Intracerebral hemorrhage in the mouse altered sleep-wake patterns and activated microglia

Abstract

Sleep-wake disturbances are both a risk factor and reported morbidity for intracerebral hemorrhage (ICH). ICH begins with a ruptured blood vessel and blood leakage into the parenchyma. In response to initial damage, pathophysiological processes ensue that both exacerbate and repair damage. Inflammation is a hallmark process of ICH, which includes microglia activation and increased cytokine signaling. Due to the dual role of cytokines as inflammatory signaling proteins and sleep regulatory substances (SRSs), we hypothesized that ICH would activate microglia, increase SRSs, and alter sleep-wake patterns following an experimental model of ICH in the mouse. Male mice were randomized to receive an injection of collagenase (ICH; n = 8) or saline (sham; n = 11) in the striatum of the right hemisphere. Sleep-wake activity was recorded for 6 full days after ICH via noninvasive sleep cages. Blood and tissue were collected at 7 days after ICH to quantify pro-inflammatory cytokines/SRSs (IL-1β, TNF-α, IL-6) and microglia deramification by skeleton analysis. There was an overall injury effect on sleep in mice subjected to ICH at the transition from dark (wake) to light (sleep) at 2, 3, 4, 5, and 6 days after ICH compared with shams. Further analysis confirmed that ICH mice had significantly earlier wake offsets at the dark/light transition and more robust circadian patterns of wake behavior than saline control mice. Spatiotemporal skeleton analysis indicated an increase in microglial cell number with a decrease in endpoints per cell (decreased ramification) for the ipsilateral ICH perihematomal region compared with saline control. There were no changes to plasma cytokine levels at 7 days after ICH when comparing each condition. This is the first known study to show changes in sleep-wake patterns after experimental ICH. Elucidation of mechanisms that link sleep, inflammation, and ICH offers new pharmacological opportunities and rehabilitative strategies to improve recovery in stroke patients.