Ketamine-Induced Changes in the Signal and Noise of Rule Representation in Working Memory by Lateral Prefrontal Neurons

Abstract

Working memory dysfunction is an especially debilitating symptom in schizophrenia. The NMDA antagonist ketamine has been successfully used to model working memory deficits in both rodents and nonhuman primates, but how it affects the strength and the consistency of working memory representations remains unclear. Here we recorded single-neuron activity in the lateral prefrontal cortex of macaque monkeys before and after the administration of subanesthetic doses of ketamine in a rule-based working memory task. The rule was instructed with a color cue before each delay period and dictated the correct prosaccadic or antisaccadic response to a peripheral stimulus appearing after the delay. We found that acute ketamine injections both weakened the rule signal across all delay periods and amplified the trial-to-trial variance in neural activities (i.e., noise), both within individual neurons and at the ensemble level, resulting in impaired performance. In the minority of postinjection trials when the animals responded correctly, the preservation of the signal strength during the delay periods was predictive of their subsequent success. Our findings suggest that NMDA receptor function may be critical for establishing the optimal signal-to-noise ratio in information representation by ensembles of prefrontal cortex neurons.

Significance statement: In schizophrenia patients, working memory deficit is highly debilitating and currently without any efficacious treatment. An improved understanding of the pathophysiology of this symptom may provide critical information to treatment development. The NMDA antagonist ketamine, when injected at a subanesthetic dose, produces working memory deficit and other schizophrenia-like symptoms in humans and other animals. Here we investigated the effects of ketamine on the representation of abstract rules by prefrontal neurons, while macaque monkeys held the rules in working memory before responding accordingly. We found that ketamine weakened the signal-to-noise ratio in rule representation by simultaneously weakening the signal and augmenting noise. Both processes may be relevant in an effective therapy for working memory impairment in schizophrenia.

Keywords: ketamine; nonhuman primate; prefrontal cortex; rule; saccade; working memory.

Figure 1.

Schematic illustrations of methods and materials. A, Experimental paradigm. Each trial started with a white fixation circle, which lasted for 0.1 s before turning green or red, signaling a prosaccade or antisaccade trial, respectively (the contingency was reversed for the other subject). In 0.2 s, the central spot turned back to white, which initiated the delay period lasting anywhere from 0.7 to 1 s and ending upon the onset of the peripheral stimulus. According to the green/red instruction cue, the animals now made either a prosaccade or antisaccade with reference to the peripheral stimulus and were rewarded for correct responses. B, Recording location. All electrodes were placed within the bilateral lateral prefrontal cortex. The locations were confirmed with MRI.

Figure 2.

Changes in behavior and descriptive statistics of LPFC neural activity throughout the sessions. A, Ketamine reduced the percentage of correct trials, which reached the lowest point during the second 10 min period after injection, and gradually recovered. B, Ketamine increased the averaged reaction time of the saccadic response, which plateaued during the first 20 min after injection, and then decreased but did not fully recover by the end of the sessions. C, The mean firing rates across all neurons recorded increased gradually after ketamine injection and eventually plateaued toward the end of the sessions. D, Ketamine injection increased the mean firing rate across neurons recorded in every session from both Monkey O and Monkey T. Each session is plotted in a distinct color. E, Ketamine injection increased the trial-to-trial SD across all neurons at a steady rate throughout the sessions. F, The CV, or the SD-to-mean ratio in activities across all trials, decreased after ketamine injection during the first 20 min after injection and remained at the same level for the rest of the recording sessions. This indicates that the mean firing rate in C increased at a greater pace than the SD shown in E. G, Ketamine injection increased the averaged CV across neurons recorded in every session from both Monkey O and Monkey T. Error bars indicate the SEM.

Figure 3.

In individual neurons, ketamine weakened the SNR for task rules, attributable to both a reduction in the signal and an increase in the noise. A, Considering correct trials only, the SNR was unchanged by acute ketamine administration (white bar, before injection; black bar, after injection). B, When error trials were also included, the SNR was significantly weakened after the injections. C, The rule signal, measured as the difference between the mean firing rates associated with prosaccade and anti-saccade trials, remained the same in correct trials after ketamine injections. D, When error trials were also included, the rule signal dropped significantly after the injections. E, After ketamine injections, the rule signal was significantly lower during the delay periods in error trials (dark gray) than in correct trials (light gray). F, Considering correct trials only, the noise, measured as the SD across all prosaccade (gray) or antisaccade (black) trials, increased as a result of ketamine. The amount increased was similar for both rules. G, When error trials were also included, the SD across all prosaccade (gray) or antisaccade (black) trials also increased as a result of ketamine. The amount increased was similar for both rules. Error bars indicate the SEM. H, Activity of a single neuron in both types of trials. In the raster plots, each line segment represents a single spike. Lines at the bottom depict the mean, and their shade reflects the SEM across all prosaccade (blue) and antisaccade (red) trials, respectively. The dashed lines delimit the delay periods. Whereas the neuron responded differently in the prosaccade (blue line) and the antisaccade (red line) trials before ketamine injection (left), this distinction mostly disappeared after the injection (right). The loss of the SNR for rules occurred despite the increase in overall activity. *p < 0.05, ***p < 0.0001.

