Regulation of synaptic plasticity in the mesocortical dopamine system

The mesocortical dopamine system is crucial for regulating goal-directed behavior. Changes in synaptic transmission in brain regions included in this system underlie modifications in cognitive flexibility, and the learning of salient contextual cues to efficiently navigate one’s environment. Chapter 1 of this thesis describes plasticity of dopamine neurons in the ventral tegmental area and how it contributes to reinforcement learning. Synaptic plasticity in several brain regions is modified by peptides associated with feeding and energy homeostasis. Leptin, an adipocyte derived cytokine, is able to modulate food and drug-seeking behaviors. In addition, dopamine signaling in the orbitofrontal cortex and its role in decision-making is also reviewed. Chapter 2 examines how leptin modifies synaptic transmission at excitatory synapses in the ventral tegmental area (VTA). Leptin caused a depression of evoked EPSCs mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and n-methyl-D-aspartate receptors (NMDARs). This effect was presynaptic in nature and required signaling through phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). Dopamine signaling in the orbitofrontal cortex (OFC) is important for adaptive decision-making in the face of salient events. In Chapter 3, we demonstrate how dopamine acts in the OFC to modify excitatory synaptic transmission mediated by NMDARs. In adult and juvenile rats, D1 receptor activation potentiated, while D2 receptor activation reduced evoked EPSCs in lateral OFC subregions. Additionally, we showed that dopamine has differential effects in juvenile versus adult rats, because a PLC-coupled dopamine receptor pathway potentiates EPSCs in juvenile rats but is not present in adult animals. Administration of SKF83959, a ligand for PLC-coupled dopamine receptors, potentiated NMDAR-mediated responses and facilitated performance on a task measuring cognitive flexibility in juvenile rats only. Chapter 4 discusses the results from the current experiments, and integrates possible ways that the actions of leptin in the VTA could influence dopamine signaling in the OFC. Future experiments to further investigate the precise mechanisms underlying the changes in synaptic transmission of the mesocortical dopamine system are also considered.Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofGraduat