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We examined the long-term evolution of white matter injury in chronically instrumented preterm fetal sheep (0.7 gestation) after 25\u2009min of complete umbilical cord occlusion or sham occlusion. Fetal brains were processed for histology after 3\u2009days (n\u2009=\u20099, sham n\u2009=\u20099), 7\u2009days (n\u2009=\u20098, sham n\u2009=\u20098), 14\u2009days (n\u2009=\u20099, sham n\u2009=\u20098) and 21\u2009days (n\u2009=\u20099, sham n\u2009=\u20099) of recovery. At 3 and 7\u2009days recovery, umbilical cord occlusion was associated with diffuse white matter injury, with loss of total and mature oligodendrocytes and reduced myelination in both the parietal and temporal lobes. At 14\u2009days after umbilical cord occlusion, extensive microglial and astrocytic activation were observed in the temporal lobe. At 21\u2009days recovery a spectrum of severe white matter degeneration was observed, including white matter atrophy, ventriculomegaly and overt cystic white matter lesions. The most severe injury was observed in the temporal lobe after 21\u2009days recovery, including the majority of cystic lesions, persistent oligodendrocyte maturational arrest and impaired myelination. The spatial distribution of delayed white matter degeneration at 21\u2009days recovery was closely related to the location of dense microglial aggregates at earlier time-points, implicating a role for exuberant inflammation originating from microglial aggregates in the pathogenesis of cystic white matter injury. The delayed appearance of cystic injury is consistent with continuing tertiary evolution of necrotic cell death. This slow evolution raises the tantalizing possibility that there may a relatively long therapeutic window to mitigate the development of cystic white matter injury. Delayed anti-inflammatory treatments may therefore represent a promising strategy to reduce neurodevelopmental disability in the preterm infants.<\/jats:p>","DOI":"10.1093\/braincomms\/fcab024","type":"journal-article","created":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T12:16:26Z","timestamp":1614946586000},"source":"Crossref","is-referenced-by-count":31,"title":["Tertiary cystic white matter injury as a potential phenomenon after hypoxia-ischaemia in preterm f sheep"],"prefix":"10.1093","volume":"3","author":[{"given":"Benjamin A","family":"Lear","sequence":"first","affiliation":[{"name":"The Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8937-0846","authenticated-orcid":false,"given":"Christopher A","family":"Lear","sequence":"additional","affiliation":[{"name":"The Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne O","family":"Davidson","sequence":"additional","affiliation":[{"name":"The Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8655-6426","authenticated-orcid":false,"given":"Jialin","family":"Sae-Jiw","sequence":"additional","affiliation":[{"name":"The Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna M","family":"Lloyd","sequence":"additional","affiliation":[{"name":"The Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0656-7035","authenticated-orcid":false,"given":"Alistair J","family":"Gunn","sequence":"additional","affiliation":[{"name":"The Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Bennet","sequence":"additional","affiliation":[{"name":"The Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"2021042608255100800_fcab024-B1","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/dmcn.14011","article-title":"Cerebral palsy trends in Australia (1995-2009): A population-based observational study","volume":"61","author":"Galea","year":"2019","journal-title":"Dev Med Child Neurol"},{"key":"2021042608255100800_fcab024-B2","doi-asserted-by":"crossref","first-page":"101114","DOI":"10.1016\/j.siny.2020.101114","article-title":"Have outcomes following extremely preterm birth improved over time?","volume":"25","author":"Cheong","year":"2020","journal-title":"Semin Fetal Neonatal Med"},{"key":"2021042608255100800_fcab024-B3","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1001\/archneur.1962.04210050022004","article-title":"Periventricular leukomalacia of infancy. 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