Neurons in Monkey Prefrontal Cortex Whose Activity Tracks the Progress of a Three-Step Self-Ordered Task

2004 ◽  
Vol 92 (3) ◽  
pp. 1524-1535 ◽  
Author(s):  
Ryohei P. Hasegawa ◽  
Ari M. Blitz ◽  
Michael E. Goldberg
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Rhesus Monkeys ◽  
Task Difficulty ◽  
Convincing Evidence ◽  
The Self ◽  
Saccade Target ◽  
Control Task ◽  
The Third ◽  
Monkey Prefrontal Cortex

The self-ordered task is a powerful tool for the analysis of dorsal prefrontal deficits. Each trial consists of a number of steps, and subjects must remember their choices in previous steps. The task becomes more difficult as the number of objects to be remembered increases. We recorded the activity of 156 neurons in the mid-dorsal prefrontal cortex of two rhesus monkeys performing an oculomotor version of the task. Although the task requires working memory, there was no convincing evidence for activity selective for the working memory of the objects that the monkey had to remember. Instead, nearly one-half of neurons (47%, 74/156) showed activity that was modulated according to the step of the task in any one or more task periods. Although the monkey's reward also increased with step, the neurons exhibited little or no step modulation in a reward control task in which reward increased without a concurrent increase in task difficulty. The activity of some neurons was also selective for the location of saccade target that the monkey voluntarily chose. Neurons showed less step modulation in error trials, and there was no increase between the second and third step responses on trials in which the error was on the third step. These results suggest that the mid-dorsal prefrontal cortex contributes to the self-ordered task, not by providing an object working memory signal, but by regulating some general aspect of the performance in the difficult task.

The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task

1994 ◽  
Vol 71 (2) ◽  
pp. 515-528 ◽  
Author(s):  
T. Sawaguchi ◽  
P. S. Goldman-Rakic
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Injection Site ◽  
Target Location ◽  
Dopamine Antagonists ◽  
Dopamine Antagonist ◽  
Delayed Response ◽  
Intracerebral Injection ◽  
Control Task

1. To examine the role of dopamine receptors in the prefrontal cortex (PFC) on working memory, we injected dopamine antagonists (SCH23390, SCH39166, haloperidol, sulpiride, and raclopride) locally into the dorsolateral PFC in two monkeys trained to perform an oculomotor delayed-response (ODR) task. In the ODR task, monkeys fixate a central spot on a cathode ray tube (CRT) monitor while a visual cue is briefly (300 ms) presented in one of several peripheral locations in the visual field. After a delay of 1.5-6 s, the fixation spot is turned off, instructing the monkey to move its eyes to the target location that had been indicated by the visuospatial cue before the delay. Each monkey also performed a control task in which the cue remained on during the delay period. In this task the monkey's response was sensory rather than memory guided. 2. Local intracerebral injection of the selective dopamine antagonists SCH23390 (10-80 micrograms) and SCH39166 (1-5 micrograms) and/or the nonselective dopamine antagonist haloperidol (10-100 micrograms) induced deficits in ODR task performance at a total of 22 sites in the dorsolateral PFC. The deficit was characterized by a decrease in the accuracy of the memory-guided saccade as well as an increase in the latency of the response. The deficit usually appeared within 1-3 min after the injection, reached a peak at 20-40 min, and recovered at 60-90 min. 3. Performance change was restricted to a few specific target locations, which varied with the injection site and were most often contralateral to the injection site. 4. The degree of impairment in the ODR task occasioned by the injection of the dopamine antagonists was sensitive to the duration of delay; longer delays were associated with larger decreases in the accuracy and delayed onset of the memory-guided saccade. 5. The deficit was dose dependent; higher doses induced larger errors and increases in the onset of the memory-guided saccade. 6. Dopamine antagonists did not affect performance on the control task, which required the same eye movements but was sensory guided. Thus, in the same experimental session in which ODR performance was impaired, the accuracy and the latency of the sensory-guided saccades were normal for every target location.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Chemogenetic actuator drugs impair prefrontal cortex-dependent working memory in rhesus monkeys

2019 ◽  
Author(s):  
Nicholas A. Upright ◽  
Mark G. Baxter
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Rhesus Monkeys ◽  
Memory Performance ◽  
Memory Function ◽  
Muscarinic Acetylcholine Receptor ◽  
Designer Drugs ◽  
Delayed Response ◽  
Response Task ◽  
Delayed Response Task

