Search

Depression and schizophrenia are two highly prevalent and severely debilitating neuropsychiatric disorders. Both conventional antidepressant and antipsychotic pharmacotherapies are often inefficient clinically, causing multiple side effects and serious patient compliance problems. Collectively, this calls for the development of novel drug targets for treating depressed and schizophrenic patients. Here, we discuss recent translational advances, research tools and approaches, aiming to facilitate innovative drug discovery in this field. Providing a comprehensive overview of current antidepressants and antipsychotic drugs, we also outline potential novel molecular targets for treating depression and schizophrenia. We also critically evaluate multiple translational challenges and summarize various open questions, in order to foster further integrative cross-discipline research into antidepressant and antipsychotic drug development. [ABSTRACT FROM AUTHOR]

Epilepsy is a highly prevalent, severely debilitating neurological disorder characterized by seizures and neuronal hyperactivity due to an imbalanced neurotransmission. As genetic factors play a key role in epilepsy and its treatment, various genetic and genomic technologies continue to dissect the genetic causes of this disorder. However, the exact pathogenesis of epilepsy is not fully understood, necessitating further translational studies of this condition. Here, we applied a computational in silico approach to generate a comprehensive network of molecular pathways involved in epilepsy, based on known human candidate epilepsy genes and their established molecular interactors. Clustering the resulting network identified potential key interactors that may contribute to the development of epilepsy, and revealed functional molecular pathways associated with this disorder, including those related to neuronal hyperactivity, cytoskeletal and mitochondrial function, and metabolism. While traditional antiepileptic drugs often target single mechanisms associated with epilepsy, recent studies suggest targeting downstream pathways as an alternative efficient strategy. However, many potential downstream pathways have not yet been considered as promising targets for antiepileptic treatment. Our study calls for further research into the complexity of molecular mechanisms underlying epilepsy, aiming to develop more effective treatments targeting novel putative downstream pathways of this disorder. [ABSTRACT FROM AUTHOR]

Psychiatric disorders are highly prevalent brain pathologies that represent an urgent, unmet biomedical problem. Since reliable clinical diagnoses are essential for the treatment of psychiatric disorders, their animal models with robust, relevant behavioral and physiological endpoints become necessary. Zebrafish (Danio rerio) display well-defined, complex behaviors in major neurobehavioral domains which are evolutionarily conserved and strikingly parallel to those seen in rodents and humans. Although zebrafish are increasingly often used to model psychiatric disorders, there are also multiple challenges with such models as well. The field may therefore benefit from a balanced, disease-oriented discussion that considers the clinical prevalence, the pathological complexity, and societal importance of the disorders in question, and the extent of its detalization in zebrafish central nervous system (CNS) studies. Here, we critically discuss the use of zebrafish for modeling human psychiatric disorders in general, and highlight the topics for further in-depth consideration, in order to foster and (re)focus translational biological neuroscience research utilizing zebrafish. Recent developments in molecular biology research utilizing this model species have also been summarized here, collectively calling for a wider use of zebrafish in translational CNS disease modeling. [ABSTRACT FROM AUTHOR]

Simple Summary: Antimicrobial drugs, in addition to exerting antibiotic, antifungal, antiparasitic, or antiviral effects, may also affect the central nervous system and gut microbiota, thereby modulating brain and behavior. Zebrafish models can be used for studying the effects of antimicrobial drugs on the central nervous system. Here, we discuss recent findings on using zebrafish for assessing the effects of a wide range of antimicrobial drugs on brain and behavior in vivo. Antimicrobial drugs represent a diverse group of widely utilized antibiotic, antifungal, antiparasitic and antiviral agents. Their growing use and clinical importance necessitate our improved understanding of physiological effects of antimicrobial drugs, including their potential effects on the central nervous system (CNS), at molecular, cellular, and behavioral levels. In addition, antimicrobial drugs can alter the composition of gut microbiota, and hence affect the gut–microbiota–brain axis, further modulating brain and behavioral processes. Complementing rodent studies, the zebrafish (Danio rerio) emerges as a powerful model system for screening various antimicrobial drugs, including probing their putative CNS effects. Here, we critically discuss recent evidence on the effects of antimicrobial drugs on brain and behavior in zebrafish, and outline future related lines of research using this aquatic model organism. [ABSTRACT FROM AUTHOR]

