Viola Salvini
Riccardo Accioli
Pietro Enea Lazzerini
Maurizio Acampa- 1Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
- 2Stroke Unit, Department of Emergency-Urgency and Transplants, Azienda Ospedaliera Universitaria Senese, “Santa Maria alle Scotte” General-Hospital, Siena, Italy
Editorial on the Research Topic
New challenges and future perspectives in autonomic neuroscience
Over the last decade, there has been growing interest and important developments in Autonomic Neuroscience research. In this Research Topic, an international selection of high-quality papers highlighted the latest advancements and the improvements in the research techniques, offering new insights into the role of autonomic nervous system (ANS) activity in regulating metabolic pathways and multiple systems such as cardiovascular, gastrointestinal, renal and immune system.
Regarding metabolism, an interesting study conducted by Faber et al. sheds light on the role of the autonomic nervous system in glucose metabolism. Recent independent research has also shown that Pressure Pain Sensitivity (PPS), a parameter that measures the maximum pain and discomfort sensation at the chest bone, in response to a gradually increased pressure during a period of 3–5 s, could serve as an indicator of ANS activity, particularly reflecting the level of ANS disruption (Faber et al., 2021). Considering the significance of the ANS in regulating glucose levels, especially in relation to HbA1c values that mirror the glycaemic control status over the previous 2–3 months (Kohzuma et al., 2021), the use of PPS bears paramount clinical importance. It can serve as both as a diagnostic tool to assess ANS activity and as a potential therapeutic target in managing metabolic disorders.
The impact of ANS on metabolism holds great potential in the context of cardiovascular disease, both indirectly, as seen before in the correction of main risk factors such as diabetes, and directly, by influencing heart rate. Kaminosono et al. introduced an innovative approach to heart rate control, using optogenetic cardiac pacing as an alternative to conventional methods like electrical stimulation or drug administration. Their animal models provided compelling evidence linking light-induced myocardial contraction with vital functions such as blood flow and respiration rhythm, leading to heart rate recovery in bradycardic mice. This groundbreaking method could pave the way for less invasive pacemaker development that eliminates the need for pacing leads. Patients with type II diabetes and high cardiovascular risk are often prone to the development of kidney disease (Wanner et al., 2016) and renal congestion similar to heart failure (HF) patients (Seo et al., 2020). The assessment of left and right doppler-derived intrarenal venous flow (IRVF) has emerged as a valuable biomarker to evaluate renal circulation and predict cardiovascular disease prognosis (Iida et al., 2016). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated their efficacy in improving the prognosis of patients with HF with reduced ejection fraction (HFrEF) and slowing down renal disease development in type II diabetes patients (Packer et al., 2020). By evaluating IRVF and administering SGLT2i, clinicians can effectively guide decongestion therapy. Another promising approach is neuromodulation, a novel treatment for HF that utilizes vagus nerve stimulation (VNS) to produce multiple cardioprotective effects (Hadaya and Ardell, 2020). In this regard, the case report by Nagai et al. showed the positive impact of transcutaneous VNS (tVNS) and SGLT-2i administration on modifying IRVF in a 77-year-old patient with HF with preserved ejection fraction (HFpEF), resulting in reduced renal congestion for HFpEF patients.
Another interesting study by Johnson et al. aimed to search for reliable markers to distinguish sacral parasympathetic nerves from other extrinsic and intrinsic nerves in the human colon, in order to better comprehend their functional role and the clinical significance of their disruption. Bowel innervation can be divided into two components: a descending innervation, which typically involves the proximal part of the bowel, and an ascending innervation, which typically involves the distal part. In this context, the authors have found that ascending nerves can be distinguished in the colorectum of humans using glucose transporter type 1 (GLUT1) labeling combined with NF200. As regards the control of gastric function, the local GABA(γ-aminobutyric acid)ergic signaling in the dorsal vagal complex plays an essential role (Gillis et al., 2022). Less well-known is the role of the GABAB receptor (Gillis et al., 2022). Injection of baclofen, a selective GABAB receptor agonist in the dorsal motor nucleus of the vagus (DMV), increases gastric tone and motility. Still to be evaluated is the effect of baclofen on gastric motility in the nucleus of the solitary tract (NTS). In their study Bellusci et al. compared the activation of the GABAB receptor on the NTS by microinjecting baclofen into the NTS, and monitoring intragastric pressure. They also compare its action to optogenetic activation of somatostatin (SST). The results of this study show that GABAB receptors in the NTS significantly increase gastric motility and tone. Optogenetic stimulation in vivo and in vitro suggests that these baclofen-activated receptors suppress glutamatergic sensory vagal afferents in the NTS and also inhibit interneurons and inhibitory neurons projecting to the DMV, which, in turn, increase motility through a cholinergic excitatory pathway to the stomach.
