Regional and cellular fractionation of working memory - PubMed (original) (raw)

Review

Regional and cellular fractionation of working memory

P S Goldman-Rakic. Proc Natl Acad Sci U S A. 1996.

Abstract

This chapter recounts efforts to dissect the cellular and circuit basis of a memory system in the primate cortex with the goal of extending the insights gained from the study of normal brain organization in animal models to an understanding of human cognition and related memory disorders. Primates and humans have developed an extraordinary capacity to process information "on line," a capacity that is widely considered to underlay comprehension, thinking, and so-called executive functions. Understanding the interactions between the major cellular constituents of cortical circuits-pyramidal and nonpyramidal cells-is considered a necessary step in unraveling the cellular mechanisms subserving working memory mechanisms and, ultimately, cognitive processes. Evidence from a variety of sources is accumulating to indicate that dopamine has a major role in regulating the excitability of the cortical circuitry upon which the working memory function of prefrontal cortex depends. Here, I describe several direct and indirect intercellular mechanisms for modulating working memory function in prefrontal cortex based on the localization of dopamine receptors on the distal dendrites and spines of pyramidal cells and on interneurons in the prefrontal cortex. Interactions between monoamines and a compromised cortical circuitry may hold the key to understanding the variety of memory disorders associated with aging and disease.

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Figures

Figure 1

Repeated recordings from one neuron during the many trials over which a monkey performed an oculomotor delayed-response working memory task. Over the course of a testing session, the monkey’s ability to make correct memory-guided responses is tested approximately 10–12 times per target location. The neuron’s response is collated over all the trials for a given target location (e.g., 135°, 45°, etc.) as a histogram of the average response per unit time for that location. The activity is shown in relation to the timed events in the task (C, cue; D, delay; R, response) for each target location. In the example shown, the neuron’s rate of discharge increases maximally during the delay when the target at 135° location is no longer present and the monkey is simply maintaining fixation; the neuronal activation is maintained for more than 5000 ms until the response is made. Delay-period activity is also observed during the delay period for the 90° and 180° targets but is less than that exhibited for the neuron’s “best direction,” indicating that the neuron’s tuning is rather broad. However, this neuron codes the same location trial after trial; different neurons (data not shown) code different locations and have different degrees of tuning in working memory. [Reproduced with permission from ref. (Copyright 1989, The American Physiological Society).]

Figure 2

Prefrontal neurons in the region of the principal sulcus exhibit a variety of patterns of activation during the oculomotor tasks. Some respond phasically to the occurrence of a target (Top); some respond in relation to the delay (Middle); and some are activated in relation to the occurrence of a response (Bottom). In all cases, neuronal activity is time-locked to the events of the task and is spatially tuned. The class of neurons with delay period activity is the focus of this essay. (Figure based on refs. , , and .)

Figure 3

(A) Diagram of a basic pyramidal–interneuronal interaction in cerebral cortex; pyramidal glutamatergic neurons innervate the dendrites of GABAergic interneurons; subsets of GABAergic neurons terminate on various segments of the pyramidal cell. In the diagram, I illustrate a basket cell subtype the terminals of which contact the cell bodies of pyramidal neurons. (B) Action potentials indicative of interneurons (Upper) and pyramidal neurons (Lower) used to define functionally characterized cells in C. (C) Inverse responses of fast-spiking (FS161) and regular-spiking (RS162) pairs of neurons recorded approximately 200 μm apart. Bin width = 40 ms; 10 trials per direction; the vector plot of tuning for the FS161/RS162 pair of neurons for 8 target locations shows that FS161 responded maximally to a stimulus presented 13° above the fixation point (at the 90° location), whereas RS162 responded maximally to stimuli presented at the 270° location below the fixation point. Firing rates were normalized so that the maximum vector length is 100%. The circles represent spontaneous firing rates. [Reproduced with permission from ref. (Copyright 1994, The National Academy of Sciences).]

Figure 4

Summary diagram illustrating the patterns of local horizontal intrinsic connections in prefrontal cortex (Walker’s areas 46 and 9) as retrogradely labeled with chholera toxin B subunit. Labeled neurons in layer IIIc in particular form spaced clusters of pyramidal cells with presumed similar best directions. [Reproduced with permission from ref. (Copyright 1995, Wiley–Liss, Inc.).]

Figure 5

A model of working memory circuitry consisting of modules or clusters of tuned pyramidal neurons (e.g., 90°, 180°, and 270°) arrayed by target location and directly interconnected with each other by their local excitatory axon collaterals (long, thin, curved arrows). Clusters of pyramidal neurons with like best directions are interconnected in a manner similar to isoorientation columns in visual cortex. Two inhibitory interneurons (circles, presumed basket cells in the diagram) provide the reciprocal interconnections (arrows) between pyramidal cells with opposite best directions that could explain the opponent memory fields observed by Funahashi et al. (17). For simplicity, only the 90° to 270° and 270° to 90° ensembles are illustrated. For now, the organization of the pyramidal cells with particular memory fields is hypothetical, as is the reciprocity of the excitatory–inhibitory units. Further analysis of these local circuits is essential for analyzing the neural substrates of working memory. [Reproduced with permission from ref. (Copyright 1995, Cell Press).]

Figure 6

Diagram illustrating two generic synaptic arrangements involving dopamine and major dopamine receptor subtypes CD1, D4, and D5 in the synaptic circuitry of the prefrontal cortex. (Left) Direct mode of pyramidal cell modulation; dopamine (DA) afferents (in red) labeled with a dopamine-specific antibody terminate on the distal dendrites (and spines) of a pyramidal cell (black triangles) in the prefrontal cortex; for further details see Goldman-Rakic et al. (60). vta, Ventral tagmental area (where dopamine cell bodies reside). (Right) Indirect mode of pyramidal cell modulation via dopamine modulation of GABAergic interneurons (blue circle) (81).

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Regional and cellular fractionation of working memory - PubMed (original) (raw)