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Restrained animals are discarded from the analysis due to the effect of restraint on the brain injury as first demonstrated by Thoresen et al 1996. However, the effects of restraint on responses to hypothermic (HT) post\u2010insult therapy are not well described. We examine the effects of restraint associated with different probe placements on HI brain injury. We have conducted a meta\u2010analysis of 23 experiments comparing probe rats (skin <jats:italic>n<\/jats:italic>\u00a0=\u200942, rectal <jats:italic>n<\/jats:italic>\u00a0=\u200935) and free\u2010moving matched non\u2010probe controls (<jats:italic>n<\/jats:italic>\u00a0=\u200980) that underwent HI injury (left common carotid artery ligation and 90\u2009min 8% O<jats:sub>2<\/jats:sub>) at postnatal day 7 (P7), followed by 5\u00a0h of NT (37\u00b0C) or HT (32\u00b0C). On P14, brain regions were analyzed for injury (by neuropathology and area loss), microglial reactivity and brain\u2010derived neurotrophic factor (BDNF). HI injury was mitigated in NT skin and rectal probe rats, with greater neuroprotection among the rectal probe rats. Following HT, the skin probe rats maintained the restraint\u2010associated neuroprotection, while brain injury was significantly exacerbated among the rectal probe rats. Microglial reactivity strongly correlated with the acquired injury, with no detectable difference between the groups. Likewise, we observed no differences in BDNF signal intensity. Our findings suggest a biphasic neuroprotection from restraint stress, which becomes detrimental in combination with HT and the presumed discomfort from the rectal probe. This finding is useful in highlighting unforeseen effects of common experimental designs or routine clinical management.<\/jats:p>","DOI":"10.14814\/phy2.15562","type":"journal-article","created":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T07:00:15Z","timestamp":1673593215000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Restraint stress during neonatal hypoxia\u2010ischemia alters brain injury following normothermia and hypothermia"],"prefix":"10.14814","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8064-7266","authenticated-orcid":false,"given":"Julia K.","family":"Gundersen","sequence":"first","affiliation":[{"name":"Department of Physiology Institute of Basic Medical Sciences, University of Oslo  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hemmen","family":"Sabir","sequence":"additional","affiliation":[{"name":"Department of Physiology Institute of Basic Medical Sciences, University of Oslo  Oslo Norway"},{"name":"Department of Neonatology and Pediatric Intensive Care Children's Hospital University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R.","family":"Wood","sequence":"additional","affiliation":[{"name":"Department of Physiology Institute of Basic Medical Sciences, University of Oslo  Oslo Norway"},{"name":"Department of Pediatrics University of Washington Medical School  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damjan","family":"Osredkar","sequence":"additional","affiliation":[{"name":"Department of Physiology Institute of Basic Medical Sciences, University of Oslo  Oslo Norway"},{"name":"Department of Pediatrics Ljubljana University Hospital  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Falck","sequence":"additional","affiliation":[{"name":"Department of Physiology Institute of Basic Medical Sciences, University of Oslo  Oslo Norway"},{"name":"Department of Pediatrics Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Else M.","family":"Loeberg","sequence":"additional","affiliation":[{"name":"Department of Pathology Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Walloe","sequence":"additional","affiliation":[{"name":"Department of Physiology Institute of Basic Medical Sciences, University of Oslo  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Menassa","sequence":"additional","affiliation":[{"name":"Department of Physiology Institute of Basic Medical Sciences, University of Oslo  Oslo Norway"},{"name":"The Queen's College| University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9615-9109","authenticated-orcid":false,"given":"Marianne","family":"Thoresen","sequence":"additional","affiliation":[{"name":"Department of Physiology Institute of Basic Medical Sciences, University of Oslo  Oslo Norway"},{"name":"Translational Health Sciences, St. Michael's Hospital, Bristol Medical School University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,1,12]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.2000.7492"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.20.8.1113"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.1987.127"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-016-4218-9"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3109\/10253890.2015.1014790"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-4280"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2019.00051"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3892\/br.2012.48"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1159\/000454949"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1159\/000452859"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0117503"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2021.100892"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1159\/000521438"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18010017"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.1999.0275"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2016.00286"},{"key":"e_1_2_10_18_1","first-page":"181","article-title":"Effect of various physical stress models on serum cortisol level in Wistar rats","volume":"8","author":"Jameel M. 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