{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T09:02:36Z","timestamp":1781168556509,"version":"3.54.1"},"posted":{"date-parts":[[2026,6,8]]},"group-title":"Neuroscience","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NS121850"],"award-info":[{"award-number":["NS121850"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NS102871"],"award-info":[{"award-number":["NS102871"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Sympathetic preganglionic neurons (SPNs) provide the sole spinal output to the peripheral sympathetic nervous system. Although sympathetic control is traditionally attributed to synaptic integration within the spinal cord and ganglia, the reliability of spike propagation along SPN axons themselves has received little attention. Here, and in companion papers, we show that axonal conduction in adult mouse thoracic SPNs is highly modifiable and constitutes a critical site of sympathetic gain control. Using an\n                  <jats:italic>ex vivo<\/jats:italic>\n                  preparation preserving intact paravertebral and splanchnic pathways while blocking synaptic transmission, we recorded compound action potentials evoked across multiple ganglia. Slower-conducting, unmyelinated SPN axons, particularly those with branching axons traversing the interganglionic nerve (IGN), exhibited pronounced, temperature-dependent conduction failures. Elevation of temperature produced membrane hyperpolarization and loss of conduction, consistent with activation of temperature-sensitive K\n                  <jats:sub>2<\/jats:sub>\n                  P leak channels, as supported by pharmacological evidence. Pharmacological activation of TREK-family channels with riluzole or arachidonic acid preferentially suppressed conduction in these axons. In contrast, blockade of voltage-gated K\n                  <jats:sup>+<\/jats:sup>\n                  channels with 4-aminopyridine (4-AP) robustly facilitated conduction, recruited previously silent axons, and restored propagation under conditions of temperature-induced failure. Surprisingly, tetraethylammonium (TEA) block of K\n                  <jats:sup>+<\/jats:sup>\n                  channels were without effect or depressant. Transmitter systems further shaped axonal reliability: agonists and antagonists of GABA\n                  <jats:sub>A<\/jats:sub>\n                  receptors, as well as cholinergic manipulations, selectively depressed conduction in slow, branching axons. Together, these findings establish SPN axons, particularly slow-conducting branching fibers, as an active and dynamically regulated substrate for sympathetic output control, revealing a presynaptic mechanism with implications for autonomic physiology and disease.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>SIGNIFICANCE<\/jats:title>\n                  <jats:p>Sympathetic output is commonly viewed as being regulated primarily through synaptic integration within spinal and autonomic circuits, while axons are often treated as passive transmission elements. Emerging evidence suggests this assumption is incomplete, particularly in slowly conducting and highly branched sympathetic preganglionic neuron (SPN) axons that may operate near the limits of conduction reliability. This study identifies branch point conduction as a dynamic and pharmacologically modifiable control mechanism governing sympathetic signal transmission. By demonstrating selective vulnerability of distinct SPN populations and revealing strong modulation by potassium channel mechanisms, these findings establish axonal conduction security as an underappreciated site of autonomic gain control. These mechanisms may represent novel therapeutic targets for restoring autonomic function after spinal cord injury and related disorders.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.03.729634","type":"posted-content","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T14:25:11Z","timestamp":1780928711000},"source":"Crossref","is-referenced-by-count":0,"title":["Ion channel and receptor-mediated regulation of axonal conduction reliability in sympathetic preganglionic neurons"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6388-493X","authenticated-orcid":false,"given":"Mallika","family":"Halder","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Emory University, Atlanta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6970-9067","authenticated-orcid":false,"given":"Shawn","family":"Hochman","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Emory University, Atlanta"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061101500926000_2026.06.03.729634v1.1","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1080\/10641960802251867","article-title":"Rhythmic Discharge Induced by Temperature Variation and Drugs in Isolated Sympathetic Ganglia","volume":"30","year":"2008","journal-title":"Clinical and Experimental Hypertension"},{"key":"2026061101500926000_2026.06.03.729634v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22691-2"},{"key":"2026061101500926000_2026.06.03.729634v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/cne.902380203"},{"key":"2026061101500926000_2026.06.03.729634v1.4","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00587.2012"},{"key":"2026061101500926000_2026.06.03.729634v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.12.004"},{"key":"2026061101500926000_2026.06.03.729634v1.6","doi-asserted-by":"crossref","unstructured":"Blum JA , Klemm S , Shadrach JL , Guttenplan KA , Nakayama L , Kathiria A , Hoang PT , Gautier O , Kaltschmidt JA , Greenleaf WJ , Gitler AD (2021) Single-cell transcriptomic analysis of the adult mouse spinal cord reveals molecular diversity of autonomic and skeletal motor neurons. 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