PROBING EFFECTS OF ADHD GENETIC RISK FACTORS AND EARLY STRESS EXPERIENCE ON THE DYNAMICS OF EXPLORATION AND EXPLOITATION

A rising concern for global mental health, attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with childhood-onset, impacting attention and motor regulation. Multiple genetic and environmental risk factors have been identified, yet how they act in combination during development to generate behavioural deficits remains unknown.
Here, we leverage the genetic tractability and high-throughput potential of the zebrafish to examine the individual and combinatorial effect of genetic and environmental risk factors on behaviour. We selected two ADHD risk genes with confirmed phenotypes in animal models and revealed their brain-wide expression across developmental stages using hybridization chain reaction. To model genetic risk factors, we generate single and double CRISPR knockouts for these genes. We complement our panel with an early chronic stress paradigm to model environmental risk factors. To assess behavioural changes reflecting attention and motor dysregulation, we opted for investigating exploration–exploitation trade-offs, shown to be biased towards exploration in human ADHD patients. We will thus record hour-long hunting behaviour of zebrafish larvae, known to show switching between exploration and exploitation states. To unbiasedly quantify alterations in exploration exploitation dynamics, we employ a method inspired by dynamical systems theory to analyse tracked behaviour. Applying the method on a published dataset of hunting larval zebrafish confirmed the natural emergence of exploration and exploitation states and revealed faster-timescale substates. Together, our approach allows us to find convergent effects of multiple ADHD risk factors on exploration exploitation dynamics, motivating further studies aimed at the neuronal basis of observed behavioural changes.