Medium spiny neurons of the anterior dorsomedial striatum mediate reversal learning in a cell-type-dependent manner
The striatum has been implicated in the regulation of cognitive flexibility. Abnormalities in the anterior dorsomedial striatum (aDMS) are revealed in many mental disorders in which cognitive inflexibility is commonly observed. However, it remains poorly understood whether the aDMS plays a special role in flexible cognitive control and what the regulation pattern is in different neuronal populations. Based on the reversal learning task in mice, we showed that optogenetic activation in dopamine receptor 1-expressing medium spiny neurons (D1R-MSNs) of the aDMS impaired flexibility; meanwhile, suppressing these neurons facilitated behavioral performance. Conversely, D2R-MSN activation accelerated reversal learning, but it induced no change through neuronal suppression. The acquisition and retention of discrimination learning were unaffected by the manipulation of any type of MSN. Through bi-direct optogenetic modulation in D1R-MSNs of the same subject in a serial reversal learning task, we further revealed the function of D1R-MSNs during different stages of reversal learning, where inhibiting and exciting the same group of neurons reduced perseverative errors and increased regressive errors. Following D1R- and D2R-MSN activation in the aDMS, neuronal activity of the mediodorsal thalamus decreased and increased, respectively, in parallel with behavioral impairment and facilitation, but not as a direct result of the activation of the striatal MSNs. We propose that D1R- and D2R-MSN sub-populations in the aDMS exert opposing functions in cognitive flexibility regulation, with more important and complex roles of D1R-MSNs involved. Mental disorders with cognitive flexibility problems may feature an underlying functional imbalance in the aDMS’ two types of neurons.
KeywordsAnterior dorsomedial striatum Behavioral flexibility Optogenetics Medium spiny neurons Dopamine receptors
This work was supported by National Natural Science Foundation of China (31571108), Beijing Natural Science Foundation (5162023) and the National Key Basic Research Program of China (2015CB553501).
XYW, YHQ and ZHD performed experiments; XYW analyzed data and wrote the manuscript; JL and NS designed experiments; FS and JJZ managed animal and designed animal model; JL and XYW finished the paper.
Compliance with ethical standards
Research involves animal participants. All procedures were approved by Institutional Review Board of the Institute of Psychology, Chinese Academy of Sciences, and were in compliance with the National Institutes of Health Guide for Care and Use of Laboratory Animals.
All the co-authors are informed and in agreement on this submission. The authors declare that there is no conflict of interests to this work.
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