Authors: Michelle Connor; Kristina Shkirkova; Krista Lamorie-Foote; Arati Patel; Qinghai Liu; William Mack (Los Angeles, CA)

Introduction: Chronic cerebral hypoperfusion (CCH) is a known mediator of vascular dementia and small vessel ischemic disease. Murine bilateral carotid artery stenosis (BCAS), an experimental model of CCH, results in blood-brain barrier breakdown, inflammation, oxidative stress, white matter injury, and behavioral deficits. The mechanism by which these changes occur, however, has yet to be established. The aim of this study was to examine microglia activation in response to CCH, as a potential mechanism for the CNS damage seen in this model. Methods: Mice underwent either BCAS (n=9) or sham (n=9) surgery. Mice were anesthetized, common carotid arteries were exposed through a midline cervical incision, and microcoils were placed around each carotid artery. Sham-operated mice underwent the same procedure, but without placement of microcoils. After 30 days, mice were sacrificed. Reactive microglia were identified by immunohistochemical staining for Iba-1. Under resting conditions, microglia are ramified with small cell bodies and extensive branching processes. When activated, microglia adopt an amoeboid morphology characterized by an enlarged cell body and thickened, retracted processes. The ratio of cell body size to dendritic process size was quantified to evaluate for these morphological changes, with higher ratios indicating a more amoeboid, and thus activated, morphology. Results: Reactive microglia cell count [p<0.05] and microglial cell body size to dendritic process size ratio [p<0.05] were significantly greater in the corpus callosum of BCAS mice when compared to sham controls. Conclusion: Microglia become activated in the corpus callosum following CCH. This inflammatory response likely contributes to the white matter damage and behavioral deficits evident in this model. These findings suggest microglia and inflammatory microvascular failure as important targets for further mechanistic study in the pathophysiology of white matter ischemic injury.