Graduate Student National Institutes of Health/Brown University
Abstract Text: Mild traumatic brain injury (mTBI) occurs when there is sudden and rapid movement of the brain within the skull. This mild and indirect brain injury leads to a pathological cascade involving many cell types and structures in the brain, and induces injury responses including excitotoxicity, impaired axonal transport, and neuroinflammation. While the overall pathology of mTBI has been widely studied, the neuron-intrinsic responses and outcomes have not been elucidated. Here, we evaluate whether injured cortical neurons activate neuron-intrinsic stress responses in a mouse model of mTBI. Anesthetized mice were administered a unilateral closed-skull controlled cortical impact injury over the motor cortex and followed up to 10 weeks post injury to evaluate degeneration, stress response activation, neuroinflammation, and cell survival. We find that layer V projection neurons (PNs) are particularly vulnerable to damage in the acute phase following mTBI, exhibiting axon swellings characteristic of diffuse axonal injury as well as dendrite degeneration. A subset of PNs upregulate Activated Transcription Factor 3 (Atf3), a transcription factor that is activated in response to axon injury. As a canonically regeneration-associated gene, expression of Atf3 in the non-regenerative environment of the central nervous system is surprising. By permanently labeling Atf3-expressing neurons, we show that layer V PNs express markers of axon injury, upregulate pre-apoptotic genes, and are ultimately phagocytosed following mTBI. The concurrent upregulation of regenerative genes as well as pre-apoptotic genes indicates an attempt at a regenerative response that is ultimately prevented. We further find that a subset of neurons in layer II/III of the cortex activates Atf3 and survives. Understanding the differential transcriptional cascades initiated in cortical neurons following mTBI may elucidate the neuron-intrinsic barriers to CNS regeneration.
