Short and Long Term Behavioral and Pathological Changes in a Novel Rodent Model of Repetitive Mild Traumatic Brain Injury.

A history of concussion, particularly repeated injury, has been linked to an increased risk for the development of neurodegenerative diseases, particularly chronic traumatic encephalopathy (CTE). CTE is characterized by abnormal accumulation of hyperphosphorylated tau and deficits in learning and memory. As yet the mechanisms associated with the development of CTE are unknown. Accordingly, the aim of the current study was to develop and characterize a novel model of repetitive mTBI that accurately reproduces the key short and long-term functional and histopathological features seen clinically. Forty male Sprague-Dawley rats were randomly assigned to receive 0, 1 or 3x mTBI spaced five days apart using a modified version of the Marmarou impact-acceleration diffuse-TBI model to deliver 110G of linear force. Functional outcomes were assessed six and twelve weeks post-injury, with histopathology assessed twenty-four hours and twelve weeks post-injury. Repetitive mTBI resulted in mild spatial and recognition memory deficits as reflected by increased escape latency on the Barnes maze and decreased time spent in the novel arm of the Y maze. There was a trend towards increased anxiety-like behavior, with decreased time spent in the inner portion of the open field. At 24 hours and 12 weeks post injury, repetitive mTBI animals showed increased tau phosphorylation and microglial activation within the cortex. Increases in APP immunoreactivity were observed in repetitive mTBI animals at 12 weeks indicating long-term changes in axonal integrity. This novel model of repetitive mTBI with its persistent cognitive deficits, neuroinflammation, axonal injury and tau hyperphosphorylation, thus represents a clinically relevant experimental approach to further explore the underlying pathogenesis of CTE

Short and Long Term Behavioral and Pathological Changes in a Novel Rodent Model of Repetitive Mild Traumatic Brain Injury

<div><p>A history of concussion, particularly repeated injury, has been linked to an increased risk for the development of neurodegenerative diseases, particularly chronic traumatic encephalopathy (CTE). CTE is characterized by abnormal accumulation of hyperphosphorylated tau and deficits in learning and memory. As yet the mechanisms associated with the development of CTE are unknown. Accordingly, the aim of the current study was to develop and characterize a novel model of repetitive mTBI that accurately reproduces the key short and long-term functional and histopathological features seen clinically. Forty male Sprague-Dawley rats were randomly assigned to receive 0, 1 or 3x mTBI spaced five days apart using a modified version of the Marmarou impact-acceleration diffuse-TBI model to deliver 110G of linear force. Functional outcomes were assessed six and twelve weeks post-injury, with histopathology assessed twenty-four hours and twelve weeks post-injury. Repetitive mTBI resulted in mild spatial and recognition memory deficits as reflected by increased escape latency on the Barnes maze and decreased time spent in the novel arm of the Y maze. There was a trend towards increased anxiety-like behavior, with decreased time spent in the inner portion of the open field. At 24 hours and 12 weeks post injury, repetitive mTBI animals showed increased tau phosphorylation and microglial activation within the cortex. Increases in APP immunoreactivity were observed in repetitive mTBI animals at 12 weeks indicating long-term changes in axonal integrity. This novel model of repetitive mTBI with its persistent cognitive deficits, neuroinflammation, axonal injury and tau hyperphosphorylation, thus represents a clinically relevant experimental approach to further explore the underlying pathogenesis of CTE.</p></div

Changes in APP expression 12 weeks post-injury.

<p>Representative images of APP staining in the cortex, thalamus and CA2 region of the hippocampus in animals at 12 weeks post-injury. Increased APP immunoreactivity was observed across 3x mTBI animals (G-I, L) compared to sham (A-C, J) and 1x mTBI animals (D-F, K) (**p<0.01, *p<0.05 compared to sham, n = 6)</p

Motor Assessment post-injury.

<p>Weekly rotarod assessments showing no significant changes in motor function over the 12 week monitoring period in all groups (Sham, 1 x mTBI n = 9; 3x mTBI n = 7).</p

Injury schedule for single and repetitive mild traumatic brain injury (TBI) animals.

<p>Injury schedule for single and repetitive mild traumatic brain injury (TBI) animals.</p

Gross Neuropathology.

<p>Gross pathology of representative rodent brains showing no lesions, hemorrhage, edema or overt tissue loss in the 3x mTBI animals compared to sham animals.</p

Open Field.

<p>Number of total line crossings 6 weeks (A) and 12 weeks (B) post-injury, and % of inner square line crossings compared to the total number at 6 weeks (C) and 12 weeks (D) post-injury. (*p<0.05 compared to sham, #p<0.05 compared to 1x mTBI animals; Sham, 1 x mTBI n = 9; 3x mTBI sham, 1 x mTBI n = 9; 3x mTBI n = 7)</p