Single‐Nucleus RNA Sequencing Reveals That Gabra6+ Neurons in Prefrontal Cortex Promote the Progression of PTSD After Shockwave‐Induced TBI
Abstract Shockwave‐induced traumatic brain injury (TBI) results in the onset of post‐traumatic stress disorder (PTSD), triggered either by the TBI itself or other stressors. However, the interplay and underlying mechanisms of how these factors synergistically induce PTSD remain inadequately elucidat...
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407000 |
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| author | Xiaowei Fei Zehan Zhang Ya‐nan Dou Weihao Lv Hongqing Chen Li Wang Xin He Wangshu Chao Peng Luo Zhou Fei |
| author_facet | Xiaowei Fei Zehan Zhang Ya‐nan Dou Weihao Lv Hongqing Chen Li Wang Xin He Wangshu Chao Peng Luo Zhou Fei |
| author_sort | Xiaowei Fei |
| collection | DOAJ |
| description | Abstract Shockwave‐induced traumatic brain injury (TBI) results in the onset of post‐traumatic stress disorder (PTSD), triggered either by the TBI itself or other stressors. However, the interplay and underlying mechanisms of how these factors synergistically induce PTSD remain inadequately elucidated. Here, mice in the TBI (induced by biological shock tube blast injury) and PTSD (induced by single prolonged stress method) groups both displayed symptoms of PTSD behaviors, with the TBI+PTSD (composite model) group exhibiting more severe manifestations. The result of snRNA‐seq demonstrated a noticeable increase in the population of Gabra6+ neurons in the prefrontal cortex region of mice in the TBI+PTSD group. Knocking down cortical Gabra6 mitigated PTSD‐related behavioral outcomes. Mechanistically, the Smad3/4 complex activation led to the upregulation of Gabra6 expression in cortical neurons. Interaction of Gabra6 with Homer1 activated downstream cAMP signaling pathways. Homer1KO‐Nestin mice show reduced susceptibility to PTSD. Subsequently, the efficacy of monoclonal antibody intervention at the 218 site of Gabra6 in ameliorating PTSD development is verified. This study suggests that TBI and stressors act as independent components in PTSD development, with Gabra6+ neurons pivotal in synergistically facilitating PTSD formation. Strategies geared toward minimizing exposure to singular or combined stressors may effectively diminish the risk of developing PTSD. |
| format | Article |
| id | doaj-art-2790a44e29a343cdbf44dfeae828585c |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-2790a44e29a343cdbf44dfeae828585c2025-02-04T13:14:54ZengWileyAdvanced Science2198-38442025-02-01125n/an/a10.1002/advs.202407000Single‐Nucleus RNA Sequencing Reveals That Gabra6+ Neurons in Prefrontal Cortex Promote the Progression of PTSD After Shockwave‐Induced TBIXiaowei Fei0Zehan Zhang1Ya‐nan Dou2Weihao Lv3Hongqing Chen4Li Wang5Xin He6Wangshu Chao7Peng Luo8Zhou Fei9Department of Neurosurgery Xijing Hospital Air Force Military Medical University Xi'an Shaanxi 710032 ChinaDepartment of Neurosurgