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• Colors are an important biological factor affecting human and animal behavior and physiology. • The zebrafish is rapidly emerging as a novel model species in neuroscience research. • Colors potently affect zebrafish affective, social and cognitive behaviors. • Color is a key factor in zebrafish neurophenomics and CNS disease modeling. Color is an important environmental factor that in multiple ways affects human and animal behavior and physiology. Widely used in neuroscience research, various experimental (animal) models may help improve our understanding of how different colors impact brain and behavioral processes. Complementing laboratory rodents, the zebrafish (Danio rerio) is rapidly emerging as an important novel model species to explore complex neurobehavioral processes. The growing utility of zebrafish in biomedicine makes it timely to consider the role of colors in their behavioral and physiological responses. Here, we summarize mounting evidence implicating colors as a critical variable in zebrafish models and neurobehavioral traits, with a particular relevance to CNS disease modeling, genetic and pharmacological modulation, as well as environmental enrichment and animal welfare. We also discuss the growing value of zebrafish models to study color neurobiology and color-related neurobehavioral phenomics, and outline future directions of research in this field. [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]

Diabetes mellitus (DM) is a common metabolic disorder that affects multiple organ systems. DM also affects brain processes, contributing to various CNS disorders, including depression, anxiety and Alzheimer's disease. Despite active research in humans, rodent models and in-vitro systems, the pathogenetic link between DM and brain disorders remains poorly understood. Novel translational models and new model organisms are therefore essential to more fully study the impact of DM on CNS. The zebrafish (Danio rerio) is a powerful novel model species to study metabolic and CNS disorders. Here, we discuss how DM alters brain functions and behavior in zebrafish, and summarize their translational relevance to studying DM-related CNS pathogenesis in humans. We recognize the growing utility of zebrafish models in translational DM research, as they continue to improve our understanding of different brain pathologies associated with DM, and may foster the discovery of drugs that prevent or treat these diseases. • Diabetes mellitus (DM) affects multiple organs, including the central nervous system (CNS). • The pathogenetic link between DM and brain disorders remains poorly understood. • Novel translational models and model organisms are critical to study the impact of DM on CNS. • The zebrafish (Danio rerio) is a powerful novel model species to study metabolic and CNS disorders. • Here, we discuss the translational relevance of zebrafish for studying DM-related CNS pathogenesis. [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]

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]

Abstract Depression is a wide-spread, debilitating psychiatric disorder. Mainly rodent-based, experimental animal models of depression are extensively used to probe the pathogenesis of this disorder. Here, we emphasize the need for innovative approaches to studying depression, and call for a wider use of novel model organisms, such as the zebrafish (Danio rerio), in this field. Highly homologous to humans and rodents, zebrafish are rapidly becoming a valuable tool in translational neuroscience research, but have only recently been utilized in depression research. Multiple conceptual and methodological problems, however, arise in relation to separating putative zebrafish depression-like states from motor and social deficits or anxiety. Here, we examine recent findings and the existing challenges in this field, to encourage further research and the use of zebrafish as novel organisms in cross-species depression modeling. [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]

Despite the high prevalence of neural and immune disorders, their etiology and molecular mechanisms remain poorly understood. As the zebrafish ( Danio rerio ) is increasingly utilized as a powerful model organism in biomedical research, mounting evidence suggests these fish as a useful tool to study neural and immune mechanisms and their interplay. Here, we discuss zebrafish neuro-immune mechanisms and their pharmacological and genetic modulation, the effect of stress on cytokines, as well as relevant models of microbiota-brain interplay. As many human brain diseases are based on complex interplay between the neural and the immune system, here we discuss zebrafish models, as well as recent successes and challenges, in this rapidly expanding field. We particularly emphasize the growing utility of zebrafish models in translational immunopsychiatry research, as they improve our understanding of pathogenetic neuro-immune interactions, thereby fostering future discovery of potential therapeutic agents. [ABSTRACT FROM AUTHOR]

Music therapy has long been used as a non-pharmacological intervention to improve cognitive function and mood in humans. Mounting rodent evidence also supports beneficial impact of music exposure on animal cognitive performance. The zebrafish (Danio rerio) is an important emerging aquatic animal model in translational biomedical and neuroscience research. Here, we evaluate the effects of intermittent (2-h or 6-h twice daily) and continuous (24-h) solfeggio-frequency music exposure on behavioral, cognitive and endocrine parameters in adult zebrafish whose circadian rhythm was disturbed by a 24-h light exposure. Overall, a 24-h light exposure stress evokes overt cognitive deficits in the inhibitory avoidance test and elevates zebrafish whole-body cortisol levels. However, these effects were reversed by solfeggio-frequency music exposure for 2 or 6 h twice daily, and by continuous 24-h exposure. Collectively, these findings suggest a positive modulation of cognitive and endocrine responses in adult zebrafish by environmental enrichment via the long-term exposure to music, and reinforces zebrafish as a robust, sensitive model organism for neurocognitive and neuroendocrine research. [ABSTRACT FROM AUTHOR]

• Animal models probe long-term biological consequences of early-life pain (ELP). • Here, we discuss experimental models of ELP in rodents and zebrafish. • We emphasize the role of ELP experience in shaping personality traits later in life. • We also note shared neural underpinnings of ELP and early-life stress. Critical for organismal survival, pain evokes strong physiological and behavioral responses in various sentient species. Clinical and preclinical (animal) studies markedly increase our understanding of biological consequences of developmental (early-life) adversity, as well as acute and chronic pain. However, the long-term effects of early-life pain exposure on human and animal emotional responses remain poorly understood. Here, we discuss experimental models of nociception in rodents and zebrafish, and summarize mounting evidence of the role of early-life pain in shaping emotional traits later in life. We also call for further development of animal models to probe the impact of early-life pain exposure on behavioral traits, brain disorders and novel therapeutic treatments. [ABSTRACT FROM AUTHOR]

