Introduction: The leading cause of death in the juvenile population is neurotrauma. Endoplasmic reticulum (ER) stress has been shown to contribute to injury expansion and behavioral deficits in adult rodents and humans. Whether ER stress contributes to injury expansion in juveniles with traumatic brain injury (TBI) is poorly delineated. We proposed that ER stress would be significantly increased in juvenile rats following TBI and that this would contribute to behavioral deficits.

Methods: A juvenile rat (post-natal day 28) controlled cortical impact model was used with 14 rats in the TBI group and 14 rats in the sham. BiP and CHOP (ER stress markers) were measured at 4 hours in the ipsilateral peri-contusion cortex. HIF 1 alpha was measured at 48 hrs, tau kinase measured at 1 week, and tauopathy at 30 days.

Results: At 4 hours following injury, BiP and CHOP were significantly elevated (F2,4 = 8.319, p=0.039) in rats exposed to TBI. Hypoxia inducible factor 1a was also significantly upregulated at 48h following TBI (F2,4 =18.451, p = 0.01) indicating that early ER stress activation induced delayed hypoxia. The early ER stress activation additionally contributed to the activation of the tau kinase GSK3ß (F2,4 = 9.855, p = 0.028) by 1 week. Tau oligomers measured with R23 were significantly increased by 30 days following TBI (t18 = -5.435, p < 0.001). These post-TBI changes were associated with increased impulsive behavior measured with elevated plus maze (t10= 2.287, p= 0.0452), deficits in short term memory measured with novel object recognition (t23 = -2.321, p= 0.029), and deficits in spatial memory measured with Morris water maze (F4, 24= 2.898, p= 0.026).

Conclusions: These results show that ER stress is a significant contributor to injury in juvenile rodents, and that pharmacologically targeting ER stress may prevent the long-term sequela associated with TBI.

Patient Care: This research shows the importance of endoplasmic reticulum stress in the progression of injury following traumatic brain injury in juveniles. Targeting endoplasmic reticulum stress following neurotrauma will be a valuable pharmaceutical approach for improving care for pediatric patients.

Learning Objectives: 1. ER stress is a significant contributor to injury in juvenile rodents 2. ER stress activation after injury in juvenile rodents contributes to delayed hypoxia and tauopathy. 3. Biochemical changes following traumatic brain injury are associated with behavioral deficits.

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