AbstractThe most common chemogenetic neuromodulatory system, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), uses a non-endogenous actuator ligand to activate a modified muscarinic acetylcholine receptor that is no longer sensitive to acetylcholine. It is crucial in studies using these systems to test the potential effects of DREADD actuators prior to any DREADD transduction, so that effects of DREADDs can be attributed to the chemogenetic system rather than the actuator drug. We investigated working memory performance after injections of three DREADD agonists, clozapine, olanzapine, and deschloroclozapine, in male rhesus monkeys tested in a spatial delayed response task. Performance at 0.1 mg/kg clozapine and 0.1 mg/kg deschloroclozapine did not differ from mean performance after vehicle in any of the four subjects. Administration of 0.2 mg/kg clozapine impaired working memory function in three of the four monkeys. Two monkeys were impaired after administration of 0.1 mg/kg olanzapine and two monkeys were impaired after the 0.3 mg/kg dose of deschloroclozapine. We speculate that the unique neuropharmacology of prefrontal cortex function makes the primate prefrontal cortex especially vulnerable to off-target effects of DREADD actuator drugs with affinity for endogenous monoaminergic receptor systems. These findings underscore the importance of within-subject controls for DREADD actuator drugs to confirm that effects following DREADD receptor transduction are not due to the actuator drug itself, as well as validating the behavioral pharmacology of DREADD actuator drugs in the specific tasks under study.Significance StatementChemogenetic technologies, such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), allow for precise and remote manipulation of neuronal circuits. In the present study, we tested monkeys in a spatial delayed response task after injections of three actuator drugs – clozapine, olanzapine, and deschloroclozapine. We found that monkeys showed significant working memory impairments after 0.2 mg/kg clozapine, 0.1 mg/kg olanzapine, and 0.3 mg/kg deschloroclozapine compared to vehicle performance. In monkeys that showed impairments, these deficits were particularly apparent at longer delay periods. It is imperative to validate the drugs and dosages in the particular behavioral test to ensure any behavior after DREADD transduction can be attributed to activation of the receptors and not administration of the actuator drug itself.

Increase of Extracellular Dopamine in Primate Prefrontal Cortex During a Working Memory Task

1997 ◽  
Vol 78 (5) ◽  
pp. 2795-2798 ◽  
Author(s):  
Masataka Watanabe ◽  
Tohru Kodama ◽  
Kazuo Hikosaka
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Cognitive Processes ◽  
Memory Task ◽  
Dopamine Level ◽  
Control Task ◽  
Extracellular Dopamine ◽  
Delayed Alternation ◽  
Delayed Alternation Task ◽  
Alternation Task

Watanabe, Masataka, Tohru Kodama, and Kazuo Hikosaka. Increase of extracellular dopamine in primate prefrontal cortex during a working memory task. J. Neurophysiol. 78: 2795–2798, 1997. The dopamine innervation of the prefrontal cortex is involved importantly in cognitive processes, such as tested in working memory tasks. However, there have been no studies directly investigating prefrontal dopamine levels in relation to cognitive processes. We measured frontal extracellular dopamine concentration using in vivo microdialysis in monkeys performing in a delayed alternation task as a typical working memory paradigm and in a sensory-guided control task. We observed a significant increase in dopamine level in the delayed alternation task as compared both with the sensory-guided control task and the basal resting level. The increase was seen in the dorsolateral prefrontal but not in the arcuate or orbitofrontal areas. The increase appeared to reflect the working memory component of the task and was observed mainly in the lip areas of principal sulcus. Although there was no significant difference in dopamine level between delayed alternation and sensory-guided control tasks in the premotor area, significant increases in dopamine concentration were observed during both tasks as compared with the basal resting level, indicating the importance of premotor dopamine for the motor response itself.

scholarly journals Electrophysiological classes of layer 2/3 pyramidal cells in monkey prefrontal cortex

2012 ◽  
Vol 108 (2) ◽  
pp. 595-609 ◽  
Author(s):  
A. V. Zaitsev ◽  
N. V. Povysheva ◽  
G. Gonzalez-Burgos ◽  
D. A. Lewis
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Functional Properties ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Spiking Neurons ◽  
Membrane Properties ◽  
Layer 2 ◽  
Monkey Prefrontal Cortex ◽  
Intrinsic Membrane Properties

