ILMA · The interplay of learning and motivational systems in addictive behaviour

The interplay of learning and motivational systems in addictive behaviour

The aim of the project was to understand the interplay between learning and motivational systems influencing the behavioural choices of flies and the effect of addictive drugs on these systems. To understand this interaction, we focussed on the decision process itself. Decisions take time if a decision-maker needs to integrate and compare information, or ‘evidence’, in favour of or against each alternative before committing to a choice; a process referred to as evidence accumulation. If the evidence in favour of one choice is compelling, the commitment to that choice builds quickly and decision times are short. If, on the contrary, the evidence is conflicting, the decision develops slowly and decision times are prolonged. To test whether flies accumulate evidence during perceptual decision-making, we measured reaction times for olfactory discrimination. Flies were trained against a specific concentration of an odour by pairing its presentation with electric shock. The flies were then tested for their ability to discriminate between the reinforced concentration and a different concentration of the same odour. The difficulty of the task was titrated by varying the ratio of the odour concentrations to be discriminated: when two concentrations were close, the tasks were difficult. We found that as the task difficulty rose, reaction times increased and perceptual accuracy declined, in quantitative agreement with an evidence accumulation model of decision-making (Fig 1). Our next goal was to use this assay to gain mechanistic insights into the decision process. We performed a candidate screen and isolated mutations affecting the transcription factor FoxP. Flies carrying mutations in FoxP took longer than wild-type flies to form decisions of similar or reduced accuracy, especially in difficult tasks, consistent with an abnormally low evidence accumulation rate. A FoxP promoter fragment highlighted neurons with axonal projections into the gamma lobes and the cores of the alpha and beta lobes of the mushroom bodies (Fig 2). RNAi mediated knockdown of FoxP in alpha-beta core neurons, or the expression of an inwardly-rectifying potassium conductance within them, mimicked the decision-making phenotype of FoxP mutants (Fig 3). Thus, FoxP not only identifies a key anatomical substrate for decision-making but also a potential molecular handle on the integration process. This project thus puts us in a unique position to test how genetic and pharmacological perturbations of an integrator circuit affect a cognitive process that has many parallels with human decision-making. The neurobiology of addiction is an area that could directly benefit from our research. Drugs of abuse may alter the response criteria during evidence accumulation, thereby biasing a subject towards making fast but incorrect decisions.

Data: CORDIS, © European Union