Elsevier

Biological Psychiatry

Volume 77, Issue 5, 1 March 2015, Pages 454-464
Biological Psychiatry

Archival Report
Interneurons Are Necessary for Coordinated Activity During Reversal Learning in Orbitofrontal Cortex

https://doi.org/10.1016/j.biopsych.2014.07.023Get rights and content

Abstract

Background

Cerebral cortical gamma-aminobutyric acidergic interneuron dysfunction is hypothesized to lead to cognitive deficits comorbid with human neuropsychiatric disorders, including schizophrenia, autism, and epilepsy. We have previously shown that mice that harbor mutations in the Plaur gene, which is associated with schizophrenia, have deficits in frontal cortical parvalbumin-expressing interneurons. Plaur mice have impaired reversal learning, similar to deficits observed in patients with schizophrenia.

Methods

We examined the role of parvalbumin interneurons in orbitofrontal cortex during reversal learning by recording single unit activity from 180 control and 224 Plaur mouse neurons during a serial reversal task. Neural activity was analyzed during correct and incorrect decision choices and reward receipt.

Results

Neurons in control mice exhibited strong phasic responses both during discrimination and reversal learning to decisions and rewards, and the strength of the response was correlated with behavioral performance. Although baseline firing was significantly enhanced in Plaur mice, neural selectivity for correct or erroneous decisions was diminished and not correlated with behavior, and reward encoding was downscaled. In addition, Plaur mice showed a significant reduction in the number of neurons that encoded expected outcomes across task phases during the decision period.

Conclusions

These data indicate that parvalbumin interneurons are necessary for the representation of outcomes in orbitofrontal cortex. Deficits in inhibition blunt selective neural firing during key decisions, contributing to behavioral inflexibility. These data provide a potential explanation for disorders of cognitive control that accompany the loss of these gamma-aminobutyric acidergic interneurons in human neuropsychiatric disorders, such as autism, epilepsy, and schizophrenia.

Section snippets

Subjects

B6.129-Plaurtm1/Mlg/Plaurtm1/Mlg mice that have a null mutation in the gene that encodes the urokinase plasminogen activator receptor protein were genotyped as described previously (26). Behavioral and anatomical analyses were performed on adult (3- to 6-month-old) male littermates from at least six separate pedigrees bred on the C57BL/6J background for >20 generations. B6.129 male wild-type littermate mice were used as control animals. Experiments were conducted in accordance with University

Behavioral Impairment on First Reversal

Research in rats (32) and primates (33) has consistently shown behavioral impairment of OFC lesions on reversal learning. However, the effects of OFC lesions and other manipulations on reversal learning are typically transient (30, 34, 35), affecting only the first or early reversal problems in a set. Here, we show a similar deficit in mice performing a serial reversal task (Figure 1A–C). As in our previous reports (17, 28, 36), control and transgenic mice learned discriminations without

Discussion

We show that neurons in mouse OFC exhibit the same correlates as observed in rats and primates during reversal learning, encoding outcome expectations and associations formed to reward predictive cues (31, 37, 42, 43, 44). Mouse OFC neurons were responsive during decision and reward delivery epochs in discrimination and reversal phases. However, neural activity was only significantly correlated to behavioral performance during reversal. Our data also show that a neurodevelopmental example of an

Acknowledgments and Disclosures

Financial support for this study was provided by National Alliance for Research on Schizophrenia and Depression Young Investigator Award (EMP) and National Institute on Drug Abuse Grants DA108826 (Principal Investigator [PI]: EMP), DA015718 (PI: GS), and DA031695 (PI: MRR).

We thank D. Calu for neural recording assistance; S. Scahill for histology assistance; and G. Martins, S. Mullins, A. Gruber, A. Keller, P. O’Donnell, and J. Smith for insightful comments on the manuscript.

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