Dopamine modulation of neuronal function in the monkey prefrontal cortex

Abstract

We developed a brain slice preparation that allowed us to apply whole-cell recordings to examine the electrophysiological properties of identified synapses, neurons, and local circuits in the dorsolateral prefrontal cortex (DLPFC) of macaque monkeys. In this article, we summarize the results from some of our recent and current in vitro studies in the DLPFC with special emphasis on the modulatory effects of dopamine (DA) receptor activation on pyramidal and nonpyramidal cell function in superficial layers in DLPFC areas 46 and 9.

Introduction

In primates, the dorsolateral prefrontal cortex (DLPFC) is involved in the planning and execution of complex behaviors, many of which require working memory (i.e., the ability to actively maintain and manipulate information in order to guide behavior). Working memory is often assessed in delayed-response tasks, in which a delay is imposed between the presentation of a cue and the execution of a response that requires cue-related information [1]. During this delay period, monkey DLPFC neurons show sustained firing, which correlates with the accuracy of task performance. Furthermore, delay-related firing can be sustained even in the presence of distractors that disrupt delay activity in other regions of the brain. Therefore, delay activity of DLPFC neurons is considered a crucial element for the active maintenance of information in working memory [1].

In primates, the DLPFC has reciprocal connections with a wide range of neocortical and subcortical regions, suggesting that neurons in the DLPFC are strategically positioned to mediate the cross-modal and cross-temporal associations required for complex behavior. In addition to its unique extrinsic connectivity, the intrinsic connections in the DLPFC may play a special role for information storage during working memory tasks. Of particular interest are the long-range horizontal connections furnished by the axon collaterals of layers 2/3 pyramidal cells, which interconnect clusters of neurons located in the same layers [2], [3]. Long-range connections between clusters seem to target almost exclusively other pyramidal cells [4], in contrast to the local “within-cluster” connections made by pyramidal neurons, which contact pyramidal cells and GABAergic interneurons with similar frequencies [4]. These long-range connections are a potential substrate for reverberating activity through recurrent excitation, which could maintain persistent delay activity [5].

Input from mesencephalic dopamine (DA) cell groups is essential to the role of the DLPFC in working memory function. Either selective DA denervation or blockade of DA receptors significantly impairs behavioral performance in delayed-response tasks [6], [7]. In addition, electrophysiological studies in vivo show that delay activity is influenced by manipulations of DA receptor activation [8], [9] suggesting that DA signaling in DLPFC may stabilize delay-period activity [10]. However, to date, the cellular mechanisms by which DA affects neuronal function in the neocortex remain unclear.

Several lines of evidence suggest that both anatomy and function of the mesoprefrontal DA system differ significantly between the brains of primate and nonprimate species. Chief among these differences is the laminar distribution of DA fibers and DA receptors, which in monkey and human PFC are abundant in both deep and superficial layers (Fig. 4), but in the PFC of rats are abundant only in layers 5 and 6 [11], [12], [13]. Because superficial layers contain the majority of DLPFC neurons that provide output to and receive input from other neocortical regions, the influence of DA on intracortical communication might be qualitatively different in primates compared to rodents. All previous in vitro electrophysiological studies on the actions of DA in the PFC employed nonprimate animal models and assumed that findings from these studies can be generalized to the primate PFC. This assumption may be valid concerning the basic cellular and molecular mechanisms by which DA exerts its neuromodulatory actions (e.g., DA acts through G-protein coupled receptors whose structure is highly conserved across mammalian species). However, due to the differences in the organization of the neocortical microcircuits between rodents and primates [14], problems might arise regarding the interpretation of the DA effects at the network level. To help gain a better understanding of the functional architecture and the cellular mechanisms of DA modulation of neuronal activity, we developed a brain slice preparation from the DLPFC of macaque monkeys [15]. In this article, we describe results from our studies, which have explored the superficial layers of areas 46 and 9, and which focus on the effects that DA has on well-defined elements of the DLPFC microcircuitry.