Acute Cellular and Behavioral Outcomes of Focal Impact Traumatic Brain Injury in Xenopus laevis

Date

2022-11-28

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Abstract

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability throughout the world. The Centers for Disease Control and Prevention estimate that up to 5.3 million people in the United States are living with a TBI-related disability, including cognitive, behavioral, and functional limitations. Although TBI represents a significant public health concern, we currently lack effective therapies to promote repair and recovery in the brain. TBI is a complex condition; characterized by an initial insult which sets in motion a secondary injury cascade including neuroinflammation, blood-brain barrier disruption, edema, and reactive astrogliosis. Reactive astrogliosis occurs on a finely graded continuum, encompassing both the initiation of essential recovery mechanisms and exacerbating inflammation. As it has been linked to chronic neurodegenerative diseases, TBI represents the initiation of a disease process, rather than an isolated event. While the initial insult causes irreversible damage, secondary injury begins minutes after and can last for years, presenting a promising opportunity for therapeutic intervention.

We begin by investigating the response to focal impact injury in the optic tectum of Xenopus laevis tadpoles. This injury disrupts the blood-brain barrier, causing edema, and produces deficits in visually-driven behaviors. Injured brains show an early transcriptional activation of inflammatory cytokines, followed by astrocytes undergoing morphological alterations and upregulation of genes consistent with reactive astrogliosis. Since our results demonstrate that the response to focal impact injury in Xenopus tadpoles resembles that of mammalian models, we present a new, scalable vertebrate model for TBI.

Next, we focus on characterizing the current literature surrounding sex differences in animal models of TBI and presenting preliminary findings in our model. Estrogen and its derivatives have recently been explored for their potentially neuroprotective capabilities. Previous works have suggested that estrogenic compounds are able to regulate reactive astrogliosis, control neuroinflammation, and reduce edema. Since treatment with estrogen comes with significant risk factors, many have suggested the use of selective estrogen receptor modulators (SERMs) like Tamoxifen. Our results support tamoxifen as an effective neuroprotectant when administered after a TBI and demonstrate a successful proof-of-concept pharmacological intervention in our X. laevis model of TBI.

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Keywords

Traumatic brain injury, Xenopus laevis, Biology, Neuroscience, Behavioral biology, Astrocytes

Citation

Portions of this document appear in: Spruiell Eldridge, S. L., Teetsel, J. F. K., Torres, R. A., Ulrich, C. H., Shah, V. V, Singh, D., Zamora, M. J., Zamora, S., Sater, A. K. (2022). A Focal Impact Model of Traumatic Brain Injury in Xenopus Tadpoles Reveals Behavioral Alterations, Neuroinflammation, and an Astroglial Response. International Journal of Molecular Sciences, 23(14), 7578.