Functional heterogeneity in the prefrontal cortex of adult and developing marmosets: insight into the individual variation in depression and its symptoms

The overarching goal is to determine the functional heterogeneity within prefrontal cortex contributing to individual variation in the aetiology and treatment of key symptoms of major depressive disorder (MDD) including sadness, anhedonia (social and non-social), negatively biased decision making and lack of control/helplessness. Insights gained should facilitate refinement of individual diagnosis and treatment strategies. Key prefrontal regions in which altered activity is linked to MDD and its treatment will be targeted in a non-human primate, common marmosets. Specifically, acute chemogenetic activation/inactivation of these regions will determine (i) the relationship of the lateral orbitofrontal cortex to reward loss and disappointment/sadness, (ii) the contribution of the dorsolateral prefrontal cortex to conflict in decision making and negative bias, (iii) the involvement of the pregenual cingulate cortex in the ability to control environmental events. Behaviour and cardiovascular activity will be measured across multiple computerized cognitive tests and PET/functional MRI will assess distributed effects on circuit activity. With MDD onset associated with adolescence, acute regional interventions during adolescence will identify windows of perturbational vulnerability, whilst multi-parametric MRI will provide neurocircuit developmental insights. Foundational work on marmoset social development will establish novel toolsets for applying our approach in the social domain; highly relevant to MDD onset.