Academic Journal
Sex-dependent cognitive and behavioral outcomes induced by repetitive cortical spreading depression in mice.
| Τίτλος: | Sex-dependent cognitive and behavioral outcomes induced by repetitive cortical spreading depression in mice. |
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| Συγγραφείς: | An Y; Department of Neurology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.; Medical School of Chinese PLA, Beijing, 100853, China., Wang Y; Beijing Institute of Basic Medical Sciences, Beijing, 100850, China., Yuan H; Xinqiao Hospital and the Second Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China., Pi C; Department of Neurology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China., Yuan C; Department of Neurology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China., Na W; Department of Neurology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.; School of Medicine, Nankai University, Tianjin, 300071, China., He Z; Department of Neurology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.; Medical School of Chinese PLA, Beijing, 100853, China., Lin X; Department of Neurology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.; Medical School of Chinese PLA, Beijing, 100853, China., Ma Z; Department of Neurology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.; Medical School of Chinese PLA, Beijing, 100853, China., Yu S; Department of Neurology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China. yusy1963@126.com., Li Y; Department of Neurology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China. leeyj_317@163.com. |
| Πηγή: | The journal of headache and pain [J Headache Pain] 2026 Mar 20; Vol. 27 (1). Date of Electronic Publication: 2026 Mar 20. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: BioMed Central Country of Publication: England NLM ID: 100940562 Publication Model: Electronic Cited Medium: Internet ISSN: 1129-2377 (Electronic) Linking ISSN: 11292369 NLM ISO Abbreviation: J Headache Pain Subsets: MEDLINE |
| Imprint Name(s): | Publication: [2018]- : [London, United Kingdom] : BioMed Central Original Publication: Milano : Springer Verlag Italia, c2000-c2017. |
| Ιατρικοί όροι (MeSH): | Cortical Spreading Depression*/physiology , Cognition*/physiology , Migraine with Aura*/physiopathology , Migraine with Aura*/psychology , Behavior, Animal*/physiology , Sex Characteristics*, Anxiety/physiopathology ; Hyperalgesia/physiopathology ; Hippocampus/physiopathology ; Neurogenesis/physiology ; Photophobia/physiopathology ; Animals ; Female ; Male ; Mice ; Disease Models, Animal ; Mice, Inbred C57BL |
| Περίληψη: | BACKGROUND: Migraine with aura is clinically linked to cognitive impairment, yet sex differences and underlying mechanisms are unclear. Cortical spreading depression (CSD) is widely regarded as the electrophysiological correlate of migraine aura. Therefore, we utilized a mouse model of repetitive CSD to model recurrent aura events and investigate how this phenomenon modulates behavior and cognition in a sex-dependent manner. METHODS: CSD was repeatedly induced in both male and female mice via epidural KCl application, using six consecutive stimuli at 20-minute intervals. Behavioral tests were performed to assess pain sensitivity, photophobia, anxiety, and cognitive function. Hippocampal neurogenesis and synaptic plasticity were examined via immunofluorescence and electrophysiology respectively. RESULTS: Repetitive CSD induced transient allodynia, which was most prominent on day 1 and fully recovered by day 5. This effect was more pronounced and longer-lasting in female mice. In contrast, photophobia observed in the CSD group was more prevalent in male mice. Repetitive CSD did not trigger anxiety-like behavior on either day 1 or day 7. During the Morris water maze probe trial on day 11, female mice in the CSD group exhibited a reduced number of platform crossings and decreased exploration distance in the target quadrant, while no such difference was observed in male mice. Conversely, in the novel location recognition test conducted on day 9 (with a 30-min interval), the CSD group showed a higher discrimination index than the SHAM group, specifically in female mice. These changes were accompanied by increased hippocampal neurogenesis. Moreover, enhanced long-term potentiation at the perforant path–dentate gyrus synapse was observed in females only. All cognitive alterations had recovered by 21 days post-CSD. CONCLUSIONS: Our study demonstrates that repetitive CSD stimulation elicits distinct, sex-dependent phenotypes. Allodynia was more pronounced and longer-lasting in female mice than in males. Moreover, cognitive alterations were observed only in female mice and exhibited a bidirectional pattern. While repetitive CSD impaired the consolidation or retrieval of long-term reference memory, it transiently enhanced short-term episodic memory. These changes occurred shortly after CSD stimulation and were reversible. Together, these results offer a novel perspective for investigating sex differences in migraine with aura and highlight the dual, dynamic influence of CSD on brain cognitive function. |
| Competing Interests: | Declarations. Ethical approval: All experimental procedures were approved by the Institutional Animal Care and Use Committee, Chinese People’s Liberation Army (PLA) General Hospital, and were performed in accordance with the Regulations for the Administration of Affairs Concerning Experimental Animals. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. |
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| Grant Information: | 82571381 National Natural Science Foundation of China; 82301385 National Natural Science Foundation of China |
| Contributed Indexing: | Keywords: Cognitive function; Cortical spreading depression; Migraine with aura; Sex difference |
| Entry Date(s): | Date Created: 20260321 Date Completed: 20260627 Latest Revision: 20260813 |
| Update Code: | 20260813 |
| PubMed Central ID: | PMC13126778 |
| DOI: | 10.1186/s10194-026-02330-1 |
| PMID: | 41862806 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1129-2377 |
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| DOI: | 10.1186/s10194-026-02330-1 |