Modeling neurodegenerative disorders in zebrafish.

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.

Understanding neurobehavioral effects of acute and chronic stress in zebrafish.

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.

Decoding the role of zebrafish neuroglia in CNS disease modeling.

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.

Cross-species Analyses of Intra-species Behavioral Differences in Mammals and Fish.

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.

DARK Classics in Chemical Neuroscience: Kava.

Kava (kava kava, Piper methysticum) is a common drug-containing plant in the Pacific islands. Kavalactones, its psychoactive compounds, exert potent central nervous system (CNS) action clinically and in animal models. However, the exact pharmacological profiles and mechanisms of action of kava on the brain and behavior remain poorly understood. Here, we discuss clinical and experimental data on kava psychopharmacology and summarize chemistry and synthesis of kavalactones. We also review its societal impact, drug use and abuse potential, and future perspectives on translational kava research.

Understanding neurobehavioral genetics of zebrafish.

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.

Developing zebrafish experimental animal models relevant to 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.

The role of intraspecies variation in fish neurobehavioral and neuropharmacological phenotypes in aquatic models.

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.

Animal models of major depressive disorder and the implications for drug discovery and development.

INTRODUCTION: Depression is a highly debilitating psychiatric disorder that affects the global population and causes severe disabilities and suicide. Depression pathogenesis remains poorly understood, and the disorder is often treatment-resistant and recurrent, necessitating the development of novel therapies, models and concepts in this field. Areas covered: Animal models are indispensable for translational biological psychiatry, and markedly advance the study of depression. Novel approaches continuously emerge that may help untangle the disorder heterogeneity and unclear categories of disease classification systems. Some of these approaches include widening the spectrum of model species used for translational research, using a broader range of test paradigms, exploring new pathogenic pathways and biomarkers, and focusing more closely on processes beyond neural cells (e.g. glial, inflammatory and metabolic deficits). Expert opinion: Dividing the core symptoms into easily translatable, evolutionarily conserved phenotypes is an effective way to reevaluate current depression modeling. Conceptually novel approaches based on the endophenotype paradigm, cross-species trait genetics and 'domain interplay concept', as well as using a wider spectrum of model organisms and target systems will enhance experimental modeling of depression and antidepressant drug discovery.

Opioid Neurobiology, Neurogenetics and Neuropharmacology in Zebrafish.

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.

DARK Classics in Chemical Neuroscience: Arecoline.

Arecoline is a naturally occurring psychoactive alkaloid from areca (betel) nuts of the areca palm ( Areca catechu) endemic to South and Southeast Asia. A partial agonist of nicotinic and muscarinic acetylcholine receptors, arecoline evokes multiple effects on the central nervous system (CNS), including stimulation, alertness, elation, and anxiolysis. Like nicotine, arecoline also evokes addiction and withdrawal symptoms (upon discontinuation). The abuse of areca nuts is widespread, with over 600 million users globally. The importance of arecoline is further supported by its being the world's fourth most commonly used human psychoactive substance (after alcohol, nicotine, and caffeine). Here, we discuss neuropharmacology, pharmacokinetics, and metabolism of arecoline, as well as social and historical aspects of its use and abuse. Paralleling clinical findings, we also evaluate its effects in animal models and outline future clinical and preclinical CNS research in this field.

Zebrafish models for personalized psychiatry: Insights from individual, strain and sex differences, and modeling gene x environment interactions.

Currently becoming widely recognized, personalized psychiatry focuses on unique physiological and genetic profiles of patients to best tailor their therapy. However, the role of individual differences, as well as genetic and environmental factors, in human psychiatric disorders remains poorly understood. Animal experimental models are a valuable tool to improve our understanding of disease pathophysiology and its molecular mechanisms. Due to high reproduction capability, fully sequenced genome, easy gene editing, and high genetic and physiological homology with humans, zebrafish (Danio rerio) are emerging as a novel powerful model in biomedicine. Mounting evidence supports zebrafish as a useful model organism in CNS research. Robustly expressed in these fish, individual, strain, and sex differences shape their CNS responses to genetic, environmental, and pharmacological manipulations. Here, we discuss zebrafish as a promising complementary translational tool to further advance patient-centered personalized psychiatry.

