Abstract
The neural mechanisms underlying cognitive deficits in schizophrenia are poorly understood. Sub-chronic treatment with the NMDA antagonist phencyclidine (PCP) produces cognitive abnormalities in rodents that reliably model aspects of the neurocognitive alterations observed in schizophrenia. Given that network activity across regions encompassing medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) plays a significant role in motivational and cognitive tasks, we measured activity across cortico-striatal pathways in PCP-treated rats to characterize neural enabling and encoding of task performance in a novel object recognition task. We found that PCP treatment impaired task performance and concurrently (1) reduced tonic NAc neuronal activity, (2) desynchronized cross-activation of mPFC and NAc neurons, and (3) prevented the increase in mPFC and NAc neural activity associated with the exploration of a novel object in relation to a familiar object. Taken together, these observations reveal key neuronal and network-level adaptations underlying PCP-induced cognitive deficits, which may contribute to the emergence of cognitive abnormalities in schizophrenia.
Highlights
Schizophrenia is a devastating mental disorder characterized by positive, negative, and cognitive symptoms
In addition to this global deficit, we found that phasic responses in both structures in response to ongoing behavior were affected: PCP pre-treatment disrupted the increase in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) activity associated with novel object exploration in control animals
To investigate cortical and NAc contributions to PCPinduced behavioral deficits, we recorded firing rates in single units recorded from mPFC and NAc shell in awake behaving rats pre-treated with either PCP or saline (Fig. 1a–c)
Summary
Schizophrenia is a devastating mental disorder characterized by positive, negative, and cognitive symptoms. Cognitive symptoms include deficits in working memory and behavioral flexibility (Forbes et al 2009; Leeson et al 2009), two processes of executive function that are essential for normal cognition. Both the Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative (MATRICS) and the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia group (CNTRICS) highlight cognitive deficits as a core feature of this disorder (Nuechterlein et al 2008, 2009).
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