{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T10:10:55Z","timestamp":1781777455871,"version":"3.54.5"},"reference-count":42,"publisher":"IOP Publishing","issue":"1","license":[{"start":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T00:00:00Z","timestamp":1575504000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"},{"start":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T00:00:00Z","timestamp":1575504000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/iopscience.iop.org\/info\/page\/text-and-data-mining"}],"content-domain":{"domain":["iopscience.iop.org"],"crossmark-restriction":false},"short-container-title":["J. Neural Eng."],"published-print":{"date-parts":[[2020,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>\n                  <jats:italic>Objective<\/jats:italic>. In the core of a brain infarct, characterized by severely reduced blood supply, loss of neuronal function is rapidly followed by neuronal death. In peripheral areas of the infarct, the penumbra, damage is initially reversible, and neuronal activity is typically reduced due to ischemia-induced synaptic failure. There is limited understanding of factors governing neuronal recovery or the transition to irreversible damage. Neuronal activity has been shown to be crucial for survival. Consequently, hypoxia induced neuronal inactivity may contribute to cell death, and activation of penumbral neurons possibly improves survival. Adversely, activation increases ATP demand, and a balance should be found between the available energy and sufficient activity. <jats:italic>Approach<\/jats:italic>. We monitored activity and viability of neurons in an <jats:italic>in vitro<\/jats:italic> model of the penumbra, consisting of (rat) neuronal networks on micro electrode arrays (MEAs) under controlled hypoxic conditions. We tested effects of optogenetic and electrical activation during hypoxia. <jats:italic>Main results<\/jats:italic>. Mild stimulation yielded significantly better recovery of activity immediately after re-oxygenation, compared with no stimulation, and a 60%\u201370% higher survival rate after 5 d. Stronger stimulation was not associated with better recovery than no stimulation, suggesting that beneficial effects depend on a delicate balance between sufficient activity and available energy. <jats:italic>Significance<\/jats:italic>. We show that mild activation during hypoxia\/ischemia is beneficial for cell survival in an <jats:italic>in vitro<\/jats:italic> model of the penumbra. This finding opposes the current common belief that suppression of neuronal activity is the cornerstone of neuroprotection during cerebral ischemia, and may open new possibilities for the treatment of secondary brain damage after stroke.<\/jats:p>","DOI":"10.1088\/1741-2552\/ab51d4","type":"journal-article","created":{"date-parts":[[2019,10,28]],"date-time":"2019-10-28T23:03:44Z","timestamp":1572303824000},"page":"016001","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Mild stimulation improves neuronal survival in an in vitro model of the ischemic penumbra"],"prefix":"10.1088","volume":"17","author":[{"given":"Lorenzo","family":"Muzzi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerco","family":"Hassink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marloes","family":"Levers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maikel","family":"Jansman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Frega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannette","family":"Hofmeijer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"van Putten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0605-1437","authenticated-orcid":false,"given":"Joost","family":"le Feber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"266","published-online":{"date-parts":[[2019,12,5]]},"reference":[{"key":"jneab51d4bib001","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1161\/STROKEAHA.111.632943","article-title":"Ischemic cerebral damage: an appraisal of synaptic failure","volume":"43","author":"Hofmeijer","year":"2012","journal-title":"Stroke"},{"key":"jneab51d4bib002","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.brainres.2014.02.027","article-title":"Mild hypoxia affects synaptic connectivity in cultured neuronal networks","volume":"1557","author":"Hofmeijer","year":"2014","journal-title":"Brain Res."},{"key":"jneab51d4bib003","doi-asserted-by":"publisher","first-page":"e0147231","DOI":"10.1371\/journal.pone.0147231","article-title":"Progression of neuronal damage in an in vitro model of the ischemic penumbra","volume":"11","author":"le Feber","year":"2016","journal-title":"PLoS One"},{"key":"jneab51d4bib004","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/S0306-4522(98)00493-X","article-title":"Changes in membrane properties of CA1 pyramidal neurons after transient forebrain ischemia","volume":"90","author":"Gao","year":"1999","journal-title":"in vivo Neuroscience"},{"key":"jneab51d4bib005","doi-asserted-by":"publisher","first-page":"1369","DOI":"10.1161\/01.STR.0000013708.54623.DE","article-title":"Persistent defect in transmitter release and synapsin phosphorylation in cerebral cortex after transient moderate ischemic injury","volume":"33","author":"Bolay","year":"2002","journal-title":"Stroke"},{"key":"jneab51d4bib006","doi-asserted-by":"publisher","first-page":"2138","DOI":"10.1152\/jn.1995.74.5.2138","article-title":"Hippocampal CA1 lacunosum-moleculare interneurons: comparison of effects of anoxia on excitatory and inhibitory postsynaptic currents","volume":"74","author":"Khazipov","year":"1995","journal-title":"J. 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