Anxiety is the most prevalent brain disorder and a common cause of human disability. Animal models are critical for understanding anxiety pathogenesis and its pharmacotherapy. The zebrafish (Danio rerio) is increasingly utilized as a powerful model organism in anxiety research and anxiolytic drug screening. High similarity between human, rodent and zebrafish molecular targets implies shared signaling pathways involved in anxiety pathogenesis. However, mounting evidence shows that zebrafish behavior can be modulated by drugs beyond conventional anxiolytics or anxiogenics. Furthermore, these effects may differ from human and/or rodent responses, as such 'unconventional' drugs may affect zebrafish behavior despite having no such profiles (or exerting opposite effects) in humans or rodents. Here, we discuss the effects of several putative unconventional anxiotropic drugs (aspirin, lysergic acid diethylamide (LSD), nicotine, naloxone and naltrexone) and their potential mechanisms of action in zebrafish. Emphasizing the growing utility of zebrafish models in CNS drug discovery, such unconventional anxiety pharmacology may provide important, evolutionarily relevant insights into complex regulation of anxiety in biological systems. Albeit seemingly complicating direct translation from zebrafish into clinical phenotypes, this knowledge may instead foster the development of novel CNS drugs, eventually facilitating innovative treatment of patients based on novel 'unconventional' targets identified in fish models. • Animal models are critical tool for understanding anxiety pathogenesis. • The zebrafish is a powerful model organism in anxiety research. • Zebrafish behavior can be modulated by various anxiotropic drugs. • Discussed here, some effects in zebrafish differ from conventional anxiotropic drugs. [ABSTRACT FROM AUTHOR]

Acute and chronic stressors are common triggers of human mental illnesses. Experimental animal models and their cross-species translation to humans are critical for understanding of the pathogenesis of stress-related psychiatric disorders. Mounting evidence suggests that both pharmacological and non-pharmacological approaches can be efficient in treating these disorders. Here, we analyze human, rodent and zebrafish (Danio rerio) data to compare the impact of non-pharmacological and pharmacological therapies of stress-related psychopathologies. Emphasizing the likely synergism and interplay between pharmacological and environmental factors in mitigating daily stress both clinically and in experimental models, we argue that environmental enrichment emerges as a promising complementary therapy for stress-induced disorders across taxa. We also call for a broader use of novel model organisms, such as zebrafish, to study such treatments and their potential interplay. [ABSTRACT FROM AUTHOR]

• Rodent grooming is an important key behavior. • The study analyzed mouse genes linked to aberrant hetero-grooming behavior. • The genes formed a molecular network with several gene clusters. • They can help clarify mechanisms of rodent grooming behavior. Highly prevalent in laboratory rodents, 'social' hetero-grooming behavior is translationally relevant to modeling a wide range of neuropsychiatric disorders. Here, we comprehensively evaluated all known to date mouse genes linked to aberrant hetero-grooming phenotype, and applied bioinformatics tools to construct a network of their established protein–protein interactions (PPI). We next identified several distinct molecular clusters within this complex network, including neuronal differentiation, cytoskeletal, WNT-signaling and synapsins-associated pathways. Using additional bioinformatics analyses, we further identified 'central' (hub) proteins within these molecular clusters, likely key for mouse hetero-grooming behavior. Overall, a more comprehensive characterization of intricate molecular pathways linked to aberrant rodent grooming may markedly advance our understanding of underlying cellular mechanisms and related neurological disorders, eventually helping discover novel targets for their pharmacological or gene therapy interventions. [ABSTRACT FROM AUTHOR]

Cognitive decline is commonly seen both in normal aging and in neurodegenerative and neuropsychiatric diseases. Various experimental animal models represent a valuable tool to study brain cognitive processes and their deficits. Equally important is the search for novel drugs to treat cognitive deficits and improve cognitions. Complementing rodent and clinical findings, studies utilizing zebrafish (Danio rerio) are rapidly gaining popularity in translational cognitive research and neuroactive drug screening. Here, we discuss the value of zebrafish models and assays for screening nootropic (cognitive enhancer) drugs and the discovery of novel nootropics. We also discuss the existing challenges, and outline future directions of research in this field. • Rising prevalence of cognitive deficits necessitates novel promnestic therapies be developed. • Animal models are a valuable tool to discover novel nootropic drugs. • Zebrafish are increasingly utilized to study cognitive processes and their deficits. • Zebrafish models markedly facilitate screening and discovery of nootropic drugs. [ABSTRACT FROM AUTHOR]

Depression is a widespread and severely debilitating neuropsychiatric disorder whose key clinical symptoms include low mood, anhedonia and despair (the inability or unwillingness to overcome stressors). Experimental animal models are widely used to improve our mechanistic understanding of depression pathogenesis, and to develop novel antidepressant therapies. In rodents, various experimental models of 'behavioral despair' have already been developed and rigorously validated. Complementing rodent studies, the zebrafish (Danio rerio) is emerging as a powerful model organism to assess pathobiological mechanisms of depression and other related affective disorders. Here, we critically discuss the developing potential and important translational implications of zebrafish models for studying despair and its mechanisms, and the utility of such aquatic models for antidepressant drug screening. [ABSTRACT FROM AUTHOR]

Cerebral cortex is found only in mammals and is particularly prominent and developed in humans. Various rodent models with fully or partially ablated cortex are commonly used to probe the role of cortex in brain functions and its multiple subcortical projections, including pallium, thalamus and the limbic system. Various rodent models are traditionally used to study the role of cortex in brain functions. A small teleost fish, the zebrafish (Danio rerio), has gained popularity in neuroscience research, and albeit (like other fishes) lacking cortex, its brain performs well some key functions (e.g., memory, consciousness and motivation) with complex, context-specific and well-defined behaviors. Can rodent and zebrafish models help generate insights into the role of cortex in brain functions, and dissect its cortex-specific (vs. non-cortical) functions? To address this conceptual question, here we evaluate brain functionality in intact vs. decorticated rodents and further compare it in the zebrafish, a naturally occurring acortical species. Overall, comparing cortical and acortical rodent models with naturally acortical zebrafish reveals both distinct and overlapping contributions of neocortex and 'precortical' zebrafish telencephalic regions to higher brain functions. Albeit morphologically different, mammalian neocortex and fish pallium may possess more functional similarities than it is presently recognized, calling for further integrative research utilizing both cortical and decorticated/acortical vertebrate model organisms. • Animal models are traditionally used to study the role of cortex in brain functions. • Decorticated rodents and naturally acortical vertebrates help probe the role of cortex. • The zebrafish is a useful model organism in neuroscience research. • Albeit lacking cortex, zebrafish help generate insights into the role of cortex in brain functions. [ABSTRACT FROM AUTHOR]

