Histological and functional outcomes after traumatic brain injury in mice null for the erythropoietin receptor in the central nervous system - PubMed (original) (raw)
Histological and functional outcomes after traumatic brain injury in mice null for the erythropoietin receptor in the central nervous system
Ye Xiong et al. Brain Res. 2008.
Abstract
Erythropoietin (EPO) and its receptor (EPOR), essential for erythropoiesis, are expressed in the nervous system. Recombinant human EPO treatment promotes functional outcome after traumatic brain injury (TBI) and stroke, suggesting that the endogenous EPO/EPOR system plays an important role in neuroprotection and neurorestoration. This study was designed to investigate effects of the EPOR on histological and functional outcomes after TBI. Experimental TBI was induced in adult EPOR-null and wild-type mice by controlled cortical impact. Neurological function was assessed using the modified Morris Water Maze and footfault tests. Animals were sacrificed 35 days after injury and brain sections stained for immunohistochemistry. As compared to the wild-type injured mice, EPOR-null mice did not exhibit higher susceptibility to TBI as exemplified by tissue loss in the cortex, cell loss in the dentate gyrus, impaired spatial learning, angiogenesis and cell proliferation. We observed that less cortical neurogenesis occurred and that sensorimotor function (i.e., footfault) was more impaired in the EPOR-null mice after TBI. Co-accumulation of amyloid precursor protein (axonal injury marker) and calcium was observed in the ipsilateral thalamus in both EPOR-null and wild-type mice after TBI with more calcium deposits present in the wild-type mice. This study demonstrates for the first time that EPOR null in the nervous system aggravates sensorimotor deficits, impairs cortical neurogenesis and reduces thalamic calcium precipitation after TBI.
Figures
Fig. 1
Cell density in the DG examined at 35 days after TBI or sham. H&E staining: a-d. TBI caused significant cell loss in the ipsilateral DG (mainly in the dorsal blade) in the wild-type (c) and EPOR-null mice (d). Scale bar: 50μm (a-d). The cell number in the DG is shown in (e). Data represent mean with SD. N (mice/group) = 6 (Sham-Wild); 8 (TBI-Wild); 6 (Sham-Null); 10 (TBI-Null).
Fig. 2
Spatial learning function examined at 31-35 days after TBI or sham. TBI significantly impaired spatial learning performance (time spent in the correct quadrant) at 34 and 35 days after TBI measured by a recent version of the water maze test. Data represent mean with SD. N (mice/group) = 6 (Sham-Wild); 8 (TBI-Wild); 6 (Sham-Null); 10 (TBI-Null).
Fig. 3
Sensorimotor function (forelimb footfault) before and after TBI or sham. “Pre” represents pre-injury level. TBI impaired sensorimotor performance (contralateral forelimb footfault). Data represent mean with SD. N (mice/group) = 6 (Sham-Wild); 8 (TBI-Wild); 6 (Sham-Null); 10 (TBI-Null).
Fig. 4
Sensorimotor function (hind limb footfault) before and after TBI or sham. “Pre” represents pre-injury level. TBI impaired sensorimotor performance (contralateral hind limb footfault). Data represent mean with SD. N (mice/group) = 6 (Sham-Wild); 8 (TBI-Wild); 6 (Sham-Null); 10 (TBI-Null).
Fig. 5
Cell proliferation in the ipsilateral DG and cortex 35 days after TBI or sham. TBI significantly increased the number of BrdU-positive cells in the ipsilateral DG (c and d) and cortex (g and h). The cells with BrdU (brown stained) that clearly localize to the nucleus (hematoxylin stained) are counted as BrdU-positive cells (i, arrows). Scale bars: 50μm (a-h); 25μm (i). The number of BrdU-positive cells is shown in (j). Data represent mean with SD. N (mice/group) = 6 (Sham-Wild); 8 (TBI-Wild); 6 (Sham-Null); 10 (TBI-Null).
Fig. 6
Double fluorescent staining for BrdU (red) and NeuN (green) to identify neurogenesis (yellow after merge) in the cortex (a and b, arrow as example) and the dentate gyrus (c and d, arrow as example) of the ipsilateral, injured hemisphere at 35 days after TBI. Newborn BrdU-positive cells (red, f) differentiate into neurons expressing NeuN (yellow, g). Scale bars: 25μm (a-d); 10μm (e-g). The percentage of NeuN/BrdU-colabeled cells is shown in (h). Data represent mean with SD. N (mice/group) = 6 (Sham-Wild); 8 (TBI-Wild); 6 (Sham-Null); 10 (TBI-Null).
Fig. 7
vWF staining for vascular structure in the ipsilateral DG and cortex at 35 days after TBI or sham. TBI significantly increased the density of vasculature in the ipsilateral DG (c and d) and cortex (g and h). The vasculature with vWF staining is counted (brown stained) as shown in (i, arrows). Scale bars: 50μm (a-h); 25μm (i). The density of vWF-stained vasculature is shown in (j). Data represent mean with SD. N (mice/group) = 6 (Sham-Wild); 8 (TBI-Wild); 6 (Sham-Null); 10 (TBI-Null).
Fig. 8
APP and calcium staining in the ipsilateral DG and cortex at 35 days after TBI. APP accumulated in the ipsilateral thalamus in both wild-type (a, e, i, and j) and EPOR-null (c and g) mice after TBI. Traumatic axonal injury was confirmed with APP staining on free floating sections (50 μm) of injured brains. The spherical (i and j, arrowheads) and segmented (i and j, arrows) appearance of injured axons was observed in the ipsilateral thalamus after TBI. Calcium deposits stained with Arilazan Red were found in the ipsilateral thalamus in both wild-type (b, f, and j) and EPOR-null mice (d and h) after TBI. Note an overlap of APP with calcium staining in adjacent sections. Scale bars: 2 mm (a-d); 1 mm (e-h); 50 μm (i); and 25 μm (j). The percentage of area of APP and calcium deposits is shown in (k). Data represent mean with SD. N (mice/group) = 6 (Sham-Wild); 8 (TBI-Wild); 6 (Sham-Null); 10 (TBI-Null).
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