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Anxiety Model of Zebrafish & Behavioral Screening Assays

Anxiety Disorder Pathology

Anxiety is a neuropsychiatry condition, that mainly affects emotion. Neurotransmitters and hormones such as serotonin, norepinephrine, dopamine, and GABA among others play a key role in emotional homeostasis. Functional reduction or loss of these neurotransmitters leads to emotional instability, a part of which is anxiety. Emotional instability or mood instability could be due to variety of reasons like death of neurotransmitter producing cells (neurodegeneration), loss of neurotransmitter binding receptors, substance abuse, stress etc. or dysregulated neurocircuitry due to behavioural events. Therefore, anxiety is a multifaceted condition which mandates a carefully considered approach to creating animal models. Anxiety is classified by International Statistical Classification of Diseases and Related Health Problems as General anxiety disorder, Phobias, Social anxiety disorder, post-traumatic stress disorder, Panic disorder with/without agoraphobia, and obsessive-compulsive disorder. To replicate the neurocircuitry of events and the severity of anxiety as in humans’ different type of zebrafish models inducers are used in zebrafish.

Zebrafish as a validated model for Anxiety

Zebrafish is an established model for the neuronal therapeutic space. Several neuropathology and psychiatric conditions such as neurodegenerative diseases, memory, learning and fear have been modelled in zebrafish with highly significant outcomes and reproducible comparator performance. Moreover, zebrafish have been widely employed for behavioral toxicity assessments due to the sensitive nature of the animal. Behavioral assessments in zebrafish are able to capture a wide array of behavioral toxicity such as fear, anxiety, lack of response, freezing behavior, hyperactivity, aggressive movements etc. Key neurotransmitters responsible for emotional homeostasis in humans are also found in zebrafish at the same ratios. Neuroanatomy of brain regions implicated in causing anxiety in humans (amygdala, medial prefrontal cortex, hippocampus, Insular cortex) are the same regions responsible for anxiety circuitry in zebrafish, thus making zebrafish a highly relevant model to replicate anxiety events as in humans.

Anxiety Zebrafish Model Design for Therapeutic Strategies

Zebrafish models of anxiety are designed based on the classification of anxiety requirement as per the table below and accordingly induced

Inducer of Anxiety in Zebrafish

Type of Anxiety Classification

Social Isolation

Phobias, Social anxiety disorder

​Dark Isolation

General Anxiety disorder, Panic disorder

Paternal Cortisol Exposure

​Post- traumatic stress disorder (PTSD)

Long Term Predator Exposure

Obsessive-compulsive disorder

Anxiety Model - Discovery Strategies using Zebrafish

  • Serotonin and noradrenalin reuptake inhibitors (SNRIs) - 5-HT1A- and Noradrenaline transporters have been identified in zebrafish and SNRIs have shown rescue in zebrafish model of anxiety. Behavioral assessments can measure the level of rescue, and serotonin and norepinephrine levels can be measured by ELISA​

  • Monoamine Oxidase inhibitors MAOI - To assess MAOIs in zebrafish, a time course study can be plotted where post dosing of MAOIs, level of MAOI can be measured periodically in groups. Behavioral assessments can be run in parallel for correlations in anxiety rescue

  • CNS Depressants - CNS depressants can be measured by locomotion or mobility experiments, where evoke responses to stimuli and non-evoked responses can measure the level of CNS depressant to dosage.

  • Neurotransmitter modulators - In this strategy again the level of neurotransmitter can be measured by biochemistry, however brain activity measures can be done by a cognitive test or local field potential assay.

Anxiety Model - Endpoint Readouts

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