{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T04:26:50Z","timestamp":1787286410357,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"crossref","award":["MSCA2024_0000071 (AGRI_PNRR_RICERCA25_01)"],"award-info":[{"award-number":["MSCA2024_0000071 (AGRI_PNRR_RICERCA25_01)"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"crossref"}]},{"award":["MSCA2024_0000071 (AGRI_PNRR_RICERCA25_01)"],"award-info":[{"award-number":["MSCA2024_0000071 (AGRI_PNRR_RICERCA25_01)"]}],"id":[{"id":"https:\/\/ror.org\/0341vw408","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Brain-derived neurotrophic factor (BDNF) impacts parasympathetic nervous system function by increasing the excitability of cardioinhibitory parasympathetic neurons in the brainstem, ultimately lowering heart rate (HR) and heightening resting parasympathetic tone. Yet, whether BDNF and its high-affinity receptor\u2014tropomyosin receptor kinase B (TrkB)\u2014also act more distally, i.e., at the level of cholinergic-sensitive intrinsic cardiac ganglia (ICGs), remains unclear. Hence, we conducted morphological and functional studies in neural crest-specific BDNF knockout mice (ncBDNF KO), a model that selectively ablates BDNF signaling in neural crest-derived autonomic structures, including the intrinsic cardiac nervous system. ncBDNF mice exhibited a significant rise in resting heart rate with unchanged baseline contractile performance, thus supporting the role of endogenous BDNF in maintaining physiological parasympathetic restraint. When examining the ICGs, immunofluorescence analysis revealed a highly compartmentalized organization, with BDNF being predominantly confined to cholinergic neuronal somata and TrkB mainly clustered instead in S100-positive satellite glial cells, thus unveiling a previously unrecognized neuron\u2013glia BDNF\/TrkB ICG pattern. Next, we directly infused BDNF in Langendorff-perfused isolated WT mouse hearts and observed a rapid and reproducible bradycardic response that was abrogated by atropine but potentiated by neostigmine, hence attesting to the cholinergic nature of such bradycardia. Of note, BDNF maintained its positive inotropic effects under muscarinic blockade, as witnessed by the enhanced left ventricular developed pressure, maximal dP\/dt, and rate-pressure product, congruent with direct BDNF-evoked myocardial TrkB agonism. Thus, ICGs are additional relevant relay stations interposed between BDNF\/TrkB signaling and parasympathetic modulation of heart function. Although through different molecular paths, BDNF-mediated modulation of ICG firing can coordinate with the previously reported BDNF positive inotropy\/lusitropy to adapt cardiac performance to increased workload and\/or stress conditions.<\/jats:p>","DOI":"10.3390\/ijms27167403","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T07:58:23Z","timestamp":1787126303000},"page":"7403","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["BDNF\/TrkB Signaling in Intracardiac Ganglia Modulates Cardiac Parasympathetic Tone"],"prefix":"10.3390","volume":"27","author":[{"given":"Jacopo","family":"Agrimi","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze Biomediche, Universit\u00e0 di Padova, 35131 Padova, Italy"},{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9905-6335","authenticated-orcid":false,"given":"Seungho","family":"Jun","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie Anne","family":"Makoudjou","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche, Universit\u00e0 di Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Luisetto","sequence":"additional","affiliation":[{"name":"DISCOG Department of Surgery, Oncology, and Gastroenterology, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Bernardele","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche, Universit\u00e0 di Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7371-2241","authenticated-orcid":false,"given":"Giovanni","family":"Piccolo","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche, Universit\u00e0 di Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenling","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell and Neuro-Vascular Biology, Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5550-4247","authenticated-orcid":false,"given":"Elizabeth H.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan D.","family":"Poston","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoh-suke","family":"Mukouyama","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell and Neuro-Vascular Biology, Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0845-2488","authenticated-orcid":false,"given":"Donald B.","family":"Hoover","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA"},{"name":"Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, TN 37614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazareno","family":"Paolocci","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche, Universit\u00e0 di Padova, 35131 Padova, Italy"},{"name":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1016\/j.jacep.2023.07.023","article-title":"Enhanced Myocardial Adenylyl Cyclase Activity Alters Heart-Brain Communication","volume":"9","author":"Agrimi","year":"2023","journal-title":"JACC Clin. 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