• U-47700) is a selective μ–opioid receptor agonist several times more potent than morphine. • Despite its growing abuse, psychopharmacological profile of U-47700 remains poorly understood. • The zebrafish is an important model species for CNS disease modeling and drug discovery. • Acute (1-50 mg/L) doses of U-47700 evoke robust sedation in adult zebrafish. • Chronic (0.1-1 mg/L) U-47700 causes hyperlocomotor and anxiolytic-like effects in zebrafish. 3,4-Dichloro- N -[2-(dimethylamino)cyclohexyl]- N -methylbenzamide (U-47700) is a selective μ–opioid receptor agonist originally synthesized as a prospective analgesic drug. Several times more potent than morphine, U-47700 has high abuse potential and may cause clinical neurotoxicity, euphoria, respiratory depression and occasional mortality. U-47700 also evokes analgesia, sedation and euphoria-like states in both humans and rodents. Despite the growing use and abuse of U-47700, its psychopharmacological and toxicological profiles in vivo remain poorly understood. The zebrafish (Danio rerio) is rapidly becoming a popular aquatic model organism for central nervous system (CNS) disease modeling and drug discovery. Here, we examine acute (1, 5, 10, 25 and 50 mg/L for 20-min) and chronic (0.1, 0.5 and 1 mg/L for 14 days) effects of U-47700 in adult zebrafish. Overall, we found overt sedation evoked in fish by acute, and hyperlocomotion with an anxiolytic-like action by chronic, drug treatments. Acute treatment with 1 and 10 mg/L U-47700 also resulted in detectable amounts of this drug in the brain samples, supporting its permeability through the blood-brain barrier. Collectively, these findings emphasize complex dose- and treatment-dependent CNS effects of U-47700 following its acute and chronic administration. Our study also supports high sensitivity of zebrafish to U-47700, and suggests these aquatic models as promising in-vivo screens for probing potential CNS effects evoked by novel synthetic opioid drugs. [ABSTRACT FROM AUTHOR]

• Neuroglia, including microglia and astrocytes, is a critical component of the central nervous system. • Complementing clinical and rodent data, the zebrafish is a key model organism in neuroscience. • Zebrafish possess some sharedand some specific biomarkers and features of neuroglia. • Here, we discuss the biology of neuroglia in fish vs. humans and rodents. • We also outline further directions of translational research of neuroglia in zebrafish models. Neuroglia, including microglia and astrocytes, is a critical component of the central nervous system (CNS) that interacts with neurons to modulate brain activity, development, metabolism and signaling pathways. Thus, a better understanding of the role of neuroglia in the brain is critical. Complementing clinical and rodent data, the zebrafish (Danio rerio) is rapidly becoming an important model organism to probe the role of neuroglia in brain disorders. With high genetic and physiological similarity to humans and rodents, zebrafish possess some common (shared), as well as some specific molecular biomarkers and features of neuroglia development and functioning. Studying these common and zebrafish-specific aspects of neuroglia may generate important insights into key brain mechanisms, including neurodevelopmental, neurodegenerative, neuroregenerative and neurological processes. Here, we discuss the biology of neuroglia in humans, rodents and fish, its role in various CNS functions, and further directions of translational research into the role of neuroglia in CNS disorders using zebrafish models. [ABSTRACT FROM AUTHOR]

• Female zebrafish are more active and anxious than males. • Melatonin caused anxiolytic effect in both sexes. • Diazepam caused anxiolytic effect only in males. • Sex differences in behavioral and pharmacological analyses in zebrafish. Sex differences are an important variable in biomedical research. The zebrafish (Danio rerio) is rapidly becoming a critical novel model organism in translational neuroscience and neuropharmacology. Here, we examine the effects of sex on locomotor activity and anxiety-like behavior in adult zebrafish tested in the novel tank test following their exposure to two clinically relevant, common anxiolytic drugs diazepam and melatonin. While control female zebrafish were more active and anxious than males, both sexes showed anxiolytic responses to melatonin (0.232 mg/L) but only males responded to diazepam (16 μg/L). Revealing sex specificity in pharmacological responses, this study emphasizes the importance of sex differences in behavioral and pharmacological analyses in zebrafish. This may also be potentially relevant to modeling sex differences in clinical responses to anxiolytic drugs. Collectively, our data support sex differences in zebrafish behavioral responses and reinforce the growing utility of this aquatic model in CNS drug screening. [ABSTRACT FROM AUTHOR]

• Multiple species display robust individual behavioral variance. • Intraspecies behavioral individuality is an important area of neuroscience research. • Zebrafish are useful an aquatic model organism to study individual differences. • Cross-species analyses of intraspecies variance is critical in experimental CNS models. 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. [ABSTRACT FROM AUTHOR]

