Abstract
Aneurysmal subarachnoid hemorrhage (SAH) leads to significant long-term cognitive deficits. Studies in survivors of SAH show an association between persistent cognitive deficits and alterations in resting state functional connectivity (RSFC). However, modalities commonly used to assess RSFC in humans, such as fMRI, have practical limitations in small animals. Therefore, we used non-invasive functional optical intrinsic signal imaging to determine the effect of SAH on measures of RSFC in mice at early (day 4), intermediate (1 month), and late (3 months) time points after prechiasmatic arterial blood injection. We assessed Morris water maze, open field test, Y-maze, and rotarod performance from approximately 2 weeks to 3 months after SAH induction. We found qualitative and quantitative differences in seed-based connectivity maps between sham and SAH mice. SAH reduced motor, retrosplenial and visual seed-based connectivity indices, which persisted in retrosplenial and visual cortex seeds at 3 months. Seed-to-seed connectivity analysis confirmed attenuation of correlation coefficients in SAH mice, which persisted in predominantly posterior network connections at later time points. Seed-independent global and interhemispheric indices of connectivity revealed decreased correlations following SAH for at least 1 month. SAH led to Morris water maze hidden platform and open field deficits at 2 weeks, and Y-maze deficits for at least 3 months, without altering rotarod performance. In conclusion, experimental SAH leads to early and persistent alterations both in hemodynamically-derived measures of RSFC and in cognitive performance.
Footnotes
Funding: This work was funded by the National Institutes of Health (R25NS065743, KL2TR002542, and K08NS112601 to D.Y.C., UL1 TR001102 to H.L., R00AG042026 and R01AA027097 to M.A.Y., R01NS091230 and R01MH111359 to S.S., and P01NS055104 and R01NS102969 to C.A.); the American Heart Association and American Stroke Association (18POST34030369 to D.Y.C.); Japanese Heart Foundation and Bayer Yakuhin Research Grant Abroad (F.O.); the Andrew David Heitman Foundation (D.Y.C. and C.A.); the Aneurysm and AVM Foundation (D.Y.C.); and the Brain Aneurysm Foundation’s Timothy P. Susco and Andrew David Heitman Foundation Chairs of Research (D.Y.C.).