Inhibition of Posterior Thalamic Nuclei Attenuates CGRP-induced Migraine-like Behavior in Mice

Greenway, A.; Huebner, M.; Waite, J.; Flinn, H.; Rea, B.; Buxton, T.; Duong, T.; Wang, M.; Uemura, H.; Dorricott, N.; Tutt, J.; Wang, K.; Russo, A.; Sowers, L.

doi:10.1101/2025.03.03.641257

bioRxiv · 10.1101/2025.03.03.641257

Inhibition of Posterior Thalamic Nuclei Attenuates CGRP-induced Migraine-like Behavior in Mice

Greenway, A.·Huebner, M.·Waite, J.·Flinn, H.·Rea, B.·Buxton, T.·Duong, T.·Wang, M.·Uemura, H.·Dorricott, N.·Tutt, J.·Wang, K.·Russo, A.·Sowers, L.

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Abstract

ObjectiveTo determine whether induction of migraine-like symptoms in mice by calcitonin gene-related peptide (CGRP) requires activation of the posterior thalamic nuclei (PoT) in the brain.BackgroundPrevious research found that both optical activation of the PoT and injection of CGRP into the PoT are sufficient to induce light aversive behavior in mice. The PoT is well known as a sensory integration center of light and pain signals in the brain. However, whether this region is required for touch hypersensitivity and light aversion following peripheral administration of CGRP was not known.MethodsThe PoT was injected in two strains of mice, inbred C57BL/6J and outbred CD-1, with viral vectors expressing inhibitory chemogenetic Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). The inhibitory DREADDs were activated by systemic intraperitoneal (ip) injection of two designer drugs, clozapine N-oxide (CNO) and DREADD agonist compound 21 (C21). We used ip injection of CGRP to induce migraine-like phenotypes and tested whether we could rescue these phenotypes by bilateral chemogenetic inhibition of the PoT. The light/dark assay was used to measure light aversive behavior (a surrogate for photophobia) and the plantar von Frey assay to measure hindpaw touch sensitivity (a surrogate for extracephalic allodynia).ResultsWe successfully induced light aversive and hindpaw touch hypersensitivity phenotypes in mice using ip injections of CGRP. Activation of the inhibitory DREADDs in the PoT using ip CNO (5 mg/kg) was sufficient to partially rescue the touch hypersensitivity phenotype, but with off target effects in the control mice. Lowering the CNO dose to 1 mg/kg alleviated off target effects but was insufficient to rescue the touch hypersensitivity phenotype. On the other hand, C21 (1 mg/kg) fully rescued the touch hypersensitivity phenotype without any off target effects. Treatment with C21 also partially rescued the light aversion phenotype. These results were consistent across both C57BL/6J and CD-1 mouse strains.ConclusionInhibition of the PoT fully rescues CGRP-induced touch hypersensitivity and partially rescues light aversion in mice, indicating that the PoT is necessary for touch hypersensitivity and partially necessary for light aversive behaviors. These data suggest the PoT is part of a central network that receives peripheral CGRP-induced signals and thus could be harnessed for future targeted therapeutics for migraine.Plain language summaryThe posterior thalamus is a central brain region that contributes to migraine pathophysiology when stimulated. In this study, we asked if inhibition of this brain region could alleviate migraine-like phenotypes in mice. We found that inhibition of the posterior thalamus fully rescues touch hypersensitivity and partially rescues light aversive behavior, suggesting that the posterior thalamus is necessary for migraine pathophysiology and could offer a potential therapeutic target for migraine.

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Greenway, A., Huebner, M., Waite, J., Flinn, H., Rea, B., Buxton, T., Duong, T., Wang, M., Uemura, H., Dorricott, N., Tutt, J., Wang, K., Russo, A., Sowers, L.. 2025-03-10. Inhibition of Posterior Thalamic Nuclei Attenuates CGRP-induced Migraine-like Behavior in Mice. https://doi.org/10.1101/2025.03.03.641257

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