The mammalian target of rapamycin (mTOR) is an important molecular regulator of cell growth and proliferation. Brain mTOR activity plays a crucial role in synaptic plasticity, cell development, migration and proliferation, as well as memory storage, protein synthesis, autophagy, ion channel expression and axonal regeneration. Aberrant mTOR signaling causes a diverse group of neurological disorders, termed 'mTORopathies'. Typically arising from mutations within the mTOR signaling pathway, these disorders are characterized by cortical malformations and other neuromorphological abnormalities that usually co-occur with severe, often treatment-resistant, epilepsy. Here, we discuss recent advances and current challenges in developing experimental models of mTOR-dependent epilepsy and other related mTORopathies, including using zebrafish models for studying these disorders, as well as outline future directions of research in this field. [ABSTRACT FROM AUTHOR]

Channelopathies are a large group of systemic disorders whose pathogenesis is associated with dysfunctional ion channels. Aberrant transmembrane transport of K+, Na+, Ca2+ and Cl− by these channels in the brain induces central nervous system (CNS) channelopathies, most commonly including epilepsy, but also migraine, as well as various movement and psychiatric disorders. Animal models are a useful tool for studying pathogenesis of a wide range of brain disorders, including channelopathies. Complementing multiple well-established rodent models, the zebrafish (Danio rerio) has become a popular translational model organism for neurobiology, psychopharmacology and toxicology research, and for probing mechanisms underlying CNS pathogenesis. Here, we discuss current prospects and challenges of developing genetic, pharmacological and other experimental models of major CNS channelopathies based on zebrafish. [ABSTRACT FROM AUTHOR]

Stress is a common cause of neuropsychiatric disorders, evoking multiple behavioral, endocrine and neuro-immune deficits. Animal models have been extensively used to understand the mechanisms of stress-related disorders and to develop novel strategies for their treatment. Complementing rodent and clinical studies, the zebrafish (Danio rerio) is one of the most important model organisms in biomedicine. Rapidly becoming a popular model species in stress neuroscience research, zebrafish are highly sensitive to both acute and chronic stress, and show robust, well-defined behavioral and physiological stress responses. Here, we critically evaluate the utility of zebrafish-based models for studying acute and chronic stress-related CNS pathogenesis, assess the advantages and limitations of these aquatic models, and emphasize their relevance for the development of novel anti-stress therapies. Overall, the zebrafish emerges as a powerful and sensitive model organism for stress research. Although these fish generally display evolutionarily conserved behavioral and physiological responses to stress, zebrafish-specific aspects of neurogenesis, neuroprotection and neuro-immune responses may be particularly interesting to explore further, as they may offer additional insights into stress pathogenesis that complement (rather than merely replicate) rodent findings. Compared to mammals, zebrafish models are also characterized by increased availability of gene-editing tools and higher throughput of drug screening, thus being able to uniquely empower translational research of genetic determinants of stress and resilience, as well as to foster innovative CNS drug discovery and the development of novel anti-stress therapies. [ABSTRACT FROM AUTHOR]

Background: A potent acetylcholinesterase inhibitor, donepezil is a cognitive enhancer clinically used to treat neurodegenerative diseases. However, its complete pharmacological profile beyond cognition remains unclear. The zebrafish (Danio rerio) is rapidly becoming a powerful novel model organism in neuroscience and central nervous system drug screening. Aim: Here, we characterize the effects of 24-h donepezil administration on anxiety-like behavioral and endocrine responses in adult zebrafish. Methods: We evaluated zebrafish anxiety-like behaviors in the novel tank, the light-dark and the shoaling tests, paralleled by assessing brain acetylcholinesterase activity and whole-body cortisol levels. Results: Overall, donepezil dose-dependently decreased zebrafish locomotor activity in the novel tank test and reduced time in light in the light-dark test, likely representing hypolocomotion and anxiety-like behaviors. Donepezil predictably decreased brain acetylcholinesterase activity, also increasing whole-body cortisol levels, thus further linking acetylcholinesterase inhibition to anxiety-like behavioral and endocrine responses. Conclusion: Collectively, these findings suggest negative modulation of zebrafish affective behavior by donepezil, support the key role of cholinergic mechanisms in behavioral regulation in zebrafish, and reinforce the growing utility of zebrafish models for studying complex behavioral processess and their neuroendocrine and neurochemical regulation. [ABSTRACT FROM AUTHOR]

