ArticleThe journal of headache and pain2026
A GABAergic neural circuit from the suprachiasmatic nucleus to DG drives cognitive impairment in migraine mice.
Article in The journal of headache and pain, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundCognitive impairment and circadian rhythm disturbances are prevalent comorbidities of migraine, yet their underlying neural circuit mechanisms remain poorly understood. The suprachiasmatic nucleus (SCN), as the master circadian pacemaker, and the hippocampus, essential for memory, are key regions involved in these symptoms. The dentate gyrus (DG) in the hippocampus acts as the main entry point for information and is essential for pattern separation, a key memory process. We hypothesized that a direct neural pathway from the SCN to the DG might link circadian dysfunction to cognitive deficits in migraine.
methodsUsing a nitroglycerin (NTG)-induced chronic migraine mouse model, we combined behavioral assays, immunofluorescence, chemogenetics, monosynaptic retrograde tracing, and projection-specific optogenetics to investigate the role of the SCN and its potential connection to the DG in migraine-related cognitive impairment.
resultsNTG-treated mice exhibited not only pain hypersensitivity but also significant circadian rhythm disruption and deficits in recognition and spatial working memory. Our immunofluorescence analysis revealed a marked increase in c-Fos expression within the SCN of NTG-induced migraine mice. Notably, despite increased total c-Fos expression in the SCN, the density and proportion of c-Fos⁺/GAD67⁺ cells were reduced, whereas c-Fos⁺/CaMKII⁺ cells showed no significant change. These findings indicate an altered recruitment of neuronal subpopulations rather than uniform changes in SCN neuronal activity. This interpretation was further supported by chemogenetic manipulation of SCN neurons, in which inhibition exacerbated, whereas activation rescued, cognitive deficits without affecting pain sensitivity. Immunostaining revealed increased c-Fos recruitment of GABAergic interneurons in the DG. Using convergent anterograde and retrograde tracing approaches, we obtained anatomical evidence supporting the presence of a direct SCN→DG projection with preferential association to DG inhibitory interneuron populations. Projection-specific optogenetic activation of SCN terminals in the DG was sufficient to reverse cognitive impairments in migraine mice.
conclusionsOur research reveals a previously underappreciated GABAergic pathway from the SCN to the DG that is functionally implicated in cognitive deficits associated with migraine. The findings suggest that migraine is associated with altered recruitment of neuronal subpopulations and network-level coordination within the SCN and along the SCN-DG pathway. This is accompanied by increased recruitment of GABAergic interneurons in the DG and impaired DG information processing. Together, these results identify the SCN-DG circuit as a potential neuromodulatory target for future investigation of cognitive symptoms associated with migraine.
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