Cognitive flexibility is the ability to rapidly adapt established patterns of behaviour in the face of changing circumstance and depends critically on the orbitofrontal cortex (OFC). Impaired flexibility also results from altered serotonin transmission in the OFC. The Y1 (Y1R) and Y5 (Y5R) receptors for neuropeptide Y (NPY) colocalize in several brain regions and have overlapping functions in regulating cognition and emotional behaviour. The targeted disruption of gene encoding Y1R (Npy1r gene) in Y5R containing neurons (Npy1rY5R-/- mice) increases anxiety-like behaviour and spatial reference memory. Here we used the same conditional system to analyse whether the coordinated expression of the Y1R and Y5R might be required for behavioural flexibility in reversal learning tasks, OFC serotoninergic tone and OFC neural activity, as detected by immunohistochemical quantification of the immediate-early gene, c-Fos. In addition, we investigated whether the acute treatment of Npy1rY5R-/- mice with the selective serotonin reuptake inhibitor escitalopram affected behavioural flexibility and OFC c-Fos expression. Npy1rY5R-/- male mice exhibit an impairment in performing the reversal task of the Morris water maze and the water T-maze but normal spatial learning, working memory and sociability, compared to their control siblings. Furthermore, Npy1rY5R-/- male mice display decreased 5-hydroxytriptamine (5-HT) positive fibres and increased baseline neural activity in OFC. Importantly, escitalopram normalizes OFC neural activity and restores behavioural flexibility of Npy1rY5R-/- male mice. These findings suggest that the inactivation of Y1R in Y5R containing neurons increases pyramidal neuron activity and dysregulates serotoninergic tone in OFC, whereby contributing to reversal learning impairment.
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