{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:14:14Z","timestamp":1788480854797,"version":"build-2803163510"},"reference-count":84,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T00:00:00Z","timestamp":1737072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004410","name":"Scientific and Technological Research Council of Turkey","doi-asserted-by":"publisher","award":["118S435"],"award-info":[{"award-number":["118S435"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cortical spreading depolarization (CSD), the neurophysiological event believed to underlie aura, might trigger migraine headaches through inflammatory signalling that originates in neurons and spreads to the meninges via astrocytes. Increasing evidence from studies on rodents and migraine patients supports this hypothesis. The transition from pro-inflammatory to anti-inflammatory mechanisms is crucial for resolving inflammation. However, the resolution of inflammation in the context of CSD and migraine headaches remains poorly understood. This study aims to elucidate the progression of post-CSD inflammatory signalling and its resolution in neurons, astrocytes and microglia in mouse brains.<\/jats:p>\n                  <jats:p>CSD was triggered optogenetically or by pinprick. High mobility group box 1 release, caspase-1 activation and cell-specific activation of nuclear factor kappa B (NF-\u03baB) pairs, along with ensuing transcriptomic changes, were evaluated using immunofluorescence, western blotting, co-immunoprecipitation, fluorescence resonance energy transfer analysis and cell-specific transcriptomics.<\/jats:p>\n                  <jats:p>Our findings indicate that after the initial burst, high mobility group box 1 release from neurons ceased, and caspase-1 activation, which peaked 1\u2005h post-CSD, diminished within 3\u20135\u2005h. This suggests that pro-inflammatory stimuli driving inflammatory signalling decreased within hours after CSD. Pro-inflammatory NF-\u03baB p65:p50 pairs, along with anti-inflammatory cRel:p65 pairs, were detected in astrocyte nuclei shortly after CSD. However, 24\u2005h post-CSD, the former had disappeared whereas the latter persisted, indicating a shift from pro- to anti-inflammatory activity in astrocytes. Pathway analysis of cell-specific transcriptomic data confirmed NF-\u03baB-related pro-inflammatory transcription in astrocytes 1\u2005h post-CSD, whereas no such activity was observed in neurons. Detailed transcriptomic analysis with Bayesian cell proportion reconstruction revealed that microglia exhibited transcriptional changes trending towards an anti-inflammatory profile, along with upregulation of several chemokines and cytokines (e.g. tumour necrosis factor). This suggests that microglia might play a role in supporting the inflammatory responses in astrocytes through the release of these mediators. The upregulation of genes involved in chemotaxis (e.g. Ccl3) and spine pruning (e.g. C1q) in microglia implies that microglia might contribute to synaptic repair, while inflammatory signalling in astrocytes could potentially modulate meningeal nociceptor activity through an extensive astrocyte endfeet syncytium abutting subarachnoid and perivascular spaces, although direct evidence remains incomplete. This nuanced understanding of the inflammatory response in CNS cell types highlights the intricate cellular interactions and responses to CSD.<\/jats:p>\n                  <jats:p>Following a single CSD, distinct transcriptomic responses occur in neurons, astrocytes and microglia, driving inflammatory and anti-inflammatory responses, potentially contributing to headache initiation and resolution.<\/jats:p>","DOI":"10.1093\/brain\/awaf015","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T06:32:02Z","timestamp":1737095522000},"page":"2522-2536","source":"Crossref","is-referenced-by-count":29,"title":["Spreading depolarization triggers pro- and anti-inflammatory signalling: a potential link to headache"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4764-8624","authenticated-orcid":false,"given":"Zeynep","family":"Kaya","sequence":"first","affiliation":[{"name":"Institute of Neurological Sciences and Psychiatry, Hacettepe University , 06230 Ankara ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nevin","family":"Belder","sequence":"additional","affiliation":[{"name":"Institute of Neurological Sciences and Psychiatry, Hacettepe University , 06230 Ankara ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melike","family":"Sever-Bahcekapili","sequence":"additional","affiliation":[{"name":"Institute of Neurological Sciences and Psychiatry, Hacettepe University , 06230 Ankara ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u015eefik Evren","family":"Erdener","sequence":"additional","affiliation":[{"name":"Institute of Neurological Sciences and Psychiatry, Hacettepe University , 06230 Ankara ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buket","family":"D\u00f6nmez-Demir","sequence":"additional","affiliation":[{"name":"Institute of Neurological Sciences and Psychiatry, Hacettepe University , 06230 Ankara ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Canan","family":"Ba\u011fc\u0131","sequence":"additional","affiliation":[{"name":"Institute of Neurological Sciences and Psychiatry, Hacettepe University , 06230 Ankara ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merve Nur","family":"K\u00f6ro\u011flu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Institute of Health Sciences, Ac\u0131badem Mehmet Ali Ayd\u0131nlar University , 34684 Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaya","family":"Bilguvar","sequence":"additional","affiliation":[{"name":"Departments of Neurosurgery and Genetics, Yale Program on Neurogenetics, Yale Center for Genome Analysis, Yale School of Medicine , New Haven, CT 06516 ,","place":["USA"]},{"name":"Department of Medical Genetics, School of Medicine, Department of Translational Medicine, Genome Studies and Biostatistics and Bioinformatics, Institute of Health Sciences, Acurare, Acibadem Mehmet Ali Ayd\u0131nlar University , 34684 Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3943-7819","authenticated-orcid":false,"given":"Turgay","family":"Dalkara","sequence":"additional","affiliation":[{"name":"Institute of Neurological Sciences and Psychiatry, Hacettepe University , 06230 Ankara ,","place":["Turkey"]},{"name":"Departments of Neuroscience and Molecular Biology and Genetics, Bilkent University , 06800 Ankara ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,1,17]]},"reference":[{"key":"2025070715520508400_awaf015-B1","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1002\/9781118967225.ch16","volume-title":"Neurobiological basis of 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