Role of dopamine in adolescent maturation of prefrontal cortical circuits and associated behaviors

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Adolescence, an age span roughly ranging from 12-18 years in humans and 4-8 weeks in rodents, is a critical period in life when contours of adult decision-making, cognitive control and reward-related behaviors typically take place. Among brain circuits, the prefrontal cortex (PFC) and its connectivity with the striatum critically support these behaviors. Developmental processes within the PFC and striatum are believed to be linked to progressive changes lasting till late adolescent/early adult ages. Interestingly, midbrain dopamine (DA) inputs, that are particularly prominent in the PFC and the basal ganglia, peak around adolescence. Due to the parallel between the development of DA innervation and cortical/striatal development, it has been suggested that adolescent DA may play a role in the maturation of behaviors linked to the PFC and striatum. However, at present, very little is known of the mechanisms by which activity of the midbrain DA neurons of the substantia nigra/ventral tegmental area (SN/VTA) orchestrate neuroadaptations in the PFC and striatum. The goal of our research programme is to examine whether and how the developmental homeostasis of DA transmission affects the refinement of neural circuits leading to characteristic adult behaviors. We hypothesize that DA regulates the maturation of PFC and cortico-striatal circuit by affecting the development of dendritic spines, synaptic pruning and differentiation of neurons in the PFC and striatum. We will use an innovative pharmacogenetic system in mice to silence or overstimulate midbrain DA neurons reversibly at defined developmental periods in order to study its long-term consequences. The method involves AAV virus-mediated expression of Cre dependent DREADD (designer receptor activated by designer drug) in the midbrain DA neurons of transgenic DA transporter-Cre mice. Using this system, the goal of the present proposal is to address the questions: (1) Will excess DA neuronal activity during adolescence alter motor, cognitive, social and reward-related behaviors of mice? (2) What is the impact of excess DA activity on the developmental trajectory of the brain monitored by magnetic resonance imaging (MRI)? We will also study the morphological and functional development of neurons using Golgi-Cox staining and immunostaining. (3) What are the mechanisms that mediate the effects of adolescent DA manipulation? We will examine the levels of cytokines and microglia cells that play a critical role in synaptic pruning during adolescence. We will also examine the development of inhibitory interneurons, specifically the parvalbumin expressing GABA neurons. (4) We want to investigate whether DA D1-like or D2-like receptors mediate the long-term neuronal and behavioral changes induced by adolescent DA hyperactivity. We expect that our studies will to fill an important gap in knowledge regarding the role of neuromodulators in fundamental processes of brain development.