The Electrophysiological Signature of Motivational Salience in Mice and Implications for Schizophrenia

1] Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany [2] JARA-Translational Brain Medicine, Jülich, Germany [3] Department of Psychiatry, Translational Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 08/2012; 37(13). DOI: 10.1038/npp.2012.156
Source: PubMed


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.Neuropsychopharmacology advance online publication, 22 August 2012; doi:10.1038/npp.2012.156.

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Available from: Steven J Siegel, May 08, 2015
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    • "Schizophrenia is associated with abnormal modulation of activity by emotionally relevant stimuli in numerous corticolimbic brain regions (Murray et al, 2008;Roiser et al, 2013;Taylor et al, 2005). In particular, the prefrontal cortex (PFC) encodes affective salience in humans (Roiser et al, 2010) and rodents (Moessnang et al, 2012), and is thought to be an area of primary pathology in schizophrenia (Lewis et al, 2004;Moghaddam, 2002;Volk and Lewis, 2002). For example, functional imaging studies have revealed that activation of the medial PFC (mPFC) is greater in response to a neutral conditioned stimulus (CS–) than an appetitive CS (CS þ ), a pattern opposite of that observed in controls (Diaconescu et al, 2011). "
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    ABSTRACT: Inhibitory gamma-aminobutyric acid (GABA) transmission within the prefrontal cortex (PFC) regulates numerous functions, and perturbations in GABAergic transmission within this region have been proposed to contribute to some of the cognitive and behavioral abnormalities associated with disorders such as schizophrenia. These abnormalities include deficits in emotional regulation and aberrant attributions of affective salience. Yet, how PFC GABA regulates these types of emotional processes is unclear. To address this issue, we investigated the contribution of PFC GABA transmission to different aspects of Pavlovian emotional learning in rats using translational discriminative fear conditioning and latent inhibition assays. Reducing prelimbic PFC GABAA-transmission via infusions of the antagonist bicuculline prior to the acquisition or expression of fear conditioning eliminated the ability to discriminate between an aversive conditioned stimulus (CS+) paired with footshock versus a neutral CS-, resembling similar deficits observed in schizophrenic patients. In a separate experiment, blockade of PFC GABAA-receptors prior to CS preexposure and conditioning did not affect subsequent expression of latent inhibition, but did enhance fear in rats that were not preexposed to the conditioned stimulus. In contrast, PFC GABA-blockade prior to a fear expression test disrupted the recall of learned irrelevance and abolished latent inhibition. These data suggest that normal PFC GABA transmission is critical for regulating and mitigating multiple aspects of aversive learning, including discrimination between fear versus safety signals and recall of information about the irrelevance of stimuli. Furthermore, they suggest that similar deficits in emotional regulation observed in schizophrenia may be driven in part by deficient PFC GABA activity.Neuropsychopharmacology accepted article preview online, 02 May 2014; doi:10.1038/npp.2014.99.
    Full-text · Article · May 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "This conceptualization of conditioning has already been adopted in studies on appetitive learning in humans (i.e. Heinz and Schlagenhauf, 2010; Jensen et al., 2008; Roiser et al., 2009), and on aversive learning in mice (Moessnang et al., 2012). The process of salience attribution should therefore apply to Pavlovian conditioning involving chemosensory stimuli as well. "
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