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The neuropsychopharmacology of reversal learning

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posted on 2023-06-08, 15:06 authored by Simon Nilsson
Reversal learning deficits are a feature of many neuropsychiatric disorders, most notably schizophrenia. These deficits could be due, in part, to altered ability to dissipate either or both associations of previous positive (perseverance) and negative (learned non-reward) valence. Studies reported in this thesis developed an egocentric maze task and a visuospatial operant task for separate assessments of spatial reversal learning, perseverance and learned non-reward in mice. These tasks were subsequently used to assess the cognitive causes for altered performance after manipulations to brain systems recognised to be involved in reversal learning and relevant for human psychopathology, with a specific focus on schizophrenia. NMDA receptor (NMDAr) antagonism through acute phencyclidine did not affect reversal learning in the operant task, but caused general impairments in the maze task. Orbitofrontal (OFC) lesioned mice showed perseverative impairments in the operant task. Mice treated with the 5-HT2C receptor (5-HT2CR) antagonist SB242084 and 5-HT2CR KO mice showed facilitated reversal learning and decreased learned nonreward in the operant task. In the maze task, SB242084 decreased perseverance but increased learned non-reward, while 5-HT2CR KO mice showed perseverance and discrimination learning deficits. The final experimental chapter investigated the effect of SB242084 on touch-screen visual reversal learning in the rat. SB242084 retarded learning in this task. These studies demonstrate that previously non-reinforced associations can be of considerable importance in tasks of cognitive flexibility. The studies also show that the NMDAr, the 5-HT2CR, and the OFC, are involved in reversal learning and can modulate mechanisms related to both perseverance and learned non-reward. Moreover, in reversal learning, few effects of manipulations affecting PFC-functioning, or activity at the NMDAr and 5-HT2CR, generalise across the procedures in the visuospatial, egocentric spatial, and visual domains.


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University of Sussex

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