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Figures
- Fig. 1.
Study design and RAD brain injury model. (A) Experimental workflow for rotational acceleration-deceleration TBI in developing mice. (B) Illustration of the major components of the RADi device. (C) Schematic of the RADi procedure. Hyperextension of the neck occurs when the plunger strikes the ‘driver bar’ at the ‘hit location’ site (white down arrow) on activation of the pneumatic cylinder. When the plunger is released (white up arrow), the neck is forced back to the flexed position by the compression spring attached to the anterior part of the rotating axle (black down arrow). Each hyperextension-flexion cycle represents one rotation. (D) Pneumatic pressure of the plunger (psi) versus the peak angular velocities (rad/s) of the head.
- Fig. 2.
Survival rate and recovery of the righting reflex. (A) Survival rate following 60 psi for 30, 60, 80 and 100 RADi (n=20 per group). (B) Recovery time of the righting reflex in sham and after 30, 60, 80, and 100 RADi with 60 psi (n=9 per group). Data are presented as mean±s.d. and were analyzed by one-way ANOVA followed by Tukey's post hoc test. ***P<0.001.
- Fig. 3.
Cerebral blood perfusion preinjury, immediately after RADi, and 4 h and 24 h following 60 psi×60 RADi. (A) Representative images of LASCA of blood perfusion in two RADi mouse brains. Baseline and RADi images show areas of yellow-red as high blood perfusion and areas of blue-black as low blood perfusion. (B) Statistical analysis of mean PU per square millimeter. Data are presented as mean±s.d. and were analyzed by one-way with repeated-measures ANOVA followed by Tukey's post hoc test. *P<0.05, **P<0.01; n=6.
- Fig. 4.
Hemorrhage and cerebral edema following RADi. (A) Subdural/subarachnoid hemorrhages of brains of sham mice (left) and mice following different repetitions of RADi at 60 psi (right). (B) Breakdown of BBB integrity owing to increased vascular permeability in sham mice and in mice subjected to 60 psi×60 RADi taken 7 h postinjury. The dramatic retention of Evans Blue in traumatized brains compared with that in sham brains indicates increased permeability of the BBB. (C) Water content in sham and RADi mice. Data are presented as mean±s.d. and were analyzed by unpaired two-tailed Student's t-test. *P<0.05, **P<0.01; n=5 per group. Arrowheads indicate subarachnoid hemorrhage.
- Fig. 5.
Proinflammatory and glial activation following RADi in the brain. (A) Western blots of proinflammatory cytokines IL-6 and TNFα, the glial-specific intermediate filament protein GFAP, and macrophage/microglia-specific protein Iba1 in two sham and RADi mouse brains at 3 dpi following 60 psi×60 RADi. (B) Statistical analysis of western blots. Data are presented as mean±s.d. and were analyzed by unpaired two-tailed Student's t-test. *P<0.05, **P<0.01; n=4 per group. (C) Photomicrographs of immunostaining showing increased GFAP- and Iba1-positive glia in the pons of sham and RADi brains at 3 dpi. Insets show higher magnifications of the boxed areas. Scale bars: 100 µm.
- Fig. 6.
Neuronal degeneration in RADi mouse cortex at 30 dpi following 60 psi×60 RADi. Silver staining showed neuronal degeneration (dark cells, arrowheads) in primary motor cortex, primary somatosensory cortex, and olfactory tubercle. Insets show higher magnifications of the boxed areas. Scale bars: 100 μm (red), 25 μm (black).
- Fig. 7.
Neurobehavioral changes in sham and RADi mice. (A) Rotarod performance at 9 dpi and 30 dpi. Mice that experienced RADi showed much shorter duration on the rotarod than sham mice at 9 dpi but recovered at 30 dpi. (B) Y-maze test at 14 dpi and 28 dpi. Y-maze score but not number of arm entries significantly declined in RADi mice only at 28 dpi. (C) EPM at 14 dpi and 28 dpi. Mice that experienced RADi showed a robust increase in the time spent in the closed arms with a decreased interval spent in the open arms only at 28 dpi. However, a significant decrease in the frequency and total duration of head dips beyond the borders of the open arms was observed in mice with RADi at 14 dpi, which became progressively worse at 28 dpi. Data are presented as mean±s.d. and were analyzed by one-way with repeated-measures ANOVA followed by Tukey's post hoc test. *P<0.05, **P<0.01; n=9 for sham, n=9 for RADi at 9 dpi and 14 dpi, n=7 for RADi at 28 dpi and 30 dpi (two mice were lost for the late stages).
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