Abstract
Mood disorders, especially depression, are a major cause of human disability. The loss of pleasure (anhedonia) is a common, severely debilitating symptom of clinical depression. Experimental ...animal models are widely used to better understand depression pathogenesis and to develop novel antidepressant therapies. In rodents, various experimental models of anhedonia have already been developed and extensively validated. Complementing rodent studies, the zebrafish (Danio rerio) is emerging as a powerful model organism to assess pathobiological mechanisms of affective disorders, including depression. Here, we critically discuss the potential of zebrafish for modeling anhedonia and studying its molecular mechanisms and translational implications.
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.
Stress-related neuropsychiatric disorders are widespread, debilitating and often treatment-resistant illnesses that represent an urgent unmet biomedical problem. Animal models of these disorders are ...widely used to study stress pathogenesis. A more recent and historically less utilized model organism, the zebrafish (Danio rerio), is a valuable tool in stress neuroscience research. Utilizing the 5-week chronic unpredictable stress (CUS) model, here we examined brain transcriptomic profiles and complex dynamic behavioral stress responses, as well as neurochemical alterations in adult zebrafish and their correction by chronic antidepressant, fluoxetine, treatment. Overall, CUS induced complex neurochemical and behavioral alterations in zebrafish, including stable anxiety-like behaviors and serotonin metabolism deficits. Chronic fluoxetine (0.1 mg/L for 11 days) rescued most of the observed behavioral and neurochemical responses. Finally, whole-genome brain transcriptomic analyses revealed altered expression of various CNS genes (partially rescued by chronic fluoxetine), including inflammation-, ubiquitin- and arrestin-related genes. Collectively, this supports zebrafish as a valuable translational tool to study stress-related pathogenesis, whose anxiety and serotonergic deficits parallel rodent and clinical studies, and genomic analyses implicate neuroinflammation, structural neuronal remodeling and arrestin/ubiquitin pathways in both stress pathogenesis and its potential therapy.
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.
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.
Impulse control disorders (ICDs) are characterized by generalized difficulty controlling emotions and behaviors. ICDs are a broad group of the central nervous system (CNS) disorders including conduct ...disorder, intermittent explosive, oppositional‐defiant disorder, antisocial personality disorder, kleptomania, pyromania and other illnesses. Although they all share a common feature (aberrant impulsivity), their pathobiology is complex and poorly understood. There are also currently no ICD‐specific therapies to treat these illnesses. Animal models are a valuable tool for studying ICD pathobiology and potential therapies. The zebrafish (Danio rerio) has become a useful model organism to study CNS disorders due to high genetic and physiological homology to mammals, and sensitivity to various pharmacological and genetic manipulations. Here, we summarize experimental models of impulsivity and ICD in zebrafish and highlight their growing translational significance. We also emphasize the need for further development of zebrafish ICD models to improve our understanding of their pathogenesis and to search for novel therapeutic treatments.
Zebrafish (Danio rerio) display aberrant impulsivity and other behavioral traits (irritability, aggression, social and/or cognitive deficits) relevant to modeling human impulse control disorders (ICDs). Several aquatic behavioral tests exist to assess these phenotypes, which can also be manipulated genetically and pharmacologically, to probe the mechanisms of ICD pathogenesis. Collectively, this mounting evidence suggests zebrafish as a promising model organism to study ICDs and their therapy.
•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.
•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 known 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 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.
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.
Highlights • The contamination of natural water bodies by psychoactive drugs is a current reality. • Fluoxetine, diazepam and risperidone affected the initial development of zebrafish. • All drugs ...increase the mortality rate, heart frequency and decrease larvae length. • Risperidone and fluoxetine decrease egg hatching. • These effects on early development may have significant environmental implications.
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