Adolescent plasticity of the dopaminergic mesofrontal circuit: cellular mechanisms and behavioral roles

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Recent evidence suggests that many psychiatric disorders such as schizophrenia are developmental disorders characterized by complex alterations in neuronal circuits. Dopamine has long been recognized as a key player in psychiatric illness and many current therapeutic strategies for psychosis target the dopaminergic system. While many of these therapeutics effectively target delusions and hallucinations in patients, no effective therapies exist to manage the cognitive symptoms of illnesses such as schizophrenia. Research in both patients and animal models indicates that mesofrontal dopaminergic circuit abnormalities are involved in cognitive deficits in psychiatric illnesses. Prior work in our lab has identified a unique adolescent activity-dependent plasticity in the mesofrontal dopaminergic projections that is lacking in adult animals. However, the mechanisms behind this adolescent plasticity process remain unclear. Previous work and preliminary experiments in our lab demonstrate that ventral tegmental area activity elicits both presynaptic axonal bouton outgrowth and postsynaptic cortical neuronal activity. In Aim 1 I will further characterize the response of cortical excitatory and inhibitory neurons to mesofrontal activity and determine if cortical postsynaptic activity is necessary for mesofrontal presynaptic plasticity through opto/chemogenetic silencing of postsynaptic excitatory and inhibitory neurons. Microglia, the innate immune cells of the central nervous system, have also been identified as key participants in neuronal plasticity, development, and neurodevelopmental disorders. In Aim 2 I will determine if microglia respond to changes in dopaminergic activity and if microglia mediate mesofrontal dopaminergic plasticity. Finally, to elucidate the unknown role that mesofrontal neural activity plays in normal development, in Aim 3 I will perturb mesofrontal activity chemogenetically during adolescence and evaluate the impact on both frontal cortical activity and frontal cortical dependent behaviors. The results obtained from these complementary, but independent aims will provide key insights into adolescent dopaminergic system development. With an improved understanding of mesofrontal circuit development and function, new pathways for therapeutic intervention can be identified and tested in the context of neurodevelopmental psychiatric diseases.