Sex-dependent cognitive and behavioral outcomes induced by repetitive cortical spreading depression in mice
Abstract
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…
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