Rodent self-grooming is an important complex behavior, and its deficits are translationally relevant to a wide range of neuropsychiatric disorders. Here, we analyzed a comprehensive dataset of 227 genes whose mutations are known to evoke aberrant self-grooming in mice. Using these genes, we constructed the network of their established protein-protein interactions (PPI), yielding several distinct molecular clusters related to postsynaptic density, the Wnt signaling, transcription factors, neuronal cell cycle, NOS neurotransmission, microtubule regulation, neuronal differentiation/trafficking, neurodevelopment and mitochondrial function. Utilizing further bioinformatics analyses, we also identified novel central ('hub') proteins within these clusters, whose genes may also be implicated in aberrant self-grooming and other repetitive behaviors in general. Untangling complex molecular pathways of this important behavior using in silico approaches contributes to our understanding of related neurological disorders, and may suggest novel potential targets for their pharmacological or gene therapy. • Self-grooming is an important, complex and patterned behavior in rodents. • Mouse self-grooming is relevant to multiple neuropsychiatric disorders. • Various mutant mice display aberrant self-grooming phenotypes. • Bioinformatics analyses of these genes reveal molecular pathways involved in grooming. • This approach may help identify potential novel targets for therapy of aberrant behavior. [ABSTRACT FROM AUTHOR]

Human neocortex controls and integrates cognition, emotions, perception and complex behaviors. Aberrant cortical development can be triggered by multiple genetic and environmental factors, causing cortical malformations. Animal models, especially rodents, are a valuable tool to probe molecular and physiological mechanisms of cortical malformations. Complementing rodent studies, the zebrafish (Danio rerio) is an important model organism in biomedicine. Although the zebrafish (like other fishes) lacks neocortex, here we argue that this species can still be used to model various aspects and brain phenomena related to human cortical malformations. We also discuss novel perspectives in this field, covering both advantages and limitations of using mammalian and zebrafish models in cortical malformation research. Summarizing mounting evidence, we also highlight the importance of translationally-relevant insights into the pathogenesis of cortical malformations from animal models, and discuss future strategies of research in the field. • Cortical malformations are a diverse family of rare human brain disorders. • Mammalian models are widely used to probe pathobiology of cortical malformations. • Lacking neocortex, zebrafish are widely used to study brain disorders. • Mounting evidence suggests zebrafish as a novel model for cortical malformations research. • We discuss advantages and limitations of animal models of cortical malformations. [ABSTRACT FROM AUTHOR]

• Schizophrenia is an extremely debilitating lifelong psychiatric disorder. • It remains poorly understood, necessitating further translational research in this field. • Animal models are becoming a valuable tool to study schizophrenia. • Rodent models have been extensively used to target schizophrenia-related phenotypes and drugs. • Mounting evidence suggests zebrafish (Danio rerio) as a useful complementary tool to model schizophrenia. Schizophrenia is a severely debilitating, lifelong psychiatric disorder affecting approximately 1% of global population. The pathobiology of schizophrenia remains poorly understood, necessitating further translational research in this field. Experimental (animal) models are becoming indispensable for studying schizophrenia-related phenotypes and pro/antipsychotic drugs. Mounting evidence suggests the zebrafish (Danio rerio) as a useful tool to model various phenotypes relevant to schizophrenia. In addition to their complex robust behaviors, zebrafish possess high genetic and physiological homology to humans, and are also sensitive to drugs known to reduce or promote schizophrenia clinically. Here, we summarize findings on zebrafish application to modeling schizophrenia, as well as discuss recent progress and remaining challenges in this field. We also emphasize the need in further development and wider use of zebrafish models for schizophrenia to better understand its pathogenesis and enhance the search for new effective antipsychotics. [ABSTRACT FROM AUTHOR]

Abstract 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. [ABSTRACT FROM AUTHOR]

Highlights • Zebrafish and other fish models are widely accepted in CNS research and drug screening. • Intraspecies behavioral variation plays a key role in fish drug-evoked responses. • Sex, strain and individual differences contribute markedly to intraspecies variance in fish. • Epigenetics, gut microbiota and gene-environment interactions influence intraspecies variance in fishes. • Here, we outline recent findings and discuss the existing challenges in this field. Abstract Intraspecies variation is common in both clinical and animal research of various brain disorders. Relatively well-studied in mammals, intraspecies variation in aquatic fish models and its role in their behavioral and pharmacological responses remain poorly understood. Like humans and mammals, fishes show high variance of behavioral and drug-evoked responses, modulated both genetically and environmentally. The zebrafish (Danio rerio) has emerged as a particularly useful model organism tool to access neurobehavioral and drug-evoked responses. Here, we discuss recent findings and the role of the intraspecies variance in neurobehavioral, pharmacological and toxicological studies utilizing zebrafish and other fish models. We also critically evaluate common sources of intraspecies variation and outline potential strategies to improve data reproducibility and translatability. [ABSTRACT FROM AUTHOR]

Abstract Despite the high prevalence of medicinal use and abuse of opioids, their neurobiology and mechanisms of action are not fully understood. Experimental (animal) models are critical for improving our understanding of opioid effects in vivo. As zebrafish (Danio rerio) are increasingly utilized as a powerful model organism in neuroscience research, mounting evidence suggests these fish as a useful tool to study opioid neurobiology. Here, we discuss the zebrafish opioid system with specific focus on opioid gene expression, existing genetic models, as well as its pharmacological and developmental regulation. As many human brain diseases involve pain and aberrant reward, we also summarize zebrafish models relevant to opioid regulation of pain and addiction, including evidence of functional interplay between the opioid system and central dopaminergic and other neurotransmitter mechanisms. Additionally, we critically evaluate the limitations of zebrafish models for translational opioid research and emphasize their developing utility for improving our understanding of evolutionarily conserved mechanisms of pain-related, addictive, affective and other behaviors, as well as for fostering opioid-related drug discovery. Highlights • Despite the growing use and abuse of opioids, their neurobiology is not fully understood. • Experimental models are critical for improving our understanding of opioid effects in vivo. • The zebrafish (Danio rerio) is becoming a powerful model organism in neuroscience research. • Here, we discuss the zebrafish opioid system and its genetic, genomic, pharmacological and behavioral regulation. • We emphasize the value of zebrafish for understanding opioid mechanisms and for CNS drug discovery. [ABSTRACT FROM AUTHOR]

