The transcriptional response of cortical neurons to concussion reveals divergent fates after injury

Abstract

Traumatic brain injury (TBI) is an important risk factor for neurodegeneration, however little is known about how individual neurons respond to this type of injury. In this study, we follow neuronal populations over several months after a single mild TBI (mTBI) to assess heterogeneous and long ranging consequences of injury. We find that Activating Transcription Factor 3 (ATF3), a stress responsive transcription factor, defines a population of cortical neurons after mTBI. We show that a key feature of all neurons that activate Atf3 is an upregulation of stress-related genes and, importantly, the substantial loss in expression of many genes, including commonly used markers for these cell types. By permanently labeling the Atf3-expressing neurons, we observe that they segregate to two spatially distinct cortical populations that exhibit differential vulnerability to the same insult. A population in layer V undergoes cell death acutely after injury, while another in layer II/III survives long term and retains the ability to fire action potentials. To investigate the mechanism controlling layer V neuron death, we genetically silenced candidate stress response pathways. We found that the axon injury responsive kinase MAP3K12, also known as dual leucine zipper kinase (DLK), is required for the layer V neuron death. This work provides a rationale for targeting the DLK signaling pathway as a therapeutic intervention for traumatic brain injury. Beyond this, our novel approach to track neurons after a mild, subclinical injury can inform our understanding of neuronal susceptibility to repeated impacts.