Abstract
According to the aberrant-salience hypothesis, attribution of motivational salience is severely disrupted in patients with schizophrenia. To provide a translational approach for investigating underlying mechanisms, neural correlates of salience attribution were examined in normal mice and in a MK-801 model of schizophrenia. Electrophysiological responses to standard and deviant tones were assessed in the medial prefrontal cortex (mPFC) using an auditory oddball paradigm. Motivational salience was induced by aversive conditioning to the deviant tone. Analysis of the auditory evoked potential (AEP) showed selective modulation of the late frontal negativity (LFN) by motivational salience, which persisted throughout a 4-week delay. MK-801, an N-methyl-D-aspartic acid receptor antagonist, abolished this differential response to motivational salience in conditioned mice. In contrast, a pronounced LFN response was observed towards the deviant, ie, perceptually salient tone, in nonconditioned mice. The finding of a selective modulation of a late frontal slow wave suggests increased top–down processing and emotional evaluation of motivationally salient stimuli. In particular, the LFN is discussed as the mouse analog to the human stimulus preceding negativity, which reflects preparatory processes in anticipation of reward or punishment. MK-801 led to a disruption of the normal response in conditioned and nonconditioned mice, including an aberrantly increased LFN in nonconditioned mice. This pattern of ‘false-negative’ and ‘false-positive’ responses suggests a degradation of salience attribution, which points to mPFC responses to be relevant for translational research on cognitive alterations in schizophrenia.
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Acknowledgements
We thank Valérie Leitman, John Saunders, Robert Lin, Robert Featherstone, Jimmy Suh, Yuling Liang, and Mike Gandal for their support during data acquisition and analysis. This work was supported by the German Research Foundation (DFG, IRTG 1328), Helmholtz Alliance for Mental Health in an Ageing Society (HelMA, HA-215), Interdisciplinary Center for Clinical Research of the Medical Faculty of the RWTH Aachen University (IZKF, N4-4), and the National Institutes of Health (NIH, grant 5R01DA023210-02).
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Steven Siegel reports having received grant support from Eli Lilly, AstraZeneca, NuPathe, and Pfizer that is unrelated to the content of this paper and consulting payments from NuPathe, Merck, Sanofi, and Wyeth that are unrelated to this work. The rest of the authors declare no conflict of interest.
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Moessnang, C., Habel, U., Schneider, F. et al. The Electrophysiological Signature of Motivational Salience in Mice and Implications for Schizophrenia. Neuropsychopharmacol 37, 2846–2854 (2012). https://doi.org/10.1038/npp.2012.156
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DOI: https://doi.org/10.1038/npp.2012.156
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