• Neurodevelopmental disorders are life-long, serious human brain illnesses. • Animal models are a valuable tool for studying neurodevelopmental disorders. • The zebrafish emerges as a promising model organism to probe these disorders and their mechanisms. • Here, we discuss zebrafish models and phenotypes relevant to neurodevelopmental disorders. Neurodevelopmental disorders (NDDs) caused by aberrant brain growth and development are life-long, debilitating illnesses that markedly impair the quality of life. Animal models are a valuable tool for studying NDD pathobiology and therapies. Mounting evidence suggests the zebrafish (Danio rerio) as a useful model organism to study NDDs, possessing both high physiological homology to humans and sensitivity to pharmacological and genetic manipulations. Here, we summarize experimental models of NDDs in zebrafish and highlight the growing translational significance of zebrafish NDD-related phenotypes. We also emphasize the need in further development of zebrafish models of NDDs to improve our understanding of their pathogenesis and therapeutic treatments. [ABSTRACT FROM AUTHOR]

Due to its fully sequenced genome, high genetic homology to humans, external fertilization, fast development, transparency of embryos, low cost and active reproduction, the zebrafish (Danio rerio) has become a novel promising model organism in biomedicine. Zebrafish are a useful tool in genetic and neuroscience research, including linking various genetic mutations to brain mechanisms using forward and reverse genetics. These approaches have produced novel models of rare genetic CNS disorders and common brain illnesses, such as addiction, aggression, anxiety and depression. Genetically modified zebrafish also foster neuroanatomical studies, manipulating neural circuits and linking them to different behaviors. Here, we discuss recent advances in neurogenetics of zebrafish, and evaluate their unique strengths, inherent limitations and the rapidly growing potential for elucidating the conserved roles of genes in neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

• Gut microbiota modulates brain functions, behavior and neuroimmune and neuroendocrine responses. • Animal models are useful tool for studying CNS disorders. • Zebrafish (Danio rerio) is a new organism in modeling the gut-brain interplay. • Here, we discuss zebrafish microbiota, and its impact on immune and behavioral processes. • We emphasize the growing utility of zebrafish models in gut-brain research. Mounting clinical and experimental evidence suggests the gut–brain interplay as a novel important paradigm in translational neuroscience, including the critical role for gut microbiota in modulating brain development and behavior, as well as neuroimmune and neuroendocrine responses. Animal models are an indispensable tool in studying the central nervous system (CNS) disorders and their mechanisms. Recently, the zebrafish (Danio rerio) has become a powerful new model organism in neuroscience, including studying the gut-brain axis. Here, we discuss zebrafish models of gut-brain interplay, endocrine and toxicological effects of zebrafish microbiota, and their impact on neuroimmune and behavioral processes. We particularly emphasize the growing utility of zebrafish models in gut-brain research, as they foster future discoveries of new interconnections between these systems. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The zebrafish (Danio rerio) is increasingly utilized as a powerful new model organism in neurobehavioral research. Aggression is a common symptom of many CNS disorders, has some genetic determinants and can be modulated pharmacologically in humans and animal model species. Mounting evidence suggests zebrafish as a useful tool to study neurobiology of aggression, and its pharmacological and genetic regulation. Here, we discuss mechanisms of zebrafish aggression and their pharmacological, pharmacogenetic and pharmacogenomic models, as well as recent developments and existing challenges in this field. We also emphasize the growing utility of zebrafish models in translational neuropharmacological research of aggression, fostering future discoveries of potential therapeutic agents for aggressive behavior. [ABSTRACT FROM AUTHOR]