Highlights • Melatonin is an important brain hormone regulating circadian rhythm, neuroprotection and neuroimmune interactions. • Zebrafish (Danio rerio) is increasingly used in biomedical and neuroscience research. • Mounting evidence implicating melatonin in brain disorders and behavior. • Animal models are becoming a valuable tool to study neurobiology of melatonin. Abstract Melatonin is an important hormone regulating circadian rhythm, neuroprotection and neuroimmune processes. However, its exact physiological roles in brain mechanisms remain poorly understood. Here, we summarize the mounting evidence implicating melatonin in brain disorders and behavior, based on clinical and experimental studies in-vivo. In addition to rodent models, the zebrafish (Danio rerio) is becoming increasingly utilized in biomedical and neuroscience research. Here, we discuss melatonin neurobiology of zebrafish, and parallel these findings with clinical and rodent data. We also discuss the genomic effects of melatonin in zebrafish, and emphasize the growing utility of zebrafish models to study melatonin neurobiology and drug discovery. [ABSTRACT FROM AUTHOR]

Highlights • Aggression is a common agonistic behavior strongly affecting social life and wellbeing. • Zebrafish is rapidly becoming a new experimental model organism in neurobehavioral research. • Zebrafish present overt, easily quantifiable aggressive behaviors. • Here we discuss their utility in probing aggression neurobiology, genetics and environmental modulation. Abstract Aggression is a common agonistic behavior affecting social life and well-being of humans and animals. However, the underlying mechanisms of aggression remain poorly understood. For decades, studies of aggression have mostly focused on laboratory rodents. The growing importance of evolutionarily relevant, cross-species disease modeling necessitates novel model organisms to study aggression and its pathobiology. The zebrafish (Danio rerio) is rapidly becoming a new experimental model organism in neurobehavioral research. Zebrafish demonstrate high genetic and physiological homology with mammals, fully sequenced genome, ease of husbandry and testing, as well as rich, robust behavioral repertoire. As zebrafish present overt aggressive behaviors, here we focus on their behavioral models and discuss their utility in probing aggression neurobiology and its genetic, pharmacological and environmental modulation. We argue that zebrafish-based models represent an excellent translational tool to understand aggressive behaviors and related pathobiological brain mechanisms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Chronic stress may cause physical, behavioral and neuropsychiatric changes, affecting the health condition of an individual. Aggression is a universal behavior with great relevance on human and animal social systems. Despite studies showing the influence of chronic stress on aggression, the effects of unpredictable chronic stress (UCS) on aggressive behavior in male and female zebrafish remain unknown. Thus, the aim of this study was to evaluate the effects of UCS on the aggressive behavior and cortisol levels in adult zebrafish of both sexes. Our results showed that UCS increased aggression in males, but not in females, which displayed more aggressive behavior at baseline than control males. Increased whole-body cortisol levels were observed in stressed males; however, no differences were found between female groups. In conclusion, we reported for the first time gender differences on behavioral parameters and cortisol levels in response to UCS in zebrafish. These results highlight the relevance of studying behavioral and physiological parameters in both sexes separately. [ABSTRACT FROM AUTHOR]

Neurodegeneration is a major cause of Alzheimer's, Parkinson's, Huntington's, multiple and amyotrophic lateral sclerosis, pontocerebellar hypoplasia, dementia and other related brain disorders. Their complex pathogenesis commonly includes genetic and neurochemical deficits, misfolded protein toxicity, demyelination, apoptosis and mitochondrial dysfunctions. Albeit differing in specific underlying mechanisms, neurodegenerative disorders typically display evolutionarily conserved mechanisms across taxa. Here, we review the role of zebrafish models in recapitulating major human and rodent neurodegenerative conditions, demonstrating this species as a highly relevant experimental model for research on neurodegenerative diseases, and discussing how these fish models can further clarify the underlying genetic, neurochemical, neuroanatomical and behavioral pathogenic mechanisms. • Zebrafish is a highly relevant model species in neurodegenerative research. • Zebrafish models can help clarify key pathogenic mechanisms of neurodegeneration. • Neurodegenerative disorders have evolutionarily conserved mechanisms across taxa. • Neurodegeneration involves complex genetic and molecular deficits across taxa. [ABSTRACT FROM AUTHOR]

Abstract: We investigated a group of Rhamdia quelen females during their entire first reproductive cycle and beginning of the 2nd cycle by evaluating the stress response at different phases of gonadal maturation. In mammals, including humans, pubertal development modulates stress response reactivity due to the maturation of the neuroendocrine stress axis. These shifts in the stress reactivity were also detected in salmonid fishes. This effect comes from changes in the sensitivity of the stress axis glands or in the capacity of the adrenal tissue to synthesise glucocorticoids. Here, for the first time, we show that similar to mammals and salmonid fishes, pre-pubertal female R. quelen exhibit a protracted stress response compared to adult fish, pointing to puberty as a key event on HPI axis modulation. [Copyright &y& Elsevier]

• Sex is an important variable in translational biomedical research. • Here, we evaluate sex differences in zebrafish behavioral responses to pain and fear. • Female adult zebrafish more robustly (than males) altered pain-like behavior. • Zebrafish of both sexes responded equally strongly to fear evoked by alarm substance. Sex is an important variable in translational biomedical research. While overt sex differences have been reported for pain and fear-like behaviors in humans and rodents, these differences in other popular model organisms, such as zebrafish, remain poorly understood. Here, we evaluate potential sex differences in zebrafish behavioral responses to pain (intraperitoneal administration of 5% acetic acid) and fear stimuli (exposure to alarm substance). Overall, both male and female zebrafish exposed to pain (acetic acid injection) show lesser distance traveled, fewer top entries and more writhing-like pain-related behavior vs. controls, whereas female fish more robustly (than males) altered some other pain-like behaviors (e.g., increasing freezing episodes and time in top) in this model. In contrast, zebrafish of both sexes responded equally strongly to fear evoked by acute alarm substance exposure. Collectively, these findings emphasize the growing importance of studying sex differences in zebrafish behavioral and pain models. [ABSTRACT FROM AUTHOR]