An acquired autoimmune disorder of ANS is represented by autoimmune autonomic gangliopathy (AAG), characterized by autonomic dysfunction, including sympathetic and parasympathetic failure (Vernino et al., 2000). In their study Yamakawa et al. established a mouse model of AAG representing an autoimmune dysautonomia, associated with MHC class II, to understand the pathogenic mechanism and pathogenicity of nicotinic acetylcholine receptor (nAChR) antibodies. The amino acid sequence of mouse nAChRα3 protein was analyzed using an epitope prediction tool to predict possible MHC class II binding mouse nAChRα3 peptides. The authors provided evidence that active immunization of mice with nAChRα3 peptides causes autonomic dysfunction as similarly occurs in human AAG, suggesting a mechanism by which different MHC class II molecules could preferentially influence the nAChR-specific immune response, thus controlling the diversification of the autoantibody response.
In conclusion, this Research Topic has made remarkable contributions, significantly advancing our understanding of various aspects within Autonomic Neuroscience. These studies have shed light on intricate and complex interrelationships between different systems, offering crucial clinical implications for patient management. Moreover, the valuable insights and recommendations provided pave the way for further exploration in this rapidly evolving field.
Author contributions
VS: Conceptualization, Writing—original draft, Writing—review and editing. RA: Conceptualization, Writing—original draft, Writing—review and editing. PL: Conceptualization, Writing—original draft, Writing—review and editing. MA: Conceptualization, Writing—original draft, Writing—review and editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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References
Faber, J., Eldrup, E., Selmer, C., Pichat, C., Hecquet, S. K., Watt, T., et al. (2021). Reduction of pressure pain sensitivity as novel non-pharmacological therapeutic approach to type 2 diabetes: a randomized trial. Front. Neurosci. 15, 613858. doi: 10.3389/fnins.2021.613858
Gillis, R. A., Dezfuli, G., Bellusci, L., Vicini, S., and Sahibzada, N. (2022). Brainstem neuronal circuitries controlling gastric tonic and phasic contractions: a review. Cell. Mol. Neurobiol. 42, 333–360. doi: 10.1007/s10571-021-01084-5
Hadaya, J., and Ardell, J. L. (2020). Autonomic modulation for cardiovascular disease. Front. Physiol. 11, 617459. doi: 10.3389/fphys.2020.617459
Iida, N., Seo, Y., Sai, S., Machino-Ohtsuka, T., Yamamoto, M., Ishizu, T., et al. (2016). Clinical implications of intrarenal hemodynamic evaluation by doppler ultrasonography in heart failure. JACC Heart Fail. 4, 674–682. doi: 10.1016/j.jchf.2016.03.016
Kohzuma, T., Tao, X., and Koga, M. (2021). Glycated albumin as biomarker: evidence and its outcomes. J. Diabetes Complicat. 35, 108040. doi: 10.1016/j.jdiacomp.2021.108040
Packer, M., Anker, S. D., Butler, J., Filippatos, G., Pocock, S. J., Carson, P., et al. (2020). Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Engl. J. Med. 383, 1413–1424. doi: 10.1056/NEJMoa2022190
Seo, Y., Iida, N., Yamamoto, M., Ishizu, T., Ieda, M., and Ohte, N. (2020). Doppler-derived intrarenal venous flow mirrors right-sided heart hemodynamics in patients with cardiovascular disease. Circ. J. 84, 1552–1559. doi: 10.1253/circj.CJ-20-0332
Vernino, S., Low, P. A., Fealey, R. D., Stewart, J. D., Farrugia, G., and Lennon, V. A. (2000). Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N. Engl. J. Med. 343, 847–855. doi: 10.1056/NEJM200009213431204
Keywords: heart failure, autonomic nervous system, GLUT1, GABAB receptor agonists, Pressure Pain Sensitivity, gangliopathy
Citation: Salvini V, Accioli R, Lazzerini PE and Acampa M (2023) Editorial: New challenges and future perspectives in autonomic neuroscience. Front. Neurosci. 17:1271499. doi: 10.3389/fnins.2023.1271499
Received: 02 August 2023; Accepted: 10 August 2023;
Published: 23 August 2023.
Edited and reviewed by: Joel C. Bornstein, The University of Melbourne, Australia
Copyright © 2023 Salvini, Accioli, Lazzerini and Acampa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Maurizio Acampa, m.acampa@ao-siena.toscana.it