Rationale: In our prior work we have studied how rodents respond to ictal respiratory challenges, to better understand ictal respiratory deaths like sudden unexpected death in epilepsy (SUDEP). This work revealed rodents without seizure survive respiratory challenges; rodents in seizure do not; and the carotid bodies significantly impact mortality in this model1,2. Carotid body afferents first synapse in the solitary nucleus (NTS). The formation of the gasp, the last respiratory effort before death, critical to autoresuscitation, lies primarily in the preBötzinger complex (preBötC), with emerging evidence suggesting a contribution of a yet-unnamed group approximately 400 microns rostral to preBötC 3,4. In this study we sought to record directly from these regions during gasps to determine if their activity is changed by seizure.
Methods:
We used 8 urethane anesthetized C57/B6 mice and inserted two Neuropixel probes: one along an anteroposterior tract that spanned the preBötC and the rostral gasp group, and a second along a dorsoventral tract that spanned the solitary nucleus. Using a gas control manifold we subjected mice to anoxic challenges to induce gasping and then recovery. We collected control data and then induced continuous seizure with kainate and repeated the challenges.Results:
We observed three discrete anatomical regions with gasp-associated firing – preBötC, the rostral group, and the NTS, as expected. preBötC associates primarily to normal respiration and does not change as significantly with gasping. Both the NTS and rostral group minimally associate with eupnea but strongly associate with gasping. In seizure neither the rostral group nor preBötC significantly change their associations. The NTS association with gasping is dramatically reduced. See Figure 1.
Figure 1: response of three brain regions to a 30 second anoxic challenge and recovery. The NTS is significantly less associated with ictal gasping than preictal gasping.
Conclusions:
The NTS normally associates with gasping, but this association is significantly reduced in seizure. Prior literature implies the NTS is critical to surviving extreme apnea. Further exploration of the role of NTS neurons in extreme apnea may reveal mechanisms relevant to SUDEP and other deaths in seizure.
These experiments comply with ARRIVE guidelines, the NIH Care and Use of Laboratory Animals, and are approved by the Animal Care and Use Committee of Seattle Children’s.
1. Budde, R. B. et al. Epilepsy Res. (2018).
2. Biggs, E. N., Budde, R. B., Jefferys, J. G. R. & Irazoqui, P. P. Epilepsy Behav. (2022).
3. Bush, N. E. & Ramirez, J.-M. Nat. Neurosci. (2024)
4. Baertsch, N. A., Severs, L. J., Anderson, T. M. & Ramirez, J.-M. Proc. Natl. Acad. Sci. (2019).
Funding:
R01 HL126523