Interactive reportD1 receptors in prefrontal cells and circuits
Introduction
A worthy goal of systems neuroscience is to dissect the cellular and circuit basis of behavior in order to extend the insights gained from the study of normal brain organization in animal models to an understanding of a clinical disorder. We have been employing this strategy to elucidate the organic basis of the cardinal symptoms of schizophrenia, including the thought process in this disorder. Our studies are based on the hypothesis that many features of schizophrenia represent a failure in the neural mechanisms by which prefrontal cortex stores and processes information in working memory 1, 2. From the broadest perspective, working memory is a system of operations for processing information in real time, i.e., on a moment to moment basis, and even subtle deficiencies in the machinery of working memory can mean substantial deficits in ideation, reasoning and planning such as are observed in psychosis [2]. Disturbances in the finely tuned mechanisms of temporal integration that are essential to working memory may also be at the core of impairments which are less obviously cognitive, such as smooth pursuit eye tracking and pre-pulse inhibition.
In the past decade, major advances have been made in our capacity to decipher the elemental basis of working memory processes as they operate in the prefrontal cortex of macaque monkeys. We and others have been able to characterize the functional properties of prefrontal neurons as they are specialized for particular operations in working memory such as encoding a specific stimulus, maintaining it `on line' and directing an appropriate memory-guided response. These studies have shown that prefrontal neurons are remarkably content specific, i.e., individual neurons encode and transiently store specific items of information, such as the location of an object 3, 4, the direction of a prior response [5], the identity of objects or faces 6, 7and the identity of voices and sounds [58]. These prefrontal neurons and the mechanisms which endow them with the capacity to represent a stimulus in its absence, have become a major focus of our interest. In this chapter, we describe our efforts to understand the pyramidal and nonpyramidal cells of the prefrontal cortex, the area of the brain most associated with the working memory functions of the brain. We also address the circuit and receptor mechanisms which regulate pyramidal and nonpyramidal cell excitability in vivo. Specifically, we review our studies on the dopamine modulation of working memory circuits. This work may seem far afield from the clinical disorder of schizophrenia, but we hope to demonstrate that a connection may exist between the disposition of neurotransmitter receptors in individual neurons and behavioral symptoms, and that such a connection may illuminate the biological basis of this disease.
Section snippets
Dopamine and cognition
Cognitive symptoms have been associated with dopamine dysregulation in numerous diseases including Huntington's disease [8], schizophrenia [9], depression [10], drug addiction [11], and Parkinson's Disease [12]as well as in normal aging [13]. This neurotransmitter has been linked to a wide variety of functions including motivation, reward, affect and movement, all of which could affect performance on cognitive tasks without affecting the brain's information processing systems per se.
Dopamine modulation of mnemonic function in prefrontal neurons
The cellular basis of receptive field properties is among the most challenging issues in the study of higher cortical function. To date, neurotransmitter-specific actions on cortical neurons have been confined largely to examination of in vitro systems. Now, very recently, we have developed the methods to analyze the pharmacological actions of drugs on neurons as they are engaged in cognitive processes in awake behaving animals. With this method we have shown that the `memory fields' of
The D1 receptor in pyramidal neurons
A major theme in cortical physiology is that the receptive field of a pyramidal neuron is established by afferent inputs, including its lateral inhibitory input. By extrapolation from estimates made on hippocampal pyramidal cells, the cortical pyramidal neuron can be assumed to integrate literally thousands of afferent inputs and, through its efferent projection, control movement and affect. A full understanding of the functional capacity of even a single pyramidal cell requires knowledge not
D1 mechanisms in interneurons
Given the microcircuitry of the prefrontal cortex, it is obvious that interneurons must be as integral to the machinery of cognitive function as are projection neurons. Indeed, recent studies in our laboratory have revealed that interneurons have `memory fields' just as do pyramidal neurons. We have recently discovered that the memory fields of interneurons mirror that of their nearest neighbor pyramidal neurons, i.e., their preferred direction of firing in a spatial task is often very similar
Feedforward inhibition model of dopamine action vis a vis cognitive circuitry
We have recently suggested a circuit model to explain the biphasic action of D1 receptor stimulation on working memory performance 49, 50, and neuronal delay period firing [16]which focuses on the interactions between pyramidal and nonpyramidal neurons. The essence of this model is that D1 receptor stimulation enhances excitatory inputs to both pyramidal cells and interneurons, but this enhancement is more effective on pyramidal cells. With this arrangement, increasing levels of dopamine
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