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Despite the initial site of damage often being injury specific, we have an incomplete understanding of how differential regional susceptibility arises. Recent studies have implicated astrocytes in this phenomenon in mice, showing regional transcriptional heterogeneity in optic nerve astrocytes in response to glaucoma and optic nerve crush. Because astrocytes provide structural support and protection from tissue deformation, we examined the length of the optic nerve for astrocyte morphology differences which could alter its biomechanical properties, and by extension, susceptibility to injury. We report that astrocyte morphology changes along the length of the nerve, with average process angle smoothly rotating in close accordance with a changing tissue environment outside the nerve. Moreover, astrocyte morphology appears driven by the local axonal environment, with cells in the chiasm more closely resembling astrocytes in the brain rather than the rest of the optic nerve or tract- likely due to the complex axon orientation that arises there. Astrocytes in the nerve also exhibit the same neuronal-associated microstructures we identified in our previous work in the retina. These observations open the possibility that astrocytes participate in a feedback loop where their structure responds to local conditions, and in turn, shapes the tissue\u2019s biomechanical properties- modulating its vulnerability to injury which may itself drive changes in the surrounding milieu.<\/jats:p>","DOI":"10.1007\/s12035-025-05552-7","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T20:47:06Z","timestamp":1764362826000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Regional Position and Axonal Environment Shape Astrocyte Morphology in the Mouse Optic Projection"],"prefix":"10.1007","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9304-6013","authenticated-orcid":false,"given":"Joseph Matthew","family":"Holden","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8475-9959","authenticated-orcid":false,"given":"David John","family":"Calkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"5552_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2021.100953","volume":"84","author":"DJ Calkins","year":"2021","unstructured":"Calkins DJ (2021) Adaptive responses to neurodegenerative stress in glaucoma. 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