Development and Validation of a Prechiasmatic Mouse Model of Subarachnoid Hemorrhage to Measure Long-Term Cognitive Deficits

Controllable and reproducible animal models of aneurysmal subarachnoid hemorrhage (SAH) are crucial for the systematic study of the pathophysiology and treatment of this debilitating condition. However, current animal models have not been successful in replicating the pathology and disabilities seen in SAH patients, especially the long-term neurocognitive deficits that affect the survivor's quality of life. Therefore, there is an unmet need to develop experimental models that reliably replicate the long-term clinical ramifications of SAH - especially in mice where genetic manipulations are straightforward and readily available. To address this need, a standardized mouse SAH model is developed that reproducibly produced significant and trackable long-term cognitive deficits. SAH is induced by performing double blood injections into the prechiasmatic cistern - a simple modification to the well-characterized single prechiasmatic injection mouse model of SAH. Following SAH, mice recapitulated key characteristics of SAH patients, including cerebral edema measured by MRI - an indicator of early brain injury (EBI), neuroinflammation, apoptosis, and long-term cognitive impairment. This newly developed SAH mouse model is considered an ideal paradigm for investigating the complex SAH pathophysiology and identifying novel druggable therapeutic targets for treating SAH severity and SAH-associated long-term neurocognitive deficits in patients.