Figure 4.

Similarity in the time course of changes in behavior and in single-unit SNR for task rules. A, The SNR at the single-unit level (black curve, left y-axis) dropped abruptly during the first 10 min after injection and recovered gradually. This time course mimics and slightly leads the course of change in the percentage of correct response from the animals (gray curve, right y-axis). B, The time course of the SNR (black curve, left y-axis) mirrored the changes in saccadic reaction time (gray curve, right y-axis), especially during the preinjection period and the first 20 min after injection. Error bars indicate the SEM.

Figure 5.

In whole ensembles, ketamine also weakened the SNR for rules via both a reduction in signal and an increase in noise. A, Considering correct trials only, the SNŖ measured as the Mahalanobis distance (D_Mah) between neural correlates of the two rules, remained unchanged by acute ketamine administration (white bar, before injection; black bar, after injection). Gray dots indicate values of individual data points. B, When all trials were considered, the ensemble SNR was significantly compromised by ketamine administration. C, Considering correct trials only, the rule signal, defined as the Euclidean distance (D_Euc) between ensemble activities associated with the two rules, remained unchanged by ketamine. D, When error trials were also included, however, the signal was weakened after ketamine injection. E and F consider correct trials only. E, The total variance, part of the noise factored into the ensemble SNR calculation, was significantly enhanced by ketamine injection (left vs right bars) to the same extent in both task rules (gray vs black bars). F, The averaged correlation coefficient, which is another contributing factor to ensemble SNR, was not changed by ketamine (left vs right bars) regardless of the task rule (gray vs black bars). G and H consider all trials, including errors. G, The total variance was enhanced by ketamine injection (left vs right bars) to the same extent in both task rules (gray vs black bars). H, The averaged correlation coefficient remained unchanged after ketamine administration (left vs right bars) in both prosaccade and antisaccade trials (gray vs black bars). *p < 0.05, **p < 0.005, ***p < 0.0001.

Figure 6.

The effects of ketamine on signal and noise, visualized in a single ensemble. A, An example of a dimension-reduced MSUA space constructed from the standardized firing rates of 61 dorsolateral PFC neurons recorded during a single session, before ketamine injection. Each dot reflects the activities of all 61 neurons in the delay period of a single trial. Trials with the same rule (blue, prosaccade rule; red, antisaccade rule) are associated with similar ensemble activities, reflected as a relatively compact cluster that is distinct from the other cluster. B, Averaged activities from each neuron in prosaccade (blue) and antisaccade (red) trials (in z-scores) before injection. Each bar represents the mean and SEM of activities from a single neuron. Gray boxes highlight neurons showing great difference in their responses to the two rules. C, The MSUA space for the same ensemble after ketamine injection, dimension reduced together with activities shown in A. Ketamine administration increased noise, or greater variance in ensemble activity across trials associated with the same rule, which is reflected as greater dispersion among dots of the same color. D, Averaged activities from each neuron in prosaccade (blue) and antisaccade (red) trials (in z-scores) after ketamine injection. The same neurons highlighted in A (gray boxes) now show reduced difference in their responses to the two rules. Hence, in these neurons, ketamine resulted in a reduction in the signal strength for task rules.

Figure 7.

Ketamine exerted similar effects on the activities of different types of neurons. A, Neurons were classified into two categories: broad-spiking and narrow-spiking neurons based on the bimodal distribution of the peak-to-valley latencies. Neurons recorded from both subjects had similar peak-to-valley latency distributions. B, Although the NSNs (right bars) fired at high rates than the BSNs (left bars), both types of neurons showed an increase in activity level after ketamine injection (open vs filled bars). C, Overall, the NSNs (right bars) fired with greater trial-to-trial variance than the BSNs (left bars). Ketamine increased this variance in both types of neurons (open vs filled bars). There was no interaction between treatment and neuron type. D, The SNR for rules across all trials, including errors, calculated the same way as in Figure 3B, was reduced by ketamine across both types of neurons. E, On correct trials only, the SNR did not change after ketamine injection (empty vs filled bars), nor did it differ between neuron types (left vs right bars). Error bars indicate the SEM. *p < 0.05, **p < 0.005, ***p < 0.0001.