Understanding Central Nervous System Effects of Deliriant Hallucinogenic Drugs through Experimental Animal Models.

Hallucinogenic drugs potently alter human behavior and have a millennia-long history of use for medicinal and religious purposes. Interest is rapidly growing in their potential as CNS modulators and therapeutic agents for brain conditions. Antimuscarinic cholinergic drugs, such as atropine and scopolamine, induce characteristic hyperactivity and dream-like hallucinations and form a separate group of hallucinogens known as "deliriants". Although atropine and scopolamine are relatively well-studied drugs in cholinergic physiology, deliriants represent the least-studied class of hallucinogens in terms of their behavioral and neurological phenotypes. As such, novel approaches and new model organisms are needed to investigate the CNS effects of these compounds. Here, we comprehensively evaluate the preclinical effects of deliriant hallucinogens in various animal models, their mechanisms of action, and potential interplay with other signaling pathways. We also parallel experimental and clinical findings on deliriant agents and outline future directions of translational research in this field.

Understanding zebrafish aggressive behavior.

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.

DARK Classics in Chemical Neuroscience: Atropine, Scopolamine, and Other Anticholinergic Deliriant Hallucinogens.

Anticholinergic drugs based on tropane alkaloids, including atropine, scopolamine, and hyoscyamine, have been used for various medicinal and toxic purposes for millennia. These drugs are competitive antagonists of acetylcholine muscarinic (M-) receptors that potently modulate the central nervous system (CNS). Currently used clinically to treat vomiting, nausea, and bradycardia, as well as alongside other anesthetics to avoid vagal inhibition, these drugs also evoke potent psychotropic effects, including characteristic delirium-like states with hallucinations, altered mood, and cognitive deficits. Given the growing clinical importance of anti-M deliriant hallucinogens, here we discuss their use and abuse, clinical importance, and the growing value in preclinical (experimental) animal models relevant to modeling CNS functions and dysfunctions.

Zebrafish models of diabetes-related CNS pathogenesis.

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.

Acute behavioral effects of deliriant hallucinogens atropine and scopolamine in adult zebrafish.

Atropine and scopolamine are classical muscarinic cholinergic antagonists that exert multiple CNS effects. Belonging to a group of deliriant hallucinogens, these drugs induce delirium-like hallucinations, hyperactivity, altered affective states and amnesia. However, as deliriants remain the least studied group of hallucinogens, their complex and poorly understood profiles necessitate further clinical and preclinical studies. The zebrafish (Danio rerio) is rapidly emerging as a powerful model organism for translational neuropsychopharmacology research. Here, we characterize acute behavioral effects of atropine (60, 90 and 120 mg/L) and scopolamine (60, 120, 180 and 240 mg/L) in adult zebrafish subjected to the novel tank (NTT), light-dark (LDT) and shoaling tests. Overall, atropine at 90 mg/L only mildly increased the NTT locomotor activity, scopolamine at 120 mg/L produced anxiogenic-like NTT effects without affecting other behaviors, and both drugs similarly disrupted zebrafish group behavior in the shoaling test. Collectively, this supports complex and partially overlapping deliriant-like effects of acute atropine and scopolamine in zebrafish. The behavioral sensitivity to these drugs suggests zebrafish as potential screens for cholinergic deliriant psychotropic agents, also necessitating further cross-species in-vivo experimental studies.

Understanding the Role of Environmental Enrichment in Zebrafish Neurobehavioral Models.

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

Zebrafish models relevant to studying central opioid and endocannabinoid systems.

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.

Understanding antidepressant discontinuation syndrome (ADS) through preclinical experimental models.

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