Dopamine's Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders

Abstract

The prefrontal cortex (PFC) elaborates and differentiates in primates, and there is a corresponding elaboration in cortical dopamine (DA). DA cells that fire to both aversive and rewarding stimuli likely project to the dorsolateral PFC (dlPFC), signaling a salient event. Since 1979, we have known that DA has an essential influence on dlPFC working memory functions. DA has differing effects via D1 (D1R) versus D2 receptor (D2R) families. D1R are concentrated on dendritic spines, and D1/5R stimulation produces an inverted U-shaped dose response on visuospatial working memory performance and Delay cell firing, the neurons that generate representations of visual space. Optimal levels of D1R stimulation gate out "noise," whereas higher levels, e.g., during stress, suppress Delay cell firing. These effects likely involve hyperpolarization-activated cyclic nucleotide-gated channel opening, activation of GABA interneurons, and reduced glutamate release. Dysregulation of D1R has been related to cognitive deficits in schizophrenia, and there is a need for new, lower-affinity D1R agonists that may better mimic endogenous DA to enhance mental representations and improve cognition. In contrast to D1R, D2R are primarily localized on layer V pyramidal cell dendrites, and D2/3R stimulation speeds and magnifies the firing of Response cells, including Response Feedback cells. Altered firing of Feedback neurons may relate to positive symptoms in schizophrenia. Emerging research suggests that DA may have similar effects in the ventrolateral PFC and frontal eye fields. Research on the orbital PFC in monkeys is just beginning and could be a key area for future discoveries.

Fig. 1.

The DA innervation of the primate PFC. (A) Dark-field microscopy of the extensive DA axonal projections in four PFC regions of the rhesus monkey brain. Note the relatively delicate innervation of the dlPFC (from Williams and Goldman-Rakic, 1993). (B) The PFC regions sectioned in (A), color-coded to indicate the DA cell groups in the midbrain (C and D) that project to the corresponding PFC region. (C and D) DA cell groups (A8, A9, A10) in the rostral (C) and caudal (D) midbrain project to PFC. In general, laterally localized neurons (blue circles) project to dorsal and lateral PFC, whereas the more medially localized neurons (yellow circles) project to the ventromedial PFC. However, there are exceptions. DSCP, decussation of the superior cerebellar peduncle; IL, infralimbic; IP, interpeduncular nucleus; PL, prelimbic; RN, red nucleus; SNc [shaded area in (C)], substantia nigra pars compacta. (B–D) Adapted from Williams and Goldman-Rakic (1998).

Fig. 2.

The dlPFC microcircuits underlying spatial working memory as discovered by Goldman-Rakic. A schematized figure illustrating a simplified version of the neuronal microcircuitry thought to contribute to spatial working memory. The dlPFC receives DA inputs to layers I–III and V–VI, likely from DA “salience cells” that respond to aversive as well as rewarding stimuli. dlPFC Delay cells generate persistent representations of visual spatial position across the delay epoch and are thought to be concentrated in deep layer III (and possibly superficial layer V), whereas Response-related cells are thought to be concentrated in layer V. The persistent firing of Delay cells across the delay epoch in a spatial working memory task is thought to arise from recurrent excitation among pyramidal cells with similar spatial tuning. dlPFC neurons receive highly processed visuospatial information from area 7 of the parietal association cortex. Pyramidal cells in deep layer III interconnect on spines via NMDAR synapses, including those with NR2B subunits. The spatial tuning of these neurons is enhanced by lateral inhibition from GABAergic interneurons. Delay cells are modulated by DA D1/5R, but not D2/3R stimulation. D1R colocalize with HCN channels in spines of deep layer III, where they contribute to the sculpting and suppressive actions of D1/5R stimulation. In contrast D5R are concentrated in dendrites and associate with internal calcium stores, whereas D4R are concentrated on interneurons. In contrast to Delay cells, Response-related cells are modulated by D2/3R but not D1/5R stimulation. Response cells fire either just before the saccadic motor response (presaccadic) or during or just after the response (postsaccadic); these cells are very reliant on AMPAR as well as NMDAR. Post-saccadic Response cells likely receive and respond to feedback regarding the motor response (corollary discharge). Both types of Response-related cells show increased and speeded firing with D2/3R stimulation. D2R are localized in pyramidal cell dendrites where they may modulate inhibitory influences (see Fig. 4). Pyramidal cells in layer V often have HCN channels concentrated in their distal apical dendrites; however, the role of HCN channels in Response cell firing is not known. See Goldman-Rakic (1995) for more in-depth discussion of dlPFC microcircuitry.

Fig. 3.

DA D1R powerfully influence Delay cell firing in dlPFC. (A) D1R and HCN channels colocalize in spines in deep layer III of the monkey dlPFC. This paired image was edited to facilitate visualization of the immunoperoxidase label for D1R. Yellow arrowheads point to D1R on the extrasynaptic and perisynaptic spine membrane and within the synapse per se (between arrows). Red arrowhead points to HCN1 channel subunits visualized with immunogold. Scale bar, 100 nm. (B) A schematic illustration of the DA D1R inverted U influence on the “memory fields” of dlPFC Delay cells. Under optimal arousal conditions, Delay cells generate persistent representations of visual space, displaying high rates of firing (orange-red) to the memory of one spatial location and low rates of firing (blue) to the memory of all other spatial locations. Low levels of D1R stimulation appear to be excitatory, e.g., phosphorylating NMDAR to increase their trafficking into the synapse. This can produce noisy firing for all directions, as represented by the generalized green-orange coloring of the memory field. With optimal levels of D1R stimulation, there are additional sculpting actions, gating out “noise.” This may involve opening of HCN channels, enhancement of lateral inhibition, and possibly selective reductions in glutamate release. At still higher levels of D1R stimulation as occurs during stress, neuronal firing is generally suppressed, and the neuron is unable to generate persistent representations of visual space.

Fig. 4.

DA D2R excite Response cells in dlPFC. (A) D2R localization in a high-order pyramidal cell dendrite in monkey dlPFC. The receptor (arrowhead) is captured at the synaptic membrane (double arrowheads). (B) RGS4 is typically found in high-order pyramidal dendrites in association with synapses (arrow) to regulate G receptor signaling within the synapse (double arrowheads). Note how this pattern of localization corresponds to that shown for the D2R in (A). Further research is needed to establish whether RGS4 inhibits D2R signaling in primate dlPFC. (C) Stimulation of D2R in dlPFC by iontophoresis of quinpirole increases the amplitude and speeds the firing of Response cells in monkeys performing a visuospatial working memory task. In postsaccadic Response cells such as this one, neuronal firing likely represents feedback regarding the motor response (“corollary discharge”). Alterations in the timing and magnitude of this feedback may have important yet unexplored ramifications for cognitive function.