Fracture shortly before stroke in mice leads to hippocampus inflammation and long-lasting memory dysfunction

Abstract

Cognitive impairment occurs in stroke and hip fracture patients. In mice, bone fracture (BF) exacerbates stroke-related neuronal damage and sensorimotor dysfunction. We hypothesize that BF exacerbates post-stroke cognitive impairment. Adult mice were randomly assigned into BF, stroke, BF+stroke (BF 6 h before stroke), and control (sham operated) groups. Memory function was evaluated weekly for eight weeks by Y maze test and at eight weeks post-surgeries by novel object recognition (NOR) test. The neuronal damage and inflammation in hippocampus were analyzed three days and eight weeks after the surgeries. In Y maze test, BF+stroke mice started making fewer alternations than controls two weeks after the surgeries. Significant difference between BF+stroke and stroke groups started at five weeks post-injury and continued to the end of the experiment. In NOR test, BF+stroke group spent less time on novel objective than that of other groups. Cx3cr1+ cells and CD68+ cells accumulated in the stratum lacunosum moleculare (SLM) on the ipsilateral side of stroke injury in stroke and BF+stroke mice. BF+stroke mice had a higher ratio of ipsilateral/contralateral Cx3cr1+ cell-density than that of stroke mice. Therefore, BF shortly before stroke exacerbates hippocampal inflammation and causes long-lasting memory dysfunction.

Bone Fracture Enhanced Blood-Brain Barrier Breakdown in the Hippocampus and White Matter Damage of Stroke Mice

“…Furthermore, BF reduced WM in the basal ganglia and enhanced WM damage in the basal ganglia of the stroke mice. All of this could contribute to the previously observed long-lasting memory dysfunction of BF+stroke mice [ 32 ].…”

“…Our team reported previously that BF occurring 6 h or 24 h before or 24 h after stroke exacerbated neuroinflammation, brain edema and neuronal damage in the infarct and peri-infarct regions, and enhanced sensorimotor dysfunction of the stroke mice [ 13 , 14 , 15 , 16 , 41 ]. Our team had also shown that BF occurring 6 h before stroke led to long-lasting memory impairment (>8 weeks) of young mice [ 32 ]. Clinically, patients with stroke plus BF need more care and have poorer recovery than those with stroke alone [ 42 ].…”

“…A p -value < 0.05 was considered to be significant. The sample size was estimated according to our previously published data [ 32 ] and indicated in figure legends.…”

“…In young mice, bone fracture-caused memory dysfunction is temporary, shorter than 1 week [ 27 , 31 ]. We found that young mice developed long-lasting (≥ 8 weeks) spatial memory dysfunction when bone fracture preceded ischemic stroke by 6 h, which was associated with an accumulation of CX3C chemokine receptor 1 + (Cx3cr1 + ) cells in the hippocampal stratum lacunosum moleculare (SLM), stratum oriens and alveus [ 32 ]. The reasons why Cx3cr1 + cells accumulated in these regions and their association with long-term spatial memory dysfunction are currently unclear.…”

“…It has been shown that the infiltration of peripheral macrophages in the hippocampus leads to cognitive dysfunction [ 31 , 36 ]. We have detected the accumulation of microglia/macrophages in SLM of mice subjected to bone fracture and ischemic stroke, which was associated with a long-lasting memory dysfunction [ 32 ]. The connection of accumulation of microglia/macrophages in the hippocampi and memory dysfunction is not clear.…”