Abstract Text: Mild traumatic brain injury (mTBI) results in physical damage to the brain including tissue bruising, axon shearing, and vasculature disruption. Such injury induces the activation of neuronal stress response pathways including the Dual leucine zipper kinase (DLK) pathway, Sarm1 axon degeneration pathway, and the Integrated Stress Response (ISR) pathway which have been shown to be essential for neurodegeneration and neuroinflammation in various injury and disease contexts. These pathways are highly interconnected and share a number of downstream effectors including Activating transcription factor 3 (Atf3), and C/EBP homologous protein (CHOP). We have recently demonstrated that layer V projection neurons in the cortex selectively activate certain stress responses one week following mTBI. Here, we investigate the role of stress response factors in mTBI-induced neurodegeneration, focusing on cell death, dendrite degeneration, and axon swellings, as well as neuroinflammation characterized by an upregulation of microgliosis in the injured region. We generated conditional knockout mice where key drivers of stress responses are selectively knocked out in layer V neurons. The animals underwent unilateral closed head controlled cortical impact injury and were assessed 7 and 14 days post injury to evaluate degeneration and inflammation. We find that genetic knockout of stress response-related factors in a murine mTBI model differentially affects various elements of injury-induced neurodegeneration and neuroinflammation. The observed selectivity suggests that such factors play collaborative roles in injury response to induce neurodegeneration, indicating the need for a more nuanced understanding of neurodegenerative cascades for future development of therapies.
