Inhibiting actions inappropriate for the behavioral context, or inhibitory control, is essential for survival and involves both reactively stopping the current prepared action and proactively adjusting behavioral tendencies to increase future performance. A powerful paradigm widely used in basic and clinical research to study inhibitory control is the stop signal task (SST). Recent years have seen a surging interest in translating the SST to rodents to study the neural mechanisms underlying inhibitory control. However, significant differences in task designs and behavioral strategies between rodent and primate studies have made it difficult to directly compare the two literatures. In this study, we developed a rodent-appropriate SST and characterized both reactive and proactive control in rats. For reactive inhibitory control, we found that, unlike in primates, incorrect stop trials in rodents result from two independent types of errors: an initial failure-to-stop error or, after successful stopping, a subsequent failure-to-wait error. Conflating failure-to-stop and failure-to-wait errors systematically overestimates the covert latency of reactive inhibition, the stop signal reaction time (SSRT). To correctly estimate SSRT, we developed and validated a new method that provides an unbiased SSRT estimate independent of the ability to wait. For proactive inhibitory control, we found that rodents adjust both their reaction time and the ability to stop following failure-to-wait errors and successful stop trials, but not after failure-to-stop errors. Together, these results establish a valid rodent model that utilizes proactive and reactive inhibitory control strategies similar to primates, and highlight the importance of dissociating initial stopping from subsequent waiting in studying mechanisms of inhibitory control using rodents.
The therapeutic potential of histone deacetylase inhibitor (HDACi) treatment has attracted considerable attention in the emerging area of cognitive neuroepigenetics. The possibility that ongoing cognitive experience importantly regulates the cell biological effects of HDACi administration, however, has not been systematically examined. In an initial experiment addressing this issue, we tested whether water maze training influences the gene expression response to acute systemic HDACi administration in the young adult rat hippocampus. Training powerfully modulated the response to HDACi treatment, increasing the total number of genes regulated to nearly 3000, including many not typically linked to neural plasticity, compared with Ͻ300 following HDACi administration alone. Although water maze training itself also regulated nearly 1800 genes, the specific mRNAs, gene networks, and biological pathways involved were largely distinct when the same experience was provided together with HDACi administration. Next, we tested whether the synaptic protein response to HDACi treatment is similarly dependent on recent cognitive experience, and whether this plasticity is altered in aged rats with memory impairment. Whereas synaptic protein labeling in the young hippocampus was selectively increased when HDACi administration was provided in conjunction with water maze training, combined treatment had no effect on synaptic proteins in the aged hippocampus. Our findings indicate that ongoing experience potently regulates the molecular consequences of HDACi treatment and that the interaction of recent cognitive experience with histone acetylation dynamics is disrupted in the aged hippocampus.
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