Abstract
Cognitive deficits are among the most severe and pervasive consequences of aneurysmal subarachnoid hemorrhage (SAH). A critical step in developing therapies targeting such outcomes is the characterization of experimentally-tractable pre-clinical models that exhibit multi-domain neurobehavioral deficits similar to those afflicting humans. We therefore searched for neurobehavioral abnormalities following endovascular perforation induction of SAH in mice, a heavily-utilized model. We instituted a functional screen to manage variability in injury severity, then assessed acute functional deficits, as well as activity, anxiety-related behavior, learning and memory, socialization, and depressive-like behavior at sub-acute and chronic time points (up to 1 month post-injury). Animals in which SAH was induced exhibited reduced acute functional capacity and reduced general activity to 1 month post-injury. Tests of anxiety-related behavior including central area time in the elevated plus maze and thigmotaxis in the open field test revealed increased anxiety-like behavior at subacute and chronic time-points, respectively. Effect sizes for subacute and chronic neurobehavioral endpoints in other domains, however, were small. In combination with persistent variability, this led to non-significant effects of injury on all remaining neurobehavioral outcomes. These results suggest that, with the exception of anxiety-related behavior, alternate mouse models are required to effectively analyze cognitive outcomes after SAH.
Highlights
The mechanisms underlying post-subarachnoid hemorrhage (SAH) cognitive impairments are poorly-understood
In an effort to develop this model for mechanistic analysis and amelioration of multi-domain post-SAH cognitive impairment, we sought to determine whether multi-domain neurobehavioral deficits can be detected with rigorous blinding across multiple independent cohorts in a group consisting of all mice subjected to endovascular perforation SAH, or in a moderate- to severely-injured subgroup
We found that NS at 3 hours correlated well with that measured at 24 hours (Spearman’s rs 0.82; Fig. 2a), the time point used for prescreening in our prior post-hoc subgroup analysis of Morris water maze (MWM) performance
Summary
The mechanisms underlying post-SAH cognitive impairments are poorly-understood. Partly as a result, there are no therapies proven to improve cognitive outcomes after SAH. Mice are a attractive model organism due to their low carrying costs, short generational time, and the deep library of genetic models that have been developed and characterized to query specific mechanistic pathways. In an effort to develop this model for mechanistic analysis and amelioration of multi-domain post-SAH cognitive impairment, we sought to determine whether multi-domain neurobehavioral deficits can be detected with rigorous blinding across multiple independent cohorts in a group consisting of all mice subjected to endovascular perforation SAH, or in a moderate- to severely-injured subgroup
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