Non-neuronal cardiac cholinergic system influences CNS via the vagus nerve to acquire a stress-refractory propensity

Abstract

We previously developed cardiac ventricle-specific choline acetyltransferase ( ChAT ) gene-overexpressing transgenic mice ( ChAT tgm), i.e., an in vivo model of the cardiac non-neuronal acetylcholine (NNA) system or non-neuronal cardiac cholinergic system (NNCCS). By using this murine model, we determined that this system was responsible for characteristics of resistance to ischemia, or hypoxia, via the modulation of cellular energy metabolism and angiogenesis. In line with our previous report, neuronal ChAT-immunoreactivity in the ChAT tgm brains was not altered from that in the WT mice brains; in contrast, the ChAT tgm hearts were the organs with the highest expression of the ChAT transgene. ChAT tgm showed specific traits in a central nervous system (CNS) phenotype, including decreased response to restraint stress, less depressive-like and anxiety-like behaviors, and anti-convulsive effects, all of which may benefit the heart. These phenotypes, induced by the activation of cardiac NNCCS, were dependent on the vagus nerve, because vagus nerve stimulation (VS) in wild-type (WT) mice also evoked phenotypes similar to those of ChAT tgm, which display higher vagus nerve discharge frequency; in contrast, lateral vagotomy attenuated these traits in ChAT tgm to levels observed in WT mice. Furthermore, ChAT tgm induced several biomarkers of VS responsible for anti-convulsive and anti-depressive-like effects. These results suggest that the augmentation of the NNCCS transduces an effective and beneficial signal to the afferent pathway, which mimics VS. Therefore, the present study supports our hypothesis that activation of the NNCCS modifies CNS to a more stress-resistant state through the vagus nerve activity.