Zebrafish (Danio rerio) are rapidly emerging in biomedicine as promising tools for disease modelling and drug discovery. The use of zebrafish for neuroscience research is also growing rapidly, necessitating novel reliable and unbiased methods of neurophenotypic data collection and analyses. Here, we applied the artificial intelligence (AI) neural network-based algorithms to a large dataset of adult zebrafish locomotor tracks collected previously in a series of in vivo experiments with multiple established psychotropic drugs. We first trained AI to recognize various drugs from a wide range of psychotropic agents tested, and then confirmed prediction accuracy of trained AI by comparing several agents with known similar behavioral and pharmacological profiles. Presenting a framework for innovative neurophenotyping, this proof-of-concept study aims to improve AI-driven movement pattern classification in zebrafish, thereby fostering drug discovery and development utilizing this key model organism. • Zebrafish is a promising tool for disease modelling and drug discovery. • Here, we applied the artificial intelligence (AI) algorithms to zebrafish locomotor tracks. • We trained AI to recognize various drugs from a wide range of psychotropic agents. • We also reconfirmed prediction accuracy by comparing agents with known profiles. • This proof-of-concept study shows AI-driven movement pattern classification in zebrafish. [ABSTRACT FROM AUTHOR]

• 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. [ABSTRACT FROM AUTHOR]

Strongly affecting human and animal physiology, sounds and vibration are critical environmental factors whose complex role in behavioral and brain functions necessitates further clinical and experimental studies. Zebrafish are a promising model organism for neuroscience research, including probing the contribution of auditory and vibration stimuli to neurobehavioral processes. Here, we summarize mounting evidence on the role of sound and vibration in zebrafish behavior and brain function, and outline future directions of translational research in this field. With the growing environmental exposure to noise and vibration, we call for more active use of zebrafish models for probing neurobehavioral and bioenvironmental consequences of acute and long-term exposure to sounds and vibration in complex biological systems. • Sounds and vibration play a complex role in behavioral and brain functions. • Zebrafish are promising model for studying CNS effects of auditory and vibration stimuli. • Here we evaluate behavioral and physiological effects of sounds and vibration in zebrafish. • Noise and vibration are also important factors for zebrafish data reproducibility and repeatability. [ABSTRACT FROM AUTHOR]

• Female zebrafish display higher baseline anxiety-like behavior. • Females demonstrated greater individual variability in locomotor activity. • Acute scopolamine exposure causes anxiogenic-like effect in males. • Acute scopolamine exposure caused anxiolytic-like effect in females. • These findings support overt sex and individual differences in zebrafish behavior. Sex differences influence human and animal behavioral and pharmacological responses. The zebrafish (Danio rerio) is a powerful, popular model system in neuroscience and drug screening. However, the impact of zebrafish sex differences on their behavior and drug responses remains poorly understood. Here, we evaluate baseline anxiety-like behavior in adult male and female zebrafish, and its changes following an acute 30-min exposure to 800-μM scopolamine, a common psychoactive anticholinergic drug. Overall, we report high baseline anxiety-like behavior and more individual variability in locomotion in female zebrafish, as well as distinct, sex-specific (anxiolytic-like in females and anxiogenic-like in males) effects of scopolamine. Collectively, these findings reinforce the growing importance of zebrafish models for studying how both individual and sex differences shape behavioral and pharmacological responses. [ABSTRACT FROM AUTHOR]

Typically triggered by stress, anxiety disorders are most common and widespread mental illnesses. The zebrafish (Danio rerio) is rapidly becoming an important aquatic model species in stress research and central nervous system (CNS) drug screening. Paracetamol is currently the most prescribed medication for pain and fever, and is among the most used drugs globally. However, its CNS effects, especially on anxiety, in both clinical and animal studies remain poorly understood. Capitalizing on zebrafish as a powerful model system, here we evaluate the effects of paracetamol on anxiety-like behavior in adult fish, and its changes following an acute stress exposure. Overall, we report an anxiolytic-like profile of acute paracetamol treatment, and its alleviation of stress-evoked anxiety, in adult short-fin wild type zebrafish. Collectively, these findings suggest complex neuroactive effects of paracetamol, and reinforce the growing importance of zebrafish models for drug screening, including the search for novel putative anti-stress therapies. [ABSTRACT FROM AUTHOR]

• Zebrafish are rapidly becoming a powerful novel organism in neuroscience research. • Estradiol (E 2) is an important estrogen whose effects in males are poorly understood. • E 2 exposure for 24 h increases social preference in adult male zebrafish. • E 2 -exposed zebrafish show anxiolytic-like looser schools and increased exploration. • E 2 also decreased whole-body cortisol levels in adult male zebrafish. Estradiol (17β-estradiol, E 2) is a crucial estrogen hormone that regulates sexual, cognitive, social and affective behaviors in various species. However, complex central nervous system (CNS) effects of E 2 , including its activity in males, remain poorly understood. The zebrafish (Danio rerio) is rapidly becoming a powerful novel model system in translational neuroscience research. Here, we evaluate the effects of a single 24-h exposure to 20 μg/L of E 2 on behavioral and endocrine (cortisol) responses in adult male zebrafish. Overall, E 2 exerted pro-social effect in the social preference test, reduced whole-body cortisol levels, elevated exploration in the novel tank test and increased the shoal size in the shoaling test, indicative of an anxiolytic-like profile of this hormone in male zebrafish. Supporting mounting human and rodent evidence on the role of E 2 in behavioral regulation, the observed pro-social and anxiolytic-like effects of E 2 in male zebrafish reinforce the use of this aquatic organism in studying steroid-mediated CNS mechanisms of complex affective and social behaviors. [ABSTRACT FROM AUTHOR]

