can become useful targets for CNS drug discovery, including modulating neuroinflammatory pathways to alleviate affective pathogenesis. Expert opinion: Mounting evidence implicates microglia, polyunsaturated fatty acids (PUFAs), glucocorticoids and gut microbiota in both inflammation and depression. It is suggested that novel antidepressants can be developed based on targeting microglia-, PUFAs-, glucocorticoid- and gut microbiota-mediated cellular pathways. In addition, the authors call for a wider application of novel model organisms, such as zebrafish, in studying shared, evolutionarily conserved (and therefore, core) neuro-immune mechanisms of depression.

Adult zebrafish in CNS disease modeling: a tank that's half-full, not half-empty, and still filling

The zebrafish (Danio rerio) is increasingly used in a broad array of biomedical studies, from cancer research to drug screening. Zebrafish also represent an emerging model organism for studying complex brain diseases. The number of zebrafish neuroscience studies is exponentially growing, significantly outpacing those conducted with rodents or other model organisms. Yet, there is still a substantial amount of resistance in adopting zebrafish as a first-choice model system. Studies of the repertoire of zebrafish neural and behavioral functions continue to reveal new opportunities for understanding the pathobiology of various CNS deficits. Although some of these models are well established in zebrafish, including models for anxiety, depression, and addiction, others are less recognized, for example, models of autism and obsessive-compulsive states. However, mounting data indicate that a wide spectrum of CNS diseases can be modeled in adult zebrafish. Here, we summarize recent findings using zebrafish CNS assays, discuss model limitations and the existing challenges, as well as outline future directions of research in this field.

Understanding zebrafish cognition

Zebrafish (Danio rerio) are rapidly becoming a popular model organism in translational and cognitive neuroscience research. Both larval and adult zebrafish continue to increase our understanding of cognitive mechanisms and their genetic and pharmacological modulation. Here, we discuss the developing utility of zebrafish in understanding cognitive phenotypes and their deficits, relevant to a wide range human brain disorders. We also discuss the potential of zebrafish models for high-throughput genetic mutant and small molecule screening (e.g., amnestics, cognitive enhancers, neurodevelopmental/neurodegenerative drugs), which becomes critical for identifying novel candidate genes and molecular drug targets to treat cognitive deficits. In addition to discussing the existing challenges and future strategic directions in this field, we emphasize how zebrafish models of cognitive phenotypes continue to form an interesting and rapidly emerging new field in neuroscience.

Understanding antidepressant discontinuation syndrome (ADS) through preclinical experimental models

&NA; Antidepressant drugs are currently one of the most prescribed medications. In addition to treatment resistance and side effects of antidepressants, their clinical use is further complicated by antidepressant discontinuation syndrome (ADS). ADS is a common problem in patients following the interruption, dose reduction, or discontinuation of antidepressant drugs. Clinically, ADS resembles a classical drug withdrawal syndrome, albeit differing from it because antidepressants generally do not induce addiction. The growing clinical importance and prevalence of ADS necessitate novel experimental (animal) models of this disorder. Currently available preclinical models of ADS are mainly rodent‐based, and study mostly serotonergic antidepressants and their combinations. Here, we systematically assess clinical ADS symptoms and discuss current trends and challenges in the field of experimental (animal) models of ADS. We also outline basic mechanisms underlying ADS pathobiology, evaluate its genetic, pharmacological and environmental determinants, and emphasize how using animal models may help generate important translational insights into human ADS condition, its prevention and therapy.

Better lab animal models for translational neuroscience research and CNS drug development

ly involve zebrafish models noting that “this model organism is not yet approved by the FDA” and that “zebrafish, unlike rodents, have primitive CNS”. While the former statement is a matter of time and policy change, the latter is scientifically incorrect. Indeed, considering zebrafish brain and behavior as ‘primitive’ is misleading, and contradicts mounting evidence showing their striking genetic and physiological homology to humans, and the growing recognition of the complexity of zebrafish neurobehavioral phenotypes2,8. Aiming to minimize the regulatory hurdles, a recent focus on drug repurposing is promising, because repositioning of FDA-approved medications may provide clinicians with new treatment options9. As this approach has been successfully applied to zebrafish for FDA-approved smoking cessation therapeutics10, it may be expanded to other classes of CNS drugs and/or disorder groups. Also encouraging to the animal research community is that the FDA itself is beginning to invest heavily in zebrafish research. For instance, their AR-based National Center for Toxicological Research (NCTR) is already using zebrafish as a toxicological tool able to screen dozens of doses (or different chemicals) in several minutes11. Positive changes in the laboratory animal research landscape necessitate further involvement of researchers in improving CNS disease modeling and drug discovery. Community-driven efforts, such as powerful rodent and zebrafish disease and phenotypic databases (Mouse Phenome Database, Mouse Genomic Informatics Databases, ZFIN), foster translational research using animal models to eventually optimize clinical trials1. However, complementing traditional, relatively simple phenotypes with a more complex spectrum of quantifiable disease endpoints (including computationally derived biomarkers and bioinformatics-empowered ‘big data’ monitoring of disease progression across time) can help counter failures of modern drug discovery and CNS disease model development. Likewise, a wider inclusion of alternative model organism, such as zebrafish, can also be a critical and timely strategy, enabling a better focus on core, evolutionarily conserved mechanisms of disease pathogenesis and therapeutic action.

Zebrafish models relevant to studying central opioid and endocannabinoid systems

&NA; The endocannabinoid and opioid systems are two interplaying neurotransmitter systems that modulate drug abuse, anxiety, pain, cognition, neurogenesis and immune activity. Although they are involved in such critical functions, our understanding of endocannabinoid and opioid physiology remains limited, necessitating further studies, novel models and new model organisms in this field. Zebrafish (Danio rerio) is rapidly emerging as one of the most effective translational models in neuroscience and biological psychiatry. Due to their high physiological and genetic homology to humans, zebrafish may be effectively used to study the endocannabinoid and opioid systems. Here, we discuss current models used to target the endocannabinoid and opioid systems in zebrafish, and their potential use in future translational research and high‐throughput drug screening. Emphasizing the high degree of conservation of the endocannabinoid and opioid systems in zebrafish and mammals, we suggest zebrafish as an excellent model organism to study these systems and to search for the new drugs and therapies targeting their evolutionarily conserved mechanisms. HighlightsThe endocannabinoid and opioid systems potently modulate brain functionsZebrafish (Danio rerio) is a novel translational model in neuroscience research.Here, we discuss models to target the endocannabinoid and opioid systems in zebrafishWe emphasize the high degree of conservation of these systems in zebrafish and mammalsZebrafish are an excellent model to study endocannabinoid and opioid mechanisms and drugs in‐vivo

Understanding the Role of Environmental Enrichment in Zebrafish Neurobehavioral Models

Environmental stimuli are critical in preclinical research that utilizes laboratory animals to model human brain disorders. The main goal of environmental enrichment (EE) is to provide laboratory animals with better choice of activity and greater control over social and spatial stressors. Thus, in addition to being a useful experimental tool, EE becomes an important strategy for increasing the validity and reproducibility of preclinical data. Although zebrafish (Danio rerio) is rapidly becoming a promising new organism for neuroscience research, the role of EE in zebrafish central nervous system (CNS) models remains poorly understood. Here we discuss EE in preclinical studies using zebrafish and its influence on brain physiology and behavior. Improving our understanding of EE effects in this organism may enhance zebrafish data validity and reliability. Paralleling rodent EE data, mounting evidence suggests the growing importance of EE in zebrafish neurobehavioral models.