Subarachnoid hemorrhage (SAH) is a devastating form of hemorrhagic stroke that results in severe long-term impairment for those who survive the initial injury. Two common morbidities associated with SAH include the development of life-long epilepsy as well as significant cognitive and functional impairment. With advances in diagnosis and treatment of SAH in the acute setting, more individuals are surviving SAH but suffer from a significant reduction in quality of life. Thus, it has become increasingly important to study these sequelae in order to predict which patients might develop epilepsy and neurobehavioral impairment in addition to developing targeted therapeutics. To date, a lack of detailed preclinical animal models has prevented the study of epileptic events and behavior over a longitudinal period of time following SAH. The first objective of this proposal is to characterize the acute and chronic electroencephalography (EEG) and behavioral effects of focal SAH in the rat. This will be accomplished by long-term video EEG monitoring and weekly behavioral and cognitive testing in rats that have undergone endovascular perforation to induce SAH. A second unexplored area in understanding long-term disability following SAH is the lack of mechanistic studies. Little is known of the underlying pathogenesis of epilepsy and neurobehavioral impairment after SAH, but one common observation is a robust increase in microglia in the brain, indicating a significant level of neuroinflammation. Given recent studies implicating microglia in activity-dependent, complement-mediated synaptic pruning in the context of neurologic and psychiatric disease, the second objective of this proposal involves the investigation of the role of activated microglia and synaptic pruning in epileptogenesis and neurobehavioral impairment after SAH. This will be done through a combination of histologic, molecular, and cytometric experiments designed to characterize microglial morphology and functional phenotype in the brain after SAH as well as the interaction of microglia with neuronal synapses. Finally, using pharmacologic inhibitors of microglial activation, we will determine whether modulation of the neuroinflammatory response after SAH results in a reduction in epileptic events and behavioral impairment. As part of a multi-disciplinary, translational, collaborative project that combines expertise in epilepsy, stroke, and neuroimmunology, this project aims to increase our understanding of the inflammatory response in the brain after SAH as well as its role in the development of epilepsy and neurobehavioral impairment.
Subarachnoid hemorrhage (SAH) is a form of hemorrhagic stroke that poses a serious public health concern due to its high mortality rate, its occurrence in younger populations than ischemic stroke, and its long-term complications including epilepsy and neurobehavioral impairment. Neuroinflammation has been implicated in playing a role in these processes and has been observed to be significantly upregulated in human and rodent brains in both SAH and epilepsy, particularly through the role of resident brain microglia. Investigation of these processes will lead to increased understanding of the role of immune cells in epileptogenesis and neurobehavioral impairment after SAH, and it may help identify new immune-based therapeutics.
