Abstract
Cognitive deficits are at the crux of why many schizophrenia patients have poor functional outcomes. One of the cognitive symptoms experienced by schizophrenia patients is a deficit in context processing, the ability to use contextual information stored in working memory to adaptively respond to subsequent stimuli. As such, context processing can be thought of as the intersection between working memory and executive control. Although deficits in context processing have been extensively characterized by neuropsychological testing in schizophrenia patients, they have never been effectively translated to an animal model of the disease. To bridge that gap, we trained monkeys to perform the same dot pattern expectancy (DPX) task, which has been used to measure context-processing deficits in human patients with schizophrenia. In the DPX task, the first stimulus in each trial provides the contextual information that subjects must remember in order to appropriately respond to the second stimulus in the trial. We found that administration of ketamine, an N-methyl-D-aspartate receptor antagonist, in monkeys caused a dose-dependent failure in context processing, replicating in monkeys the same specific pattern of errors committed by patients with schizophrenia when performing the same task. Therefore, our results provide the first evidence that context-processing dysfunction can be modeled in animals. Replicating a schizophrenia-like behavioral performance pattern in monkeys performing the same task used in humans provides a strong bridge to better understand the biological basis for this psychiatric disease and its cognitive manifestations using animal models.
Original language | English (US) |
---|---|
Pages (from-to) | 2090-2100 |
Number of pages | 11 |
Journal | Neuropsychopharmacology |
Volume | 38 |
Issue number | 11 |
DOIs | |
State | Published - Oct 2013 |
Bibliographical note
Funding Information:Rachael Blackman has received funding to support the work contained in this manuscript as outlined in the Acknowledgements section of this manuscript. Rachael Blackman has received funding from the University of Minnesota and U.S. National Institutes of Health. Dr MacDonald receives funding through the U.S. National Institutes of Health. Dr Chafee receives funding through the U.S. National Institutes of Health.
Funding Information:
This work was supported by the National Institutes of Health (R01 MH077779), the Department of Veterans Affairs, and the American Brain Sciences Chair. In addition, Rachael Blackman was supported by NIH MSTP grant T32 GM008244 and the Wilfred Wetzel Graduate Fellowship. We thank Dr David Crowe for important insights into the data analyses for this study as well as valuable discussions regarding the manuscript. In addition, we thank Dean Evans and Dale Boeff for their exceptional technical support of this work (animal care and computer programming, respectively). The views and opinions expressed in this paper are those of the authors and not those of the United States Federal Government.
Keywords
- Context processing
- Executive control
- Monkey
- NMDA antagonist
- Schizophrenia
- Translational