Long-Term Effects of Intracerebral Hemorrhage on Behavior and Inflammation - PROJECT SUMMARY Stroke is the second highest cause of death and the leading cause of disability worldwide. Intracerebral hemorrhage (ICH) is the second most prevalent form of stroke and has the highest disability rate among survivors1. ICH survivors remain at high risk for negative outcomes including rebleeding, depression, anxiety, and progressive cognitive impairment, which may be due to chronic neuroinflammation2. The early immune cell response to ICH is well studied—pro-inflammatory cytokines, activation of microglia, and infiltration of peripheral immune cells increase, followed by reparative stages of reduced brain edema and phagocytosis3. However, the long-term effects of innate immune cell activation is largely unknown. Our preliminary work suggests that microglia, the resident immune cells of the brain, show continued activation 28- and 60-days following ICH, suggesting long-term inflammation that persisted more in females. Indeed, we also detect behavioral deficits in females but not males at late timepoints, suggesting there may be a link between chronic inflammation and behavioral phenotype. I hypothesize that continued activation of innate immune cells in the brain contribute to chronic neuroinflammation and behavioral changes at late timepoints in a sex- specific manner. The goal of this project is to utilize an in-vivo mouse model of ICH, collagenase injection, to map microglial activation and behavioral changes following stroke. Aim 1 will elucidate the mechanism driving inflammatory phenotypes in microglia and the catalyst of interferon activation. Aim 2 will establish the factors leading to downstream interferon stimulated genes, characterize changes in the neurotransmitter serotonin following brain injury, and map out differences in mice behavior depending on sex. Aim 3 will explore human data to determine whether inflammatory markers are still upregulated years later in stroke survivors, and if they correlate with depression and anxiety. These experiments will map out the long-term effects of innate immune activation on behavior in both animal models and patients. My results have the potential to shape our understanding of long-term effects of neuroinflammation in order to improve survivors’ quality of life following stroke, while also having implications for brain injury, degeneration, and aging.
