A cellular and behavioral analysis of prefrontal cortical function and its modulation by dopamine

The activity of neurons in the prefrontal cortex (PFC) may underlie working memory processes in the brain. Both the performance of working memory tasks and the activity of PFC neurons are modulated by dopamine. The goal of the present thesis was to gain insight into the neural basis of working memory by studying the PFC, and the DA system in the PFC, from both a behavioral and cellular perspective. The functional contribution of the PFC to working memory processes in the rat was assessed in Chapter 2 of the present thesis using memory-based foraging tasks on an 8-arm radial maze. The results of these studies indicated that lidocaine-induced inactivations of the PFC selectively disrupted the ability to use mnemonic information to guide foraging, but not the ability to acquire or retain such information. The ability to use mnemonic information to guide foraging was also disrupted by microinjection of a D1 but not D2 receptor antagonist into the PFC. Chapters 3-5 investigated how PFC neurons process synaptic inputs to their dendrites to produce spike output. The intrinsic membrane properties and synaptic responses at the soma and dendrites of deep layer PFC pyramidal neurons were recorded using sharp intracellular or whole-cell patch-clamp techniques in a brain-slice preparation. Different passive and active membrane properties of the soma and dendrites of PFC neurons were observed. The distal dendrites of PFC neurons responded most effectively to strong, highly coincident synaptic inputs. Ca²⁺currents near the soma both amplified the effects of these inputs and modulated the spike output pattern. Spike output at the soma was also controlled by the interplay of slowly-inactivating Na⁺ and K⁺ currents. Chapter 6 investigated the modulation of PFC neurons by DA. DA or a D1 but not D2 receptor agonist increased the evoked firing of PFC neurons via a D1- mediated modulation of slowly-inactivating Na⁺ and K⁺ currents. Concurrently, D1 receptor activation reduced burst firing in PFC neurons, due to a attenuation of Ca²⁺ currents. D1 receptor activation also increased both GABA[sub A] IPSPs and NMDA EPSPs. The final chapter of this thesis integrated these data into a cellular model of PFC function and its modulation by DA. It is proposed that DA may tune PFC neurons such that they respond selectively to strong synchronized inputs from other cortical areas. In the presence of DA, working memory processes mediated by the PFC may be influenced selectively by stimuli of behavioral significance.Arts, Faculty ofPsychology, Department ofGraduat