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


CONCLUSIONS
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.
Department of Physiology and Pharmacology, liyamariama@gmail.com.
Liya
http://orcid.org/0000-0003-0183-7155
L
Ma
Department of Anatomy and Cell Biology.
Kevin
K
Skoblenick
Brain Research Centre and Department of Psychiatry, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, V6T 2B5 Canada.
Jeremy K
JK
Seamans
Department of Physiology and Pharmacology, Department of Anatomy and Cell Biology, Brain and Mind Institute, and Robarts Research Institute, University of Western Ontario, London, Ontario, N6A 3K7 Canada, and.
Stefan
S
Everling
D000778:Anesthetics, Dissociative; D000818:Animals; D007649:Ketamine; D008253:Macaca mulatta; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology*; D011597:Psychomotor Performance / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012559:Schizophrenia / Q000139:chemically induced / Q000503:physiopathology*; D059629:Signal-To-Noise Ratio
D000778:Anesthetics, Dissociative; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine
ketamine; nonhuman primate; prefrontal cortex; rule; saccade; working memory