Effects of a primary blast-induced traumatic brain injury on the susceptibility to behavioral and neuronal deficits on a susequent blunt trauma

Author

• Aswati Aravind, New Jersey Institute of Technology

Document Type

Dissertation

Date of Award

5-31-2020

Degree Name

Doctor of Philosophy in Biomedical Engineering - (Ph.D.)

Department

Biomedical Engineering

First Advisor

Bryan J. Pfister

Second Advisor

N. Chandra

Third Advisor

James Haorah

Fourth Advisor

Kevin Pang

Fifth Advisor

Vijayalakshmi Santhakumar

Sixth Advisor

Bruce G. Lyeth

Abstract

Soldiers are often exposed to more than one traumatic brain injury (TBI) event over the course of their service. In recent years, more attention has been drawn to the increased risk of neurological deficits caused by the 'blast plus' polytrauma, which typically is a blast trauma combined with other forms of TBI. The objective of this dissertation is to investigate if exposure to a blast TBI predisposes the brain to increased neurological deficits when followed with a second blunt head trauma. The behavioral and neuronal deficits resulting from a blast plus injury involving a mild-moderate blast followed by a mild blunt trauma using the fluid percussion injury model are investigated here. Further, in order to investigate the increased susceptibility following the blast injury, the role of death receptor mediated apoptosis and/or inflammation induced pyroptosis pathway in neuronal death is examined following the single blast and single blunt injury.

Blast plus injured animals manifest increased cognitive deficits, chronic ventricular enlargement, neurodegeneration at acute time points and chronic neuronal loss when compared to animals only receiving the single blunt injury. This suggests that the blast injury predisposes the rodent brain to increased neurological deficits on a subsequent blunt impact. Interestingly, a single blast and single blunt injury differ in their onset and manifestation of cognitive and regional neuronal loss. While the single blast injury does not result in overt cognitive, motor deficits or acute neurodegeneration unlike the single blunt injury, chronic neuronal loss appears similar to the blunt injury.

Inflammation mediated death receptor pathways play key roles in acute and chronic neuronal loss following TBI. In this dissertation, the role of apoptosis, necroptosis and pyroptosis in initiating neuronal death at different timepoints are evaluated in the hippocampus of the single blast, blunt and blast plus injured animals. Immediate neuronal death is assessed by studying the expression levels of apoptosis marker caspase 8 and necroptosis marker Receptor-interacting serine/threonine-protein kinase 1 (RIP1). Elevated levels of caspase 8 in the single and blast plus injuries indicate activation of extrinsic apoptosis and correlated with the early neurodegeneration observed in the blunt injury. Further, caspase 8 mediated cleavage of RIP1 is observed in blunt and blast plus TBI indicating inhibition of necroptosis. Single blast injury causes slightly elevated levels of caspase 8 activation and RIP1 cleavage that does not reach significance. At PID6 (post injury day), an increase in Absent in myeloma 2 (AIM2) inflammasome involved in pyroptosis mediated cell death is observed in the single blast injury. Increased expression of downstream pyroptosis markers such as caspase-1 and cleavage of gasdermin D is observed in the single blast, blunt and blast plus injuries at PID 6. These results indicate that extrinsic apoptosis activates acute neuronal death in blunt injured hippocampus with a subsequent activation of pyroptosis at PID 6. The blast injury, on the other hand, causes no immediate activation of neurodegeneration and neuronal death but leads to pyroptotic cell death at PID 6. The results in this dissertation indicate that a single blast and single blunt injury differ in the onset and propagation of cognitive deficits and neuronal loss leading to an exacerbation of deficits in the blast plus injury model.

Recommended Citation

Aravind, Aswati, "Effects of a primary blast-induced traumatic brain injury on the susceptibility to behavioral and neuronal deficits on a susequent blunt trauma" (2020). Dissertations. 1904.
https://digitalcommons.njit.edu/dissertations/1904