The activity of supragranular pyramidal neurons in the dorsolateral prefrontal cortex (DLPFC) neurons is hypothesized to be a key contributor to the cellular basis of working memory in primates. Therefore, the intrinsic membrane properties, a crucial determinant of a neuron's functional properties, are important for the role of DLPFC pyramidal neurons in working memory. The present study aimed to investigate the biophysical properties of pyramidal cells in layer 2/3 of monkey DLPFC to create an unbiased electrophysiological classification of these cells. Whole cell voltage recordings in the slice preparation were performed in 77 pyramidal cells, and 24 electrophysiological measures of their passive and active intrinsic membrane properties were analyzed. Based on the results of cluster analysis of 16 independent electrophysiological variables, 4 distinct electrophysiological classes of monkey pyramidal cells were determined. Two classes contain regular-spiking neurons with low and high excitability and constitute 52% of the pyramidal cells sampled. These subclasses of regular-spiking neurons mostly differ in their input resistance, minimum current that evoked firing, and current-to-frequency transduction properties. A third class of pyramidal cells includes low-threshold spiking cells (17%), which fire a burst of three-five spikes followed by regular firing at all suprathreshold current intensities. The last class consists of cells with an intermediate firing pattern (31%). These cells have two modes of firing response, regular spiking and bursting discharge, depending on the strength of stimulation and resting membrane potential. Our results show that diversity in the functional properties of DLPFC pyramidal cells may contribute to heterogeneous modes of information processing during working memory and other cognitive operations that engage the activity of cortical circuits in the superficial layers of the DLPFC.

A pen-and-paper human analogue of a monkey prefrontal cortex activation task: spatial working memory in patients with schizophrenia

1995 ◽  
Vol 17 (1) ◽  
pp. 25-33 ◽  
Author(s):  
Richard S.E. Keefe ◽  
Sonia E. Lees Roitman ◽  
Philip D. Harvey ◽  
Cynthia S. Blum ◽  
Rachel L. DuPre ◽  
...  
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Spatial Working Memory ◽  
Monkey Prefrontal Cortex

Perseveration and Strategy in a Novel Spatial Self-Ordered Sequencing Task for Nonhuman Primates: Effects of Excitotoxic Lesions and Dopamine Depletions of the Prefrontal Cortex

1998 ◽  
Vol 10 (3) ◽  
pp. 332-354 ◽  
Author(s):  
P. Collins ◽  
A. C. Roberts ◽  
R. Dias ◽  
B. J. Everitt ◽  
T. W. Robbins
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Cognitive Function ◽  
Cognitive Abilities ◽  
Memory Task ◽  
Common Marmoset ◽  
The Self ◽  
Delayed Response ◽  
Impaired Performance ◽  
Sequencing Task

Damage to the prefrontal cortex disrupts the performance of self-ordered sequencing tasks, although the precise mechanisms by which this effect occurs is unclear. Active working memory, inhibitory control, and the ability to generate and perform a sequence of responses are all putative cognitive abilities that may be responsible for the impaired performance that results from disruption of prefrontal processing. In addition, the neurochemical substrates underlying prefrontal cognitive function are not well understood, although active working memory appears to depend upon an intact mesocortical dopamine system. The present experiments were therefore designed to evaluate explicitly the contribution of each of these abilities to successful performance of a novel spatial self-ordered sequencing task and to examine the contribution of the prefrontal cortex and its dopamine innervation to each ability in turn. Excitotoxic lesions of the prefrontal cortex of the common marmoset profoundly impaired the performance of the self-ordered sequencing task and induced robust perseverative responding. Task manipulations that precluded perseveration ameliorated the effect of this lesion and revealed that the ability to generate and perform sequences of responses was unaffected by excitotoxic damage to prefrontal cortex. In contrast, large dopamine and noradrenaline depletions within the same areas of prefrontal cortex had no effect on any aspect of the self-ordered task but did impair the acquisition of an active working memory task, spatial delayed response, to the same degree as the excitotoxic lesion. These results demonstrate that a lesion of the ascending monoamine projections to the pre-frontal cortex is not always synonymous with a lesion of the prefrontal cortex itself and thereby challenge existing concepts concerning the neuromodulation of prefrontal cognitive function.

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