Highlights • Lidocaine evoked sedative effect in adult zebrafish at 10 mg/L applied systemically. • Lidocaine caused hypolocomotor effect at 4% applied peripherally. • Lateral line is important for driving adult zebrafish locomotion. • Lidocaine decrease brain AChE activity. • Zebrafish sensitivity to lidocaine supports their growing value for CNS drug screening. Abstract Lidocaine is a voltage-gated Na+ channel blocker, commonly used as a fast-acting local and general anesthetic. Lidocaine also has central action, affecting behavior both clinically and in animal models. Adult zebrafish are rapidly becoming a critical novel model organism in translational neuroscience research. Here, we examine the effects of acute peripheral (lateral line application, 4%) and systemic (water immersion, 1, 5 and 10 mg/L) administration of lidocaine on adult zebrafish behavior tested in the novel tank test. Overall, the drug evoked hypolocomotor effect when applied systemically (at 10 mg/L) and peripherally. Peripheral lidocaine also reduced top exploration in the novel tank test (vs. sham), suggesting anxiogenic-like effect of the lateral line blockage, Our findings show the importance of the lateral line system in driving adult zebrafish locomotion, and suggest sedative-like effects of systemic lidocaine in aduld zebrafish. In addition, reflecting the role of central cholinergic contribution in lidocaine action, brain acetylcholinesterase (AChE) activity was lower following peripheral and systemic administration of lidocaine at behaviorally active doses. Collectively, our data support the effects of lidocaine on behavioral responses in zebrafish, and reinforce the growing utility of this aquatic model to screen various CNS drugs. [ABSTRACT FROM AUTHOR]

Highlights • Epigenetic regulation has become a key focus of neuroscience and biological psychiatry. • Animal (experimental) models are a useful tool for epigenetic studies. • Zebrafish are rapidly emerging as a new promising organism for epigenetic research. • Here, we discuss mounting evidence of epigenetic regulation of CNS functions in zebrafish. • We also outline future directions of translational neuroscience research in this field. Abstract Epigenetic regulation has become a key focus of neuroscience and biopsychiatry, implicating DNA methylation, histone modification and other epigenetic mechanisms in various CNS disorders. Animal (experimental) models are a useful tool for epigenetic studies. Although most such research has been performed in rodents, the zebrafish (Danio rerio) is rapidly emerging as a new promising model organism in neuroscience. These fish are particularly suitable for genetic and epigenetic studies due to their fully sequenced genome, easiness of genetic analyses and high physiological and genetic homology with humans. Here, we discuss mounting evidence of epigenetic regulation of CNS functions in zebrafish, and outline future directions of translational research in this field. [ABSTRACT FROM AUTHOR]

The monoamines serotonin and dopamine are important neuromodulators present in the central nervous system, known to be active regulators of social behaviour in fish as in other vertebrates. Our aim was to investigate the region-specific brain monoaminergic differences arising when individual cleaners face a client (mutualistic context) compared to when they are introduced to another conspecific (conspecific context), and to understand the relevance of visual assessment compared to the impact of physical contact with any partner. We demonstrated that serotoninergic activity at the diencephalon responds mostly to the absence of physical contact with clients whereas cerebellar dopaminergic activity responds to actual cleaning engagement. We provide first insights on the brain’s monoaminergic (region-specific) response variations, involved in the expression of cleaner fishes’ mutualistic and conspecific behaviour. These results contribute to a better understanding of the monoaminergic activity in accordance to different socio-behavioural contexts. [ABSTRACT FROM AUTHOR]

Dietary supplements are commonly used by animals and humans and play key roles in diverse systems, such as the immune and reproductive systems, and in metabolism. Essential oils (EOs), which are natural substances, have potential for use in food supplementation; however, their effects on organisms remain to be elucidated. Here, we examine the effects of dietary Aloysia triphylla EO supplementation on zebrafish behavior, metabolism, stress response, and growth performance. We show that fish fed diets containing A. triphylla EO presented an anxiolytic response, with reduced exploratory activity and oxygen consumption; no changes were observed in neuroendocrine stress axis functioning and growth was not impaired. Taken together, these results suggest that the A. triphylla EO supplementation is a strong candidate for use in feed, since it ensures fish welfare (anxiolytic behavior) with decreased oxygen consumption. This makes it suitable for use in high-density production systems without causing damage to the neuroendocrine stress axis and without growth performance being impaired. [ABSTRACT FROM AUTHOR]