{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:10:15Z","timestamp":1792786215367,"version":"4.5.0"},"posted":{"date-parts":[[2025,8,24]]},"group-title":"Neuroscience","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T00:00:00Z","timestamp":1755993600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Neurological Disorders and Stroke","award":["R01NS135005"],"award-info":[{"award-number":["R01NS135005"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of General Medical Sciences","id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"crossref"}]},{"award":["FG-2024-21522"],"award-info":[{"award-number":["FG-2024-21522"]}],"id":[{"id":"https:\/\/ror.org\/052csg198","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/003ghvj67","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Proprioceptive group Ia afferents detect muscle stretch to guide effortless and purposeful movement and make monosynaptic connections with spinal a-motor neurons to mediate reflexes, such as the stretch reflex. It is thought that proprioceptive Ia afferents target motor neurons of the same spinal segment; yet, how this specificity, if any, is established during early development is unknown. Using\n                  <jats:italic>ex vivo<\/jats:italic>\n                  spinal cord electrophysiology preparations from neonatal mice of both sexes, we identified a developmental period during which proprioceptive la afferents evoke both segmental and intersegmental responses at monosynaptic latencies. We provide anatomical evidence that motor neurons in the lumbar segment 4 (L4) receive direct input from proprioceptive Ia afferents in L5 during early postnatal development. Intersegmental responses (L4\/L5) were prominent at postnatal days (P) 4\u20137 but were virtually absent by P11\u201313. To test the role of proprioceptor activity on segmental specification, we analyzed Na\n                  <jats:sub>V<\/jats:sub>\n                  1.6 conditional knockout mice (Na\n                  <jats:sub>V<\/jats:sub>\n                  1.6\n                  <jats:sup>cKO<\/jats:sup>\n                  ), in which proprioceptor signaling is impaired, and found that intersegmental responses persist up to P11\u201313 but were absent in age-matched floxed controls. We predict this is due to impaired activation of complement signaling pathways, as Na\n                  <jats:sub>V<\/jats:sub>\n                  1.6\n                  <jats:sup>cKO<\/jats:sup>\n                  mice showed reduced C1qA expression in the ventral spinal cord at P9. Consistent with this, C1qA knockout mice also retain intersegmental responses at P11\u201313. Collectively, these findings identify an important postnatal window during which segmental specificity of proprioceptive circuits emerges and suggest that proprioceptor activity induces C1qA-mediated elimination of excessive intersegmental connectivity.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Key points summary<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>During the first ten days of postnatal development, the spinal monosynaptic reflex arc possesses intersegmental proprioceptive afferent projections onto motor neurons of an adjacent segment.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>These exuberant Ia-motoneuron projections are accompanied by evocable intersegmental reflex responses. In normal conditions, the intersegmental response is lost by postnatal day 11. Conversely, in a mouse model of impaired proprioceptive signaling, the intersegmental response persists.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>We find that impaired proprioceptive signaling through the monosynaptic reflex arc leads to low expression levels of the complement signaling protein, C1qA, near ChAT-positive motor neurons, whereas microglia recruitment is unaffected. This was consistent with the persistence of robust intersegmental responses in C1qA knockout mice.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Collectively, our results show that proprioceptor activity induces complement cascade signaling to prune exuberant intersegmental synapses in the spinal cord formed during early development, resulting in segmental restriction of the monosynaptic reflex arc by the end of the second postnatal week.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.08.22.671861","type":"posted-content","created":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T09:45:15Z","timestamp":1756028715000},"source":"Crossref","is-referenced-by-count":0,"title":["Activity-driven proprioceptive synaptic refinement in the developing spinal cord by complement signaling mechanisms"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9768-9462","authenticated-orcid":false,"given":"Chetan","family":"Nagaraja","sequence":"first","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4872-1360","authenticated-orcid":false,"given":"Serena","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7696-0505","authenticated-orcid":false,"given":"Akash R.","family":"Murali","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA, USA"},{"name":"Undergraduate Program in Neurobiology, Physiology and Behavior, University of California, Davis, Davis, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiza","family":"Sarwar","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA, USA"},{"name":"Undergraduate Program in Neurobiology, Physiology and Behavior, University of California, Davis, Davis, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0090-6286","authenticated-orcid":false,"given":"Theanne N.","family":"Griffith","sequence":"additional","affiliation":[{"name":"Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA, USA"},{"name":"Howard Hughes Medical Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091716251396000_2025.08.22.671861v2.1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2008.159129"},{"key":"2026091716251396000_2025.08.22.671861v2.2","doi-asserted-by":"crossref","first-page":"3201","DOI":"10.1038\/s41598-019-39881-0","article-title":"Dye-coupling between neonatal spinal motoneurons and interneurons revealed by prolonged back-filling of a ventral root with a low molecular weight tracer in the mouse","volume":"9","year":"2019","journal-title":"Scientific Reports"},{"key":"2026091716251396000_2025.08.22.671861v2.3","first-page":"eabq7806","article-title":"Microglia mediate neurocognitive deficits by eliminating C1q-tagged synapses in sepsis-associated encephalopathy","volume":"9","year":"2025","journal-title":"Science Advances"},{"key":"2026091716251396000_2025.08.22.671861v2.4","doi-asserted-by":"publisher","DOI":"10.1038\/nature12776"},{"key":"2026091716251396000_2025.08.22.671861v2.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.275.5298.356"},{"key":"2026091716251396000_2025.08.22.671861v2.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.10.014"},{"key":"2026091716251396000_2025.08.22.671861v2.7","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1957.sp005794"},{"key":"2026091716251396000_2025.08.22.671861v2.8","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1987.sp016676"},{"key":"2026091716251396000_2025.08.22.671861v2.9","doi-asserted-by":"crossref","first-page":"e79917","DOI":"10.7554\/eLife.79917","article-title":"NaV1.1 is essential for proprioceptive signaling and motor behaviors ed. 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