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Asymmetric c-fos expression in the ventral orbital cortex is associated with impaired reversal learning in a right-sided neuropathy

Hugo Leite-Almeida1*, Marco Rafael Guimarães12, João José Cerqueira12, Nuno Ribeiro-Costa12, Helena Anjos-Martins12, Nuno Sousa12 and Armando Almeida12

Author Affiliations

1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, Braga 4710-057, Portugal

2 ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal

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Molecular Pain 2014, 10:41  doi:10.1186/1744-8069-10-41

Published: 23 June 2014



Recently we showed that unilateral peripheral neuropathic lesions impacted differentially on rat’s emotional/cognitive behavior depending on its left/right location; importantly, this observation recapitulates clinical reports. The prefrontal cortex (PFC), a brain region morphofunctionally affected in chronic pain conditions, is involved in the modulation of both emotion and executive function and displays functional lateralization. To test whether the PFC is involved in the lateralization bias associated with left/right pain, c-fos expression in medial and orbital areas was analyzed in rats with an unilateral spared nerve injury neuropathy installed in the left or in the right side after performing an attentional set-shifting, a strongly PFC-dependent task.


SNI-R animals required more trials to successfully terminate the reversal steps of the attentional set-shifting task. A generalized increase of c-fos density in medial and orbital PFC (mPFC/OFC), irrespectively of the hemisphere, was observed in both SNI-L and SNI-R. However, individual laterality indexes revealed that contrary to controls and SNI-L, SNI-R animals presented a leftward shift in c-fos density in the ventral OFC (VO). None of these effects were observed in the neighboring primary motor area.


Our results demonstrate that chronic neuropathic pain is associated with a bilateral mPFC and OFC hyperactivation. We hypothesize that the impaired performance of SNI-R animals is associated with a left/right activity inversion in the VO, whose functional integrity is critical for reversal learning.

Neuropathic pain; Lateralization; Attentional set-shifting task; Reversal learning; Prefrontal cortex; C-fos