title: 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 ischaemia, or hypoxia, via the modulation of cellular energy metabolism and angiogenesis. In line with our previous study, neuronal ChAT-immunoreactivity in the ChAT tgm brains was not altered from that in the wild-type (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 behaviours 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 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 vagus nerve activity.
authors.affiliation: Department of Physiology, Nippon Medical School Graduate School of Medicine, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
authors.forename: Shino
authors.initials: S
authors.lastname: Oikawa
authors.affiliation: Department of Physiology, Nippon Medical School Graduate School of Medicine, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kai
authors.affiliation: Institute for Laboratory Animal Research, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Department of Physiology, Nippon Medical School Graduate School of Medicine, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Ohata
authors.affiliation: Department of Physiology, Nippon Medical School Graduate School of Medicine, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Mano
authors.affiliation: Department of Physiology, School of Dentistry, Meikai University, Sakaido, Saitama 350-0283, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Mizoguchi
authors.affiliation: Department of Physiology, Nippon Medical School Graduate School of Medicine, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
authors.forename: Shuei
authors.initials: S
authors.lastname: Sugama
authors.affiliation: Department of Physiology, Nippon Medical School Graduate School of Medicine, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nemoto
authors.affiliation: Department of Physiology, Nippon Medical School Graduate School of Medicine, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Pathology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kurabayashi
authors.affiliation: Department of Physiology, School of Dentistry, Meikai University, Sakaido, Saitama 350-0283, Japan.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Muramoto
authors.affiliation: Department of Physiology, Nippon Medical School Graduate School of Medicine, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kaneda
authors.affiliation: Department of Physiology, Nippon Medical School Graduate School of Medicine, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan k12417853@nms.ac.jp.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kakinuma
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002490:Central Nervous System / Q000201:enzymology / Q000502:physiology*; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013312:Stress, Physiological; D014630:Vagus Nerve / Q000201:enzymology / Q000378:metabolism
chemical_list: D002795:Choline O-Acetyltransferase; D000109:Acetylcholine
keywords: acetylcholine; autonomic nervous system; heart failure; stress; vagus nerve