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

Author

Listed:
  • Mor R. Alkaslasi

    (National Institutes of Health
    Brown University)

  • Eliza Y. H. Lloyd

    (National Institutes of Health)

  • Austin S. Gable

    (National Institutes of Health)

  • Hanna Silberberg

    (National Institutes of Health)

  • Hector E. Yarur

    (National Institutes of Health)

  • Valerie S. Tsai

    (National Institutes of Health)

  • Mira Sohn

    (National Institutes of Health)

  • Gennady Margolin

    (National Institutes of Health)

  • Hugo A. Tejeda

    (National Institutes of Health)

  • Claire E. Le Pichon

    (National Institutes of Health)

Abstract

Traumatic brain injury (TBI) is a risk factor for neurodegeneration, however little is known about how this kind of injury alters neuron subtypes. In this study, we follow neuronal populations over time after a single mild TBI (mTBI) to assess long ranging consequences of injury at the level of single, transcriptionally defined neuronal classes. We find that the stress-responsive Activating Transcription Factor 3 (ATF3) defines a population of cortical neurons after mTBI. Using an inducible reporter linked to ATF3, we genetically mark these damaged cells to track them over time. We find that a population in layer V undergoes cell death acutely after injury, while another in layer II/III survives long term and remains electrically active. To investigate the mechanism controlling layer V neuron death, we genetically silenced candidate stress response pathways. We found that the axon injury responsive 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 approach to track neurons after a mild, subclinical injury can inform our understanding of neuronal susceptibility to repeated impacts.

Suggested Citation

  • Mor R. Alkaslasi & Eliza Y. H. Lloyd & Austin S. Gable & Hanna Silberberg & Hector E. Yarur & Valerie S. Tsai & Mira Sohn & Gennady Margolin & Hugo A. Tejeda & Claire E. Le Pichon, 2025. "The transcriptional response of cortical neurons to concussion reveals divergent fates after injury," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56292-0
    DOI: 10.1038/s41467-025-56292-0
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    References listed on IDEAS

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    1. Zizhen Yao & Hanqing Liu & Fangming Xie & Stephan Fischer & Ricky S. Adkins & Andrew I. Aldridge & Seth A. Ament & Anna Bartlett & M. Margarita Behrens & Koen Berge & Darren Bertagnolli & Hector Roux , 2021. "A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex," Nature, Nature, vol. 598(7879), pages 103-110, October.
    2. Jan C. Frankowski & Alexa Tierno & Shreya Pavani & Quincy Cao & David C. Lyon & Robert F. Hunt, 2022. "Brain-wide reconstruction of inhibitory circuits after traumatic brain injury," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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