title: Dopamine-mediated stabilization of delay-period activity in a network model of prefrontal cortex.
abstract: The prefrontal cortex (PFC) is critically involved in working memory, which underlies memory-guided, goal-directed behavior. During working-memory tasks, PFC neurons exhibit sustained elevated activity, which may reflect the active holding of goal-related information or the preparation of forthcoming actions. Dopamine via the D1 receptor strongly modulates both this sustained (delay-period) activity and behavioral performance in working-memory tasks. However, the function of dopamine during delay-period activity and the underlying neural mechanisms are only poorly understood. Recently we proposed that dopamine might stabilize active neural representations in PFC circuits during tasks involving working memory and render them robust against interfering stimuli and noise. To further test this idea and to examine the dopamine-modulated ionic currents that could give rise to increased stability of neural representations, we developed a network model of the PFC consisting of multicompartment neurons equipped with Hodgkin-Huxley-like channel kinetics that could reproduce in vitro whole cell and in vivo recordings from PFC neurons. Dopaminergic effects on intrinsic ionic and synaptic conductances were implemented in the model based on in vitro data. Simulated dopamine strongly enhanced high, delay-type activity but not low, spontaneous activity in the model network. Furthermore the strength of an afferent stimulation needed to disrupt delay-type activity increased with the magnitude of the dopamine-induced shifts in network parameters, making the currently active representation much more stable. Stability could be increased by dopamine-induced enhancements of the persistent Na(+) and N-methyl-D-aspartate (NMDA) conductances. Stability also was enhanced by a reduction in AMPA conductances. The increase in GABA(A) conductances that occurs after stimulation of dopaminergic D1 receptors was necessary in this context to prevent uncontrolled, spontaneous switches into high-activity states (i.e., spontaneous activation of task-irrelevant representations). In conclusion, the dopamine-induced changes in the biophysical properties of intrinsic ionic and synaptic conductances conjointly acted to highly increase stability of activated representations in PFC networks and at the same time retain control over network behavior and thus preserve its ability to adequately respond to task-related stimuli. Predictions of the model can be tested in vivo by locally applying specific D1 receptor, NMDA, or GABA(A) antagonists while recording from PFC neurons in delayed reaction-type tasks with interfering stimuli.
authors.affiliation: Computational Neurobiology Laboratory, Howard Hughes Medical Institute, Salk Institute, La Jolla 92037, California.
authors.forename: D
authors.initials: D
authors.lastname: Durstewitz
authors.forename: J K
authors.initials: JK
authors.lastname: Seamans
authors.forename: T J
authors.initials: TJ
authors.lastname: Sejnowski
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology; D004298:Dopamine / Q000502:physiology*; D007395:Interneurons / Q000502:physiology; D015640:Ion Channel Gating / Q000502:physiology; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D008959:Models, Neurological; D016571:Neural Networks, Computer; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D017397:Prefrontal Cortex / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D015222:Sodium Channels / Q000502:physiology
chemical_list: D015220:Calcium Channels; D015221:Potassium Channels; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D015222:Sodium Channels; D011188:Potassium; D002118:Calcium; D004298:Dopamine