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.

Grant Number: 1F31NS141558-01A1
NIH Institute/Center: NIH
Principal Investigator: Efrat Abramson