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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]

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]

• 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]

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]

Abstract Despite the growing emphasis on translational neuropharmacology and drug discovery research, the legality underlying these fields are seldom considered. The zebrafish (Danio rerio) is an increasingly utilized model organism in neuropharmacology and neurotoxicology. As the acceptance of zebrafish in biomedicine continues to grow, the legal aspects of their applications remain outpaced by this exponential growth. Therefore, there is a need to evaluate the legal aspects of zebrafish applications to CNS drug research. Here, we discuss a wide range of regulatory topics relevant to zebrafish research, such as the bioethics of experimentation (including studies of stress and pain), welfare protection laws, the recent advances in CNS drug discovery, and specific legal aspects of controlled substance research in this aquatic species. The conceptualization and understanding of the zebrafish welfare and its promise as a model in toxicology can also potentially shape environmental protection practices and inform policy making. Highlights • We examine the bioethics of experimentation in zebrafish. • We highlight welfare protection laws for animals used in research. • We emphasize legal aspects related to controlled substance research in zebrafish. • The understanding of the bioethics can shape environmental protection practices. [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]

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

• 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]

Stress is known to modulate behavioral responses and rapid decision-making processes, especially under challenging contexts which often occur in social and cooperative interactions. Here, we evaluated the effects of acute stress on cooperative behavior of the Indo-Pacific cleaner wrasse (Labroides dimidiatus) and the implications of pre-treatment with monoaminergic compounds: the selective serotonin reuptake inhibitor – fluoxetine, the 5-HT 1A receptor antagonist - WAY-100,635, the D 1 receptor agonist - SKF-38393, and the D 1 receptor antagonist - SCH-23390. We demonstrated that stress decreased the predisposal to interact and increased cortisol levels in cleaners, which are alleviated by fluoxetine and the dopaminergic D 1 antagonist. Overall, our findings highlight the crucial influence of stress on cooperative behavior. • Acute stress modulates cooperative behavior in cleaner fish. • Acute stress decreased the predisposal to interact and increased cortisol levels in cleaner fish. • Acute stress effects are alleviated by fluoxetine and dopaminergic D 1 antagonist. [ABSTRACT FROM AUTHOR]

• Zebrafish are a powerful novel organism in neuroscience and physiology research. • Housing in transparent and white tanks for 15 days increased their anxiety-like behavior. • Housing in black and blue tanks lowered zebrafish anxiety-like behavior. • Housing in blue (vs. white) tanks also reduced whole-body cortisol levels. • Color of housing environment strongly modulates behavioral and endocrine phenotypes in zebrafish. Color of the environment is an important factor modulating human and animal behavior and physiology. Animal models are a valuable tool to understand how colors affect social, cognitive and affective responses. The zebrafish (Danio rerio) is rapidly emerging as an important organism in neuroscience and physiology. Here, we examine whether the color of housing environment influences zebrafish anxiety-like behavior and whole-body cortisol levels. Overall, housing for 15 days in transparent and white holding tanks increases, and in black or blue tanks decreases, baseline anxiety-like behavior in adult zebrafish. Housing in blue tanks (vs. white) also reduced their whole-body cortisol levels. Taken together, our data suggest that color of the housing environment affects neurobehavioral and endocrine responses in zebrafish, with multiple implications for behavioral phenomics and animal welfare. Our study also reinforces zebrafish as a promising model organism to study neurobiology of compex brain-environment interactions. [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]

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]

Widespread, debilitating and often treatment-resistant, depression and other stress-related neuropsychiatric disorders represent an urgent unmet biomedical and societal problem. Although animal models of these disorders are commonly used to study stress pathogenesis, they are often difficult to translate across species into valuable and meaningful clinically relevant data. To address this problem, here we utilized several cross-species/cross-taxon approaches to identify potential evolutionarily conserved differentially expressed genes and their sets. We also assessed enrichment of these genes for transcription factors DNA-binding sites down- and up- stream from their genetic sequences. For this, we compared our own RNA-seq brain transcriptomic data obtained from chronically stressed rats and zebrafish with publicly available human transcriptomic data for patients with major depression and their respective healthy control groups. Utilizing these data from the three species, we next analyzed their differential gene expression, gene set enrichment and protein–protein interaction networks, combined with validated tools for data pooling. This approach allowed us to identify several key brain proteins (GRIA1, DLG1, CDH1, THRB, PLCG2, NGEF, IKZF1 and FEZF2) as promising, evolutionarily conserved and shared affective 'hub' protein targets, as well as to propose a novel gene set that may be used to further study affective pathogenesis. Overall, these approaches may advance cross-species brain transcriptomic analyses, and call for further cross-species studies into putative shared molecular mechanisms of affective pathogenesis. [ABSTRACT FROM AUTHOR]

Although zebrafish are increasingly utilized in biomedicine for CNS disease modelling and drug discovery, this generates big data necessitating objective, precise and reproducible analyses. The artificial intelligence (AI) applications have empowered automated image recognition and video-tracking to ensure more efficient behavioral testing. Capitalizing on several AI tools that most recently became available, here we present a novel open-access AI-driven platform to analyze tracks of adult zebrafish collected from in vivo neuropharmacological experiments. For this, we trained the AI system to distinguish zebrafish behavioral patterns following systemic treatment with several well-studied psychoactive drugs - nicotine, caffeine and ethanol. Experiment 1 showed the ability of the AI system to distinguish nicotine and caffeine with 75 % and ethanol with 88 % probability and high (81 %) accuracy following a post-training exposure to these drugs. Experiment 2 further validated our system with additional, previously unexposed compounds (cholinergic arecoline and varenicline, and serotonergic fluoxetine), used as positive and negative controls, respectively. The present study introduces a novel open-access AI-driven approach to analyze locomotor activity of adult zebrafish. Taken together, these findings support the value of custom-made AI tools for unlocking full potential of zebrafish CNS drug research by monitoring, processing and interpreting the results of in vivo experiments. • The artificial intelligence (AI) applications empower behavioral testing in animal models. • We present novel AI-driven platform to analyze behavior of adult zebrafish. • The system can be used to distinguish profiles of various CNS drugs. • The system can predict drug neuropharmacology with high probability and precision. • AI tools can be used for unlocking full potential of zebrafish CNS drug research. [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]

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]

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]

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]

• 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]

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]

• 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]

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]

• 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]

Delirium is an acute neuropsychiatric condition characterized by impaired behavior and cognition. Although the syndrome has been known for millennia, its CNS mechanisms and risk factors remain poorly understood. Experimental animal models, especially rodent-based, are commonly used to probe various pathogenetic aspects of delirium. Complementing rodents, the zebrafish (Danio rerio) emerges as a promising novel model organism to study delirium. Zebrafish demonstrate high genetic and physiological homology to mammals, easy maintenance, robust behaviors in various sensitive behavioral tests, and the potential to screen for pharmacological agents relevant to delirium. Here, we critically discuss recent developments in the field, and emphasize the developing utility of zebrafish models for translational studies of delirium and deliriant drugs. Overall, the zebrafish represents a valuable and promising aquatic model species whose use may help understand delirium etiology, as well as develop novel therapies for this severely debilitating disorder. [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]