The Translational Benefits of Sheep as Large Animal Models of Human Neurological Disorders

Abstract

The past two decades have seen a considerable rise in the use of sheep to model human neurological disorders. While each animal model has its merits, sheep have many advantages over small animal models when it comes to studies on the brain. In particular, sheep have brains more comparable in size and structure to the human brain. They also have much longer life spans and are docile animals, making them useful for a wide range of in vivo studies. Sheep are amenable to regular blood and cerebrospinal fluid sampling which aids in biomarker discovery and monitoring of treatment efficacy. Several neurological diseases have been found to occur naturally in sheep, however sheep can also be genetically engineered or experimentally manipulated to recapitulate disease or injury. Many of these types of sheep models are currently being used for pre-clinical therapeutic trials, particularly gene therapy, with studies from several models culminating in potential treatments moving into clinical trials. This review will provide an overview of the benefits of using sheep to model neurological conditions, and highlight naturally occurring and experimentally induced sheep models that have demonstrated translational validity.

Keywords: epilepsy; genetics; neurodegeneration; neuroscience; sheep; spinal cord injury; stroke; traumatic brain injury.

Figure 1

Comparison of size and gross neuroanatomy of the sheep, human, and mouse brain. Images reproduced from the University of Wisconsin and Michigan State Comparative Mammalian Brain Collections and National Museum of Health and Medicine. Preparation of images and specimens funded by the National Science Foundation, as well as by the National Institutes of Health. University of Wisconsin and Michigan State Comparative Mammalian Brain Collections website http://neurosciencelibrary.org/index.html.

Figure 2

Sheep brain MRI atlas. 3D surface renderings of gyri segmented from a population-average template MR images of sheep brains displayed in: (A) frontal, (B) posterior, and (C) ventral views. Figure reproduced from Computation of a high-resolution MRI 3D stereotaxic atlas of the sheep brain by Ella et al. (1) with permission from John Wiley and Sons.

Figure 3

Comparison of the anatomy of the circle of Willis in humans and sheep. MCA, middle cerebral artery; ICA, internal carotid artery; ACoA, anterior communicating artery; ACA, anterior cerebral artery; PCoA, posterior communicating artery; PCA, posterior cerebral artery; BA, basilar artery; VA, vertebral artery. Figure adapted from Large animal models of stroke and traumatic brain injury as translational tools by Sorby-Adams et al. (15) with permission from The American Physiological Society.