Dysfunction in the anterior cingulate cortex and the ventral tegmental area in relation to decision making and motivation in an animal model of schizophrenia

Abstract

Difficulties in decision-making and motivation can impact functional outcomes in schizophrenia. Two brain regions that play a role in decision-making and motivation are the ACC and VTA, with both showing dysfunction in the disease. In order to investigate this dysfunction in more detail we used the MIA animal model of schizophrenia, which models the development of schizophrenia and the associated brain abnormalities observed in human patients. The aim of this study was to investigate decision-making and motivation in the MIA model and whether any changes relate to deficits observed in schizophrenia. Additionally, we investigated if there was any dysfunction in neuronal activity within and between the ACC and VTA, and whether any abnormalities are related to any of the behavioural deficits observed. To these ends neuronal activity in the ACC and VTA was recorded whilst the MIA and control rats ran in a figure-eight maze that offered a choice between a high cost and high reward, or a low cost and low reward option. Halfway through each session the location of the choices reversed. We found that decision-making in the MIA rats was affected by memory deficits on the first trial of a session, with rats apparently failing to recall the configuration from the end of the previous session. Memory deficits or behavioural inflexibility also resulted in a lack of anticipatory choices prior to the reversal in the MIA rats. This reflected either a failure to recall the reversal or inability to adapt to the approaching reversal. Following the reversal, behavioural inflexibility resulted in the MIA rats continuing to select the arm that had previously contained the preferred choice post-reversal. We observed an increase in beta activity in the ACC including abnormal synchrony of ACC neurons to the beta activity throughout the task, which may link to the increased behavioural inflexibility of the MIA rats. At the decision point we observed abnormal ACC-VTA coherence in the delta frequency band immediately post-reversal when the impact of behavioural inflexibility was the greatest. The MIA rats also displayed increased vicarious trial and error, suggesting increased deliberative decision-making likely due to avolition or due to difficulties in mentally exploring possible outcomes because of memory deficits. An avolition explanation was supported as MIA rats had an increase in ACC neurons encoding the cost and low-cost choice, indicating an increased perception of cost and increased preference for the low-cost choice compared to controls, which would have reduced motivation. Additionally, a general decrease in theta activity in the VTA of the MIA rats suggests a decrease in the motivation signal. ACC neurons also showed abnormal synchrony to the VTA theta activity suggesting that the connectivity between the two regions is involved in this dysfunction. We therefore modelled difficulties in decision-making and motivation observed in schizophrenia and linked these deficits to dysfunction within and between the ACC and VTA, increasing and deepening our understanding of the potential neurological basis of these behavioural deficits in schizophrenia.