First Advisor

Thomas, Mark P.

Document Type

Dissertation

Date Created

12-2017

Embargo Date

4-5-2020

Abstract

Executive functions (e.g. working memory [WM]) are known to be mediated by prefrontal cortical areas of the human brain which share homology with mouse medial prefrontal cortex (mPFC). Furthermore, it is well established that optimal dopaminergic input is required for proper WM function in the PFC. While it is well established that the mPFC receives inputs from several different brain areas, impinging on different compartmental regions of cells, it remains unknown how layer V pyramidal cells, the major output cells of the mPFC, integrate this information. Additionally, it remains unknown how dopamine modulates this integration by way of separate afferents and compartments within the PFC. A subset of studies presented here focus attention on the excitatory synaptic responses of layer V cells in response to compartmentalized stimulation (i.e. within the somatic region [layer V] or within the apical tufts [layer I]). Overall, these data suggest that dopamine, through D1 receptor (R) activation promotes local connectivity (primarily layer V to layer V connections) in the somatic region, while simultaneously inhibiting synaptic plasticity within the apical tufts through the suppression of NMDAR-mediated responses. Additionally, D2R activation had no effect on local layer V connectivity, but may play a role in regulating the signal-to-noise ratio in the apical tufts, by inhibiting low-frequency inputs and promoting inputs firing at high frequencies. Taken together, these results suggest that in the presence of normal dopamine levels local influences (i.e. environmental / "bottom-up") and plasticity will be promoted within layer V, while "top-down" or contextual information impinging on layer I is stabilized. Additional studies presented here focus attention on the excitatory synaptic responses, and modulation of dopamine, of layer V pyramids in response to inputs from the contralateral mPFC. These data suggest that D1R modulation enhances the ability of layer V cells to integrate information from the contralateral mPFC. In combination, these experiments provide insight into how normal dopaminergic receptor activation alters signal processing and integration properties of layer V cells within the mPFC and shed light on cellular mechanism disruptions in schizophrenia, a disorder characterized by dopaminergic dysregulation.

Extent

153 pages

Local Identifiers

Jackson_unco_0161D_10621

Rights Statement

Copyright is held by the author.

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