The use of zebrafish to identify genes affecting working memory and age-related cognitive decline


Brock A. J, Sudwarts A., Brennan C. H. (2016). Neuroscience 2016 poster session - Executive Function: In Vivo Recording and Functional Study.

SBCS, Queen Mary, Univ. of London, London, United Kingdom

Abstract

Aim

To identify genes influencing cognitive performance (memory and learning, impulse control) using zebrafish as a model system.

Method

GBT Screen: We screened lines of mutant zebrafish at 3 months for performance in behavioral tasks that assess aspects of cognition. So far we have screened over 50 gene-break transposon (GBT) lines (n=4 for each line) as well as wild-type (n=20) in a 5-choice serial reaction time task (5-CSRTT) starting at the 3-month stage. The 5-CSRTT system is fully automated as designed by Parker et al. (2012).

Development of MTS system: In collaboration with Bill Budenburg (Zantiks Ltd, Cambridge, UK) we have developed an automated, scalable system for measuring a number of behaviors including matching-to-sample (MTS), a measure of memory. The system is designed along the lines of a ‘Skinner Box’ for zebrafish can currently be used to measure 2-5 choice discrimination as well as MTS. Stimuli are presented using a computer screen positioned beneath the holding tank.

Results

GBT Screen: We have identified several lines of interest that show significantly altered performance from controls. When measuring the mean number of correct responses in the task, 2 lines (p=0.03 & p=0.001) clustered to the right of the distribution. There were 2 lines (p=0.02 & p=0.05) showing faster response when assaying latency to approach the stimuli. When using trials to steady state as a measure of learning rate 2 line (p=0.03 & p=0.05) show faster learning rates and one line (p=0.01) slower. Work is ongoing to rescreen the siblings from these families and characterize the mutations involved.

Automated Operant system: Using this system, we have trained adult 4 month (at start) zebrafish to perform 3-choice discriminations to over 80% accuracy within 3 weeks, 5-choice discriminations to 70% accuracy within 5 weeks and 3-choice matching-to-sample to over 60% accuracy within 8 weeks.

Discussion: Recently a number of high profile publications have suggested that zebrafish can also be used to explore the genetics and aetiology of behavior including complex behavioral phenotypes associated with psychiatric disease. However, progress has been limited. This is partly due to the lack of an automated system that can be used for analysis of cognitive behaviors in large-scale genetic or pharmaceutical screens.

We demonstrate that in our old 5-CSRTT system using a population screen approach, differing lines can be shown to cluster on either side of a distribution curve, demonstrating the ability to pick out genes affecting aspects of cognition. By developing the new operant system which is capable of measuring MTS we will be able to screen current GBT lines for their performance in this task.