Progression of histopathological and behavioral abnormalities following mild traumatic brain injury in the male ferret

Abstract

White matter damage is an important consequence of traumatic brain injury (TBI) in humans. Unlike rodents, ferrets have a substantial amount of white matter and a gyrencephalic brain; therefore, they may represent an ideal small mammal model to study human-pertinent consequences of TBI.Here we report immunohistochemical and behavioral results after a controlled cortical impact (CCI) injury to the sensorimotor cortex of adult male ferrets. We assessed inflammation in the neocortex and white matter, and behavior at 1 day post injury and 1, 4, and 16 weeks post injury (WPI). CCI in the ferret produced inflammation that originated in the neocortex near the site of the injury and progressed deep into the white matter with time. The density of microglia and astrocytes increased in the neocortex near the injury, peaking at 4WPI and remaining elevated at 16WPI. Microglial morphology in the neocortex was significantly altered in the first 4 weeks, but showed a return toward normal at 16 weeks. Clusters of microglial cells in the white matter persisted until 16WPI. We assessed motor and cognitive behavior using the open field, novel object recognition, T-maze, and gait tests. A transient deficit in memory occurred at 4WPI, with a reduction of rearing and motor ability at 12 and 16WPI. Behavioral impairments coincide with features of the inflammatory changes in the neocortex revealed by immunohistochemistry. The ferret represents an important animal model to explore ongoing damage in the white matter and cerebral cortex after TBI. K E Y W O R D Sastrocytes, astrogliosis, attention, behavior, brain, cerebral cortex, cognitive impairment, GFAP, gray matter, mammals, memory, neuroinflammation, reactive microglia, TBI (traumatic brain injury), white matter

Detection and Distinction of Mild Brain Injury Effects in a Ferret Model Using Diffusion Tensor MRI (DTI) and DTI-Driven Tensor-Based Morphometry (D-TBM)

“…Recent histological analysis of the brains analyzed by DTI in the present study demonstrated a progressive pattern of reactive microglia and astrocytes emerging following CCI with pronounced cortical gliosis during the acute stage followed by the appearance of reactive glia – both astrocytes and microglia – in the WM during the chronic stage ( Schwerin et al, 2018 ). Focal template-based ROI analysis of Trace and FA values in these same brains and regions revealed consistent radiologic-pathologic relationship within the WM for which significant differences were observed in both the SC WM and in a focal region of the IC.…”

“…Immunoreactivity for the three WM regions studied for FA and Trace analysis showed altered staining patterns for GFAP and Iba-1 reactivity ( Figure 5C ). Although these glial markers exhibited changes from 1-week post injury not strongly evident in the FA data, there were strong immunoreactivity modifications that correlated with the FA alterations seen in WM regions, especially at our longer survival times (also see Schwerin et al, 2018 ). These were most consistent with the temporal dependence of FA changes in the same brains (red lines, Figure 5B ).…”

“…The DTI values were evaluated in the CTX, SC WM, and in a focal region of the IC using template-defined ROIs placed according to previous histological findings ( Schwerin et al, 2018 ). Extracted FA and Trace values for each brain in template space are shown in Figure 5 according to time after CCI.…”

“… DTI values in regions of known histologic abnormality. Based on histologic observations following mCCI made by Schwerin et al (2018) , ROIs were placed on the ex vivo template (A) and used to extract FA and Trace values in the cortex (CTX), subcortical white matter (SC WM) and internal capsule (IC) corresponding to regions defined in the histologic study. Regional DTI values from the side of injury (triangular points) and those from the contralateral side (circular points) are plotted (B) for each time interval after CCI with lines connecting ipsilateral and contralateral values from individual samples and the results of two-way ANOVA with factors of side and time after CCI are given with asterisk to indicate significance levels ( ∗ p < 0.05 and ∗∗ p < 0.01).…”

Reflections on traumatic brain injury research in 2018

“…Kajstura et al provide evidence that serotonergic axons regrow after TBI in rodents (Kajstura, Dougherty, & Linden, ). Schwerin et al show that the ferret presents a strong model to study TBI in a gyrencephalic animal (Schwerin et al, ). Perhaps as a reflection of the very heterogeneous nature of TBI causes and outcomes, a broad range of animal models help in understanding the mechanistic and multifaceted nature of TBI to provide platforms for the development and testing of hypotheses conducive to therapeutic interventions.…”