Despite high prevalence, medical impact and societal burden, anxiety, depression and other affective disorders remain poorly understood and treated. Clinical complexity and polygenic nature complicate their analyses, often revealing genetic overlap and cross-disorder heritability. However, the interplay or overlaps between disordered phenotypes can also be based on shared molecular pathways and 'crosstalk' mechanisms, which themselves may be genetically determined. We have earlier predicted (Kalueff et al., 2014) a new class of 'interlinking' brain genes that do not affect the disordered phenotypes per se, but can instead specifically determine their interrelatedness. To test this hypothesis experimentally, here we applied a well-established rodent chronic social defeat stress model, known to progress in C57BL/6J mice from the Anxiety-like stage on Day 10 to Depression-like stage on Day 20. The present study analyzed mouse whole-genome expression in the prefrontal cortex and hippocampus during the Day 10, the Transitional (Day 15) and Day 20 stages in this model. Our main question here was whether a putative the Transitional stage (Day 15) would reveal distinct characteristic genomic responses from Days 10 and 20 of the model, thus reflecting unique molecular events underlining the transformation or switch from anxiety to depression pathogenesis. Overall, while in the Day 10 (Anxiety) group both brain regions showed major genomic alterations in various neurotransmitter signaling pathways, the Day 15 (Transitional) group revealed uniquely downregulated astrocyte-related genes, and the Day 20 (Depression) group demonstrated multiple downregulated genes of cell adhesion, inflammation and ion transport pathways. Together, these results reveal a complex temporal dynamics of mouse affective phenotypes as they develop. Our genomic profiling findings provide first experimental support to the idea that novel brain genes (activated here only during the Transitional stage) may uniquely integrate anxiety and depression pathogenesis and, hence, determine the progression from one pathological state to another. This concept can potentially be extended to other brain conditions as well. This preclinical study also further implicates cilial and astrocytal mechanisms in the pathogenesis of affective disorders. • Here, we used the 20-day chronic social defeat stress model in C57BL/6 J male mice. • The model progresses from 'Anxiety' stage on Day 10 to 'Depression' stage on Day 20. • We assessed the whole-genome expression in the prefrontal cortex and hippocampus. • Expression was altered for neurotransmitter (Day 10), astrocytal (Day 15) and inflammation (Day 20) genes. • This reveals a complex temporal dynamics of the evolving mouse affective syndrome. [ABSTRACT FROM AUTHOR]

Arecoline is a naturally occurring psychoactive alkaloid with partial agonism at nicotinic and muscarinic acetylcholine receptors. Arecoline consumption is widespread, making it the fourth (after alcohol, nicotine and caffeine) most used substance by humans. However, the mechanisms of acute and chronic action of arecoline in-vivo remain poorly understood. Animal models are a valuable tool for CNS disease modeling and drug screening. Complementing rodent studies, the zebrafish (Danio rerio) emerges as a promising novel model organism for neuroscience research. Here, we assessed the effects of acute and chronic arecoline on adult zebrafish behavior and physiology. Overall, acute and chronic arecoline treatments produced overt anxiolytic-like behavior (without affecting general locomotor activity and whole-body cortisol levels), with similar effects also caused by areca nut water extracts. Acute arecoline at 10 mg/L disrupted shoaling, increased social preference, elevated brain norepinephrine and serotonin levels and reduced serotonin turnover. Acute arecoline also upregulated early protooncogenes c-fos and c-jun in the brain, whereas chronic treatment with 1 mg/L elevated brain expression of microglia-specific biomarker genes egr2 and ym1 (thus, implicating microglial mechanisms in potential effects of long-term arecoline use). Finally, acute 2-h discontinuation of chronic arecoline treatment evoked withdrawal-like anxiogenic behavior in zebrafish. In general, these findings support high sensitivity of zebrafish screens to arecoline and related compounds, and reinforce the growing utility of zebrafish for probing molecular mechanisms of CNS drugs. Our study also suggests that novel anxiolytic drugs can eventually be developed based on arecoline-like molecules, whose integrative mechanisms of CNS action may involve monoaminergic and neuro-immune modulation. • Arecoline is a naturally occurring psychoactive alkaloid agonist of nicotinic and muscarinic receptors. • Here, we assessed the effects of acute and chronic arecoline on adult zebrafish behavior and physiology. • Acute and chronic arecoline evoked anxiolytic-like behavior in adult zerbafish. • Chronic arecoline elevated brain expression of microglia-specific biomarker genes egr2 and ym1. • Acute arecoline also elevated brain norepinephrine and serotonin levels in zebrafish. [ABSTRACT FROM AUTHOR]

• Zebrafish exposure to 24-h light demonstrated cognitive deficits. • The 24-h light exposure increased cortisol levels in zebrafish. • Melatonin reverted cognitive and endocrine deficits caused by 24-h light exposure. • Reinforce the growing utility of zebrafish for studying cognitive and behavioral processes. Melatonin is an important pineal hormone that regulates human and animal circadian rhythms and sleep. Mounting clinical and rodent evidence indicates that melatonin also modulates affective behaviors and cognition. The zebrafish (Danio rerio) is rapidly becoming a powerful novel model organism in translational neuroscience research. Here, we evaluate the effects of a 24-h melatonin treatment on behavior and physiology of adult zebrafish with circadian rhythm disturbed by a 24-h light exposure. While such light exposure evoked overt cognitive and neuroendocrine (cortisol) deficits in zebrafish, these effects were reversed by a 24-h melatonin treatment. Collectively, these findings suggest a positive modulation of affective and cognitive phenotypes in zebrafish by melatonin, and reinforce the growing utility of zebrafish models for studying circadian, cognitive and behavioral processes and their neuroendocrine regulation in vivo. [ABSTRACT FROM AUTHOR]

