Performance of a Touchscreen-Based Visual Discrimination Task Is Restored with Electrical

Performance of a touchscreen-based visual discrimination task is restored with electrical stimulation of the ventral tegmental area (VTA)in rats sedated with isoflurane

Authors:

Jonathan D. Kenny, Norman E. Taylor, JunZhu Pei, Jie-Yoon Yang, Ksenia Y. Vlasov, Emery N. Brown, Ken Solt

Introduction:Electrical stimulation of the VTArestores righting in anesthetized rats [1]. It is unknown whether VTA stimulation also restores cognitive function. In this studyrats were trained to perform avisual discrimination task to test if VTA stimulation restores performance during isoflurane (ISO)sedation.

Methods:Male Sprague-Dawley rats (n=8) were first trained to perform a visual discrimination task. The chamber was in a sealedenclosure with ports for gas in/outflow and sampling.Two imageswere presented simultaneously on a touchscreen, and ratswere trained totouch the correct image for a food reward. During each 30-minute session, rats were able to initiate a new trial 30 sec after completion of a previous trial. After reaching >85% correct responses for at least 3 consecutive days, the animals underwent stereotaxic implantation ofbipolar stimulation electrodes in the VTA. The rats recovered for at least 7 days, and then were re-introduced to the testing chambers.Three weeks after surgery, the rats recovered to their baseline performance level. A dose-response was then performed by exposing them to steady-state ISO(0.1-0.5%) while performing the cognitive task. The rats were only exposed to one dose of ISO once per week.

After establishing that 0.5% ISO reliably extinguished task performance, once a week (for 5 weeks) the ratsunderwent electrical VTA stimulation during steady-state 0.5% ISO sedation, and task performance was assessed. During week 3, the D1 dopamine receptor antagonist SCH-2330 was administered before VTA stimulation. Fig A shows the anesthesia protocol used to ensure steady-state ISO, while Fig B shows the waveform characteristics of electrical stimulation. Cognitive performance was assessed by: 1) number of trials completed per session, and 2) overall accuracy (percent correct). After completing all experiments, histological analysis of electrode placement was performed. The electrode tip was in the VTA in 5/8 animals. Only these animals were used for analysis.

Results: The trials completed by each rat over time are shown in Fig C (black circles= correct responses, white=incorrect responses). At 0.5% ISO, all rats were heavily sedated, rarely moved, and performed no trials. However, during VTA stimulation 5/5 rats performed the task despite continuous 0.5% ISO(weeks 1,2,4,5). Administration of SCH-23390prior to VTA simulation (week 3)reversibly abolished task performance.Figs D and E show number of trials and accuracy (mean with 95% CIs) for each week. Although VTA stimulation during ISOsedation restored task performance, mean accuracy was not restored to baseline.

Conclusions:At a dose of ISO insufficient to induce loss of righting (0.5%) the ability of rats to perform a visual discrimination task was reliably extinguished, suggesting that this many be a useful endpoint for loss of cognitive function. VTA stimulation restores task performance but not accuracy, and this effect is likely mediated by dopamine. Activation of this dopamine circuit may provide a novel target to treat POCD.

Refs:

[1] Anesthesiology 2014;121:3119

[2] Learning and Memory 2008;15:516