Concurrent LI-rTMS induces changes in c-Fos expression but not behavior during a progressive ratio task with adult ephrin-A2A5-/- mice

Changes within the dopaminergic system induced by repetitive transcranial magnetic stimulation (rTMS) may contribute to its therapeutic effects; however, dopamine-related behavioral effects of rTMS have not been widely investigated. We recently showed that ephrin-A2A5(-/-) mice completed significantly fewer trials in a visual task than wildtype mice, and that concurrent low-intensity (LI-) rTMS during the task could partially rescue the abnormal behavior [Poh et al. 2018, eNeuro, vol. 5]. Here, we investigated whether the behavioral differences in ephrin-A2A5(-/-) mice are due to abnormal motivation, primarily a dopamine-modulated behavior, and whether LI-rTMS would increase motivation. Ephrin-A2A5(-/-) and wildtype mice underwent 14 daily sessions of progressive ratio (PR) tasks and received either sham or LI-rTMS during the first 10 min. Ephrin-A2A5(-/-) mice responded more than wildtype comparisons, and LI-rTMS did not influence task performance for either strain. Therefore concurrent stimulation does not influence motivation in a PR task. However, ephrin-A2A5(-/-) mice did have abnormal performance in the PR tasks after a change in the PR schedule which suggests perseverative behavior. We stained for c-Fos in the prelimbic area (PrL), ventral tegmental area and nucleus accumbens (NAc) core and shell to examine neuronal activity from the final PR session. Sham ephrin-A2A5(-/-) mice had lower c-Fos expression in the PrL and NAc vs. wildtype mice. Ephrin-A2A5(-/-) mice that received LI-rTMS showed c-Fos expression closer to wildtype levels in the NAc. Combined with high PR performance, ephrin-A2A5(-/-) mice show an abnormal shift to habitual responding and LI-rTMS may attenuate this shift.

Automated summary

Changes in the dopaminergic system induced by rTMS may contribute to its therapeutic effects, with ephrin-A2A5(-/-) mice showing abnormal behavior in visual tasks, partially rescued by LI-rTMS stimulation. However, LI-rTMS did not influence task performance in progressive ratio tasks for ephrin-A2A5(-/-) and wildtype mice. Neuronal activity examination revealed lower c-Fos expression in specific brain regions in sham ephrin-A2A5(-/-) mice, suggesting LI-rTMS could attenuate the abnormal shift to habitual responding seen in these mice.