• PTSD is a severely debilitating stress-related brain disorder. • Zebrafish emerge as a promising novel organism to model PTSD. • Here, we expose fish to acute stress, evoking lasting PTSD-like states 1 week later. • Anxiety behavior was accompanied by upregulated brain gene biomarkers. • We found higher brain expression of neuroglial, apoptotic and epigenetic genes. Stress is a common trigger of stress-related illnesses, such as anxiety, phobias, depression and post-traumatic stress disorder (PTSD). Various animal models successfully reproduce core behaviors of these clinical conditions. Here, we develop a novel zebrafish model of stress (potentially relevant to human stress-related disorders), based on delayed persistent behavioral, endocrine and genomic responses to an acute severe 'combined' stressor. Specifically, one week after adult zebrafish were exposed to a complex combined 90-min stress, we assessed their behaviors in the novel tank and the light-dark box tests, as well as whole-body cortisol and brain gene expression, focusing on genomic biomarkers of microglia, astrocytes, neuroinflammation, apoptosis and epigenetic modulation. Overall, stressed fish displayed persistent anxiety-like behavior, elevated whole-body cortisol, as well as upregulated brain mRNA expression of genes encoding the glucocorticoid receptor, neurotrophin BDNF and its receptors (TrkB and P75), CD11b (a general microglial biomarker), COX-2 (an M1-microglial biomarker), CD206 (an M2-microglial biomarker), GFAP (a general astrocytal biomarker), C3 (an A1-astrocytal biomarker), S100α 10 (an A2-astrocytal biomarker), as well as pro-inflammatory cytokines IL-6, IL-1β, IFN-γ and TNF-α. Stress exposure also persistently upregulated the brain expression of several key apoptotic (Bax, Caspase-3, Bcl-2) and epigenetic genes (DNMT3a, DNMT3b, HAT1, HDAC4) in these fish. Collectively, the present model not only successfully recapitulates lasting behavioral and endocrine symptoms of clinical stress-related disorders, but also implicates changes in neuroglia, neuroinflammation, apoptosis and epigenetic modulation in long-term effects of stress pathogenesis in vivo. [ABSTRACT FROM AUTHOR]

Kava kava (Piper methysticum) is a medicinal plant containing kavalactones that exert potent sedative, analgesic and anti-stress action. However, their pharmacological effects and molecular targets remain poorly understood. The zebrafish (Danio rerio) has recently emerged as a powerful new model organism for neuroscience research and drug discovery. Here, we evaluate the effects of acute and chronic exposure to kava and kavalactones on adult zebrafish anxiety, aggression and sociality, as well as on their neurochemical, neuroendocrine and genomic responses. Supporting evolutionarily conserved molecular targets, acute kava and kavalactones evoked dose-dependent behavioral inhibition, upregulated brain expression of early protooncogenes c - fos and c - jun , elevated brain monoamines and lowered whole-body cortisol. Chronic 7-day kava exposure evoked similar behavioral effects, did not alter cortisol levels, and failed to evoke withdrawal-like states upon discontinuation. However, chronic kava upregulated several microglial (iNOS , Egr - 2 , CD11b), astrocytal (C3 , C4B , S100a), epigenetic (ncoa - 1) and pro-inflammatory (IL - 1 β, IL - 6 , TNFa) biomarker genes, downregulated CD206 and IL - 4 , and did not affect major apoptotic genes in the brain. Collectively, this study supports robust, evolutionarily conserved behavioral and physiological effects of kava and kavalactones in zebrafish, implicates brain monoamines in their acute effects, and provides novel important insights into potential role of neuroglial and epigenetic mechanisms in long-term kava use. • Kava (Piper methysticum) is a medicinal plant containing kavalactones with potent neuroactive effects. • However, their pharmacological effects and molecular targets remain poorly understood. • Zebrafish (Danio rerio) is a new powerful model organism for neuroscience and drug discovery. • Acute kava evoked overt sedation, elevated brain monoamines and reduced whole-body cortisol levels. • Chronic kava evoked similar behavioral effects and upregulated neuroglial biomarker genes [ABSTRACT FROM AUTHOR]

• Zebrafish may have despair-like behavior, similarly to rodents. • Zebrafish despair-like behavior can be assessed using the Zebrafish Tail Immobilization test (ZTI). • Zebrafish subjected to stress prior to the ZTI test exposure increase despair-like behavior. • Exposure to antidepressant, but not anxiolytic, agents reduces the ZTI test despair-like behavior. • ZTI performance may be associated with altered serotonin and dopamine brain metabolism. Affective disorders, especially depression and anxiety, are highly prevalent, debilitating mental illnesses. Animal experimental models are a valuable tool in translational affective neuroscience research. A hallmark phenotype of clinical and experimental depression, the learned helplessness, has become a key target for 'behavioral despair'-based animal models of depression. The zebrafish (Danio rerio) has recently emerged as a promising novel organism for affective disease modeling and CNS drug screening. Despite being widely used to assess stress and anxiety-like behaviors, there are presently no clear-cut despair-like models in zebrafish. Here, we introduce a novel behavioral paradigm, the zebrafish tail immobilization (ZTI) test, as a potential tool to assess zebrafish despair-like behavior. Conceptually similar to rodent 'despair' models, the ZTI protocol involves immobilizing the caudal half of the fish body for 5 min, leaving the cranial part to move freely, suspended vertically in a small beaker with water. To validate this model, we used exposure to low-voltage electric shock, alarm pheromone, selected antidepressants (sertraline and amitriptyline) and an anxiolytic drug benzodiazepine (phenazepam), assessing the number of mobility episodes, time spent 'moving', total distance moved and other activity measures of the cranial part of the body, using video-tracking. Both electric shock and alarm pheromone decreased zebrafish activity in this test, antidepressants increased it, and phenazepam was inactive. Furthermore, a 5-min ZTI exposure increased serotonin turnover, elevating the 5-hydroxyindoleacetic acid/serotonin ratio in zebrafish brain, while electric shock prior to ZTI elevated both this and the 3,4-dihydroxyphenylacetic acid/dopamine ratios. In contrast, preexposure to antidepressants sertraline and amitriptyline lowered both ratios, compared to the ZTI test-exposed fish. The ZTI test is the first despair-like experimental model in zebrafish. Collectively, this study suggests the ZTI test as a potentially useful protocol to assess stress-/despair-related behaviors, potentially relevant to CNS drug screening and behavioral phenotyping of zebrafish. [ABSTRACT FROM AUTHOR]