Role of dopamine in the maturation of prefrontal cortex and associated behaviors.

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The refinement of mature cognitive, motivational and social behaviors typically takes place during adolescence, and is linked to the protracted development of the prefrontal cortex (PFC). Among neural inputs to the PFC, the mesofrontal dopamine (DA) system is interesting as DAergic afferents peak when key organizational events are taking place in the PFC. DAergic signaling, besides its acute effects on cortical excitatory and inhibitory neuron excitability, also mediates synaptic remodeling and long-term plasticity. While a large body of literature exists on the role of adult DA system, very little is known of the long-term consequences of early dysregulated DA homeostasis on the development of prefrontal networks and associated behaviors. To study the effects of disruption in DA homeostasis, we are using the cre-inducible DREADD (designer receptors activated by designer drugs) pharmacogenetic system in mice to remotely silence or stimulate the mid-brain DA neurons up to several hours, reversibly and at defined developmental periods. The method involves adeno-associated virus (AAV)-mediated expression of genetically engineered hM3Dq (for neuronal activation) or hM4Di (for inhibition) in DA transporter (DAT)-cre mice. The receptors are stimulated by a synthetic (and otherwise physiologically inert) drug clozapine-N-oxide (CNO). Our preliminary data using the viral vector with hM3Dq shows that mid-adolescence sub-chronic activation of ventral tegmental area (VTA) neurons led to a marked increase in novelty-induced locomotor activity and deficits in a task of temporal order memory that is linked to the activity of PFC circuits. In the proposed research programme, we want to systematically examine post-adolescent developmental trajectory of PFC-linked behaviors such as locomotion, PPI, anxiety, social interaction, and social and working memories in mice with sub-chronic adolescent stimulation of VTA DA neurons using the pharmacogenetic system. We have previous experience with the assessment of behaviors in rats and mice of different ages and required equipment is available in our laboratory or the Douglas Neurophenotyping Centre. We will also longitudinally assess cortical gray matter development and synaptic pruning in the PFC using structural magnetic resonance imaging (MRI) and histological techniques. Possible mechanisms that may mediate the effects of DA stimulation will be studied, e.g., the role of different DA receptors and intracellular signaling pathways. Future studies will similarly examine the effects of adolescent DA inhibition on brain and behavior, as well as the effects of early adolescent and neonatal DA manipulations. We believe that these studies will contribute significantly to our understanding of regulatory mechanisms that participate in the transition from adolescent to adult behavior.