Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task

Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR) function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT2CR on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT2CR antagonist SB242084 (0.5 mg/kg) in a between-groups serial design and Experiment 2 used 5-HT2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS−), in a T- or Y-maze configuration. This was followed by three conditions; (1) Full reversal, where contingencies reversed; (2) Perseverance, where the previous CS+ became CS− and the previous CS− was replaced by a novel CS+; (3) Learned non-reward, where the previous CS− became CS+ and the previous CS+ was replaced by a novel CS-. SB242084 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT2CR KO mice showed increased perseverance. 5-HT2CR KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT2CR function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT2CR antagonism and constitutive loss of the 5-HT2CR have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT2CR loss on the development and maintenance of cognitive function

The rat's not for turning: Dissociating the psychological components of cognitive inflexibility.

Executive function is commonly assessed by assays of cognitive flexibility such as reversal learning and attentional set-shifting. Disrupted performance in these assays, apparent in many neuropsychiatric disorders, is frequently interpreted as inability to overcome prior associations with reward. However, non-rewarded or irrelevant associations may be of considerable importance in both discrimination learning and cognitive flexibility. Non-rewarded associations can have greater influence on choice behaviour than rewarded associations in discrimination learning. Pathology-related deficits in cognitive flexibility can produce selective disruptions to both the processing of irrelevant associations and associations with reward. Genetic and pharmacological animal models demonstrate that modulation of reversal learning may result from alterations in either rewarded or non-rewarded associations. Successful performance in assays of cognitive flexibility can therefore depend on a combination of rewarded, non-rewarded, and irrelevant associations derived from previous learning, accounting for some inconsistencies observed in the literature. Taking this combination into account may increase the validity of animal models and may also reveal pathology-specific differences in problem solving and executive function.Supported by BBSRC and Eli Lilly through CASE studentship (BB/F529054/1). J.A. was supported by the Swedish Research Council (350-2012-230). The Behavioural and Clinical Neuroscience Institute is co-funded by the Medical Research Council and the Wellcome Trust.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.neubiorev.2015.06.01

Rule-based category learning in patients with Parkinson's disease

Measures of explicit rule-based category learning are commonly used in neuropsychological evaluation of individuals with Parkinson’s disease (PD) and the pattern of PD performance on these measures tends to be highly varied. We review the neuropsychological literature to clarify the manner in which PD affects the component processes of rule-based category learning and work to identify and resolve discrepancies within this literature. In particular, we address the manner in which PD and its common treatments affect the processes of rule generation, maintenance, shifting and selection. We then integrate the neuropsychological research with relevant neuroimaging and computational modeling evidence to clarify the neurobiological impact of PD on each process. Current evidence indicates that neurochemical changes associated with PD primarily disrupt rule shifting, and may disturb feedback-mediated learning processes that guide rule selection. Although surgical and pharmacological therapies remediate this deficit, it appears that the same treatments may contribute to impaired rule generation, maintenance and selection processes. These data emphasize the importance of distinguishing between the impact of PD and its common treatments when considering the neuropsychological profile of the disease