Unconventional animal models for traumatic brain injury and chronic traumatic encephalopathy

Abstract

Traumatic brain injury (TBI) is one of the main causes of death worldwide. It is a complex injury that influences cellular physiology, causes neuronal cell death, and affects molecular pathways in the brain. This in turn can result in sensory, motor, and behavioral alterations that deeply impact the quality of life. Repetitive mild TBI can progress into chronic traumatic encephalopathy (CTE), a neurodegenerative condition linked to severe behavioral changes. While current animal models of TBI and CTE such as rodents, are useful to explore affected pathways, clinical findings therein have rarely translated into clinical applications, possibly because of the many morphofunctional differences between the model animals and humans. It is therefore important to complement these studies with alternative animal models that may better replicate the individuality of human TBI. Comparative studies in animals with naturally evolved brain protection such as bighorn sheep, woodpeckers, and whales, may provide preventive applications in humans. The advantages of an in-depth study of these unconventional animals are threefold. First, to increase knowledge of the often-understudied species in question; second, to improve common animal models based on the study of their extreme counterparts; and finally, to tap into a source of biological inspiration for comparative studies and translational applications in humans.

Keywords: CTE; TBI; blast trauma; concussion; translational medicine.

FIGURE 1

Comparative illustrations of cranial cross sections showcasing skull and brain anatomy across various species. (a) Human, Homo sapiens, (b) Mouse, Mus musculus, (c) Domestic sheep, Ovis aries, (d) Bighorn sheep, Ovis canadensis (♂), (e) Domestic pig, Sus scrofa domesticus, (f) Woodpecker, (Picidae), g: Minke whale, Balaenoptera acutorostrata. Illustration by Ni‐Ka Ford

FIGURE 2

Blast‐induced alterations in the vasculature of blast‐exposed rats (Rattus norvegicus). Brain sections from blast‐exposed and control rats (3 × 75 kPa, 10 months post‐exposure) were immunostained with antibodies against the vascular extracellular matrix protein collagen type IV (green) and glial fibrillary acidic protein (GFAP, red). Nuclei were visualized with DAPI staining (blue). Arrows indicate blast‐induced alterations to blood vessels: tortuous vessels (a–f) and pinched vessels (g–i) in the brains of blast‐exposed animals. A control vessel is shown in panels j–l. Scale bar = 30 µm

FIGURE 3

Two male bottlenose dolphins (Tursiops truncatus) headbutting in midair in Doubtful Sound New Zealand. Photograph courtesy of David Lusseau