Christina L. Nemeth, Mallory S. Shurte, Dana M. McTigue, Charles B. Nemeroff, Gretchen N. Neigh

Microvascular disease is defined by microvascular events including arterial wall thickening, microvascular lesions, and microembolic stroke. Characteristics of microvascular disease are observed in the vast majority of patients presenting with late-life depression, and changes in affective behavior may precede microvascular-associated changes in cognitive decline. The current study used a microsphere injection model to test the hypothesis that microembolism infarcts induce depressive-like behaviors in rodents. Further, the study sought to determine whether microembolism-induced changes in affective-like behavior preceded deficits in spatial memory. Microbeads were injected into the internal carotid artery to generate microembolic lesions and behavior was assessed at either a short recovery (SR) time point (4-6 days post-surgery) or long recovery (LR) time point (14-17 days post-surgery). A separate cohort of rats was used to assess spatial memory in the Barnes Maze at the LR time point and beyond (35 days post-surgery). Microembolism infarcts led to an increase in anxiety- and depressive-like behaviors at the LR, but not the SR, time point as evidenced by reduced time in the center of the open field, reduced consumption of a sucrose solution, increased latency to approach a novel female at 14 days and impaired spatial memory at 33 days. A thorough analysis of histological markers and lesion volume revealed that gross histological damage was not predictive of behavioral outcomes, suggesting that alterations in neuronal function may underlie behavioral deficits. Collectively, these data demonstrate that microembolism infarcts are sufficient to induce changes in affective-like behavior and these changes precede alterations in spatial memory.