1. High Frequency Neuronal Oscillations in a Cynomolgus Macaque Test of Working
Memory Following NMDA Receptor Antagonism
AV Goonawardena1*
, J Heiss1
, C Glavis-Bloom1
, E Borroni2
, D Alberati2
, TL
Wallace1
1
Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, CA,
USA. 2
Neuroscience, Opthalmology and Rare Diseases, F. Hoffmann-La Roche Ltd,
Basel, Switzerland.
Disruptions in sensory processing and abnormal temporal integration of neuronal
oscillations, especially within the gamma frequency range (30-80 Hz), have been
identified in schizophrenic patients during working memory tasks and may contribute to
the poor performance within this cognitive domain. Experimentally, alterations in gamma
oscillations as well as the induction of other schizophrenia-like symptoms including
cognitive deficits can be induced with NMDA receptor antagonists (e.g., phencyclidine
[PCP], ketamine) in rodents, non-human primates (NHPs) and humans. Given that
NHPs and humans have homologous prefrontal cortical structures that mediate attention
and working memory processes, our objective was to characterize neuronal oscillations
and event-related potentials (ERPs) to assess sensory and cognitive processing in
cynomolgus macaques performing a delayed-match-to-sample (DMTS) working memory
task. Macaques (n=7) were trained to match a sample stimulus following a delay period
on a touchscreen in exchange for food rewards. Subsequently, all subjects were
implanted with EEG electrodes [placed on the dura mater above the frontal cortex (FC)
and primary visual cortex (V1)]. Thereafter, all animals received acute doses of PCP
(0.03, 0.056, 0.1 mg/kg) or vehicle (Veh) and the effects on DMTS performance and high
frequency brain oscillations were measured. Compared to vehicle treatment, PCP
produced a significant dose-dependent decrease in DMTS performance accuracy. EEG
analyses during DMTS performance demonstrated that high gamma (51-80Hz)
oscillations showed a significant treatment (Veh vs PCP) x stimulus (pre- vs post-
stimulus) interaction in FC during correct responding. Moreover, PCP significantly
elevated the amplitude of low gamma (30-50Hz), while suppressing alpha (8-12Hz)
oscillations in FC. Similarly, PCP elevated both low and high gamma oscillations in the
V1 with both high gamma and beta (16-24Hz) showing a significant treatment x stimulus
interaction during correct responding. In addition, PCP significantly prolonged the
cognitively-relevant P300 component of the mean ERP during correct responses in FC
but not V1. Overall, our results suggest that acute administration of a NMDA receptor
antagonist disrupts neuronal oscillations and cognitive processing, especially in the FC,
and this may contribute to impaired cognitive performance in macaques. These studies
may help to define the role of high frequency oscillations in cognitive processes in higher
order species, and to enhance our understanding of EEG recordings as a translatable
biomarker for cognitive impairments associated with schizophrenia.
Supported by: Roche postdoctoral fellowship (RPF) program, F. Hoffmann – La Roche
Ltd., Basel, Switzerland.
Keywords - monkey, working memory, NMDA receptor antagonist, quantitative EEG,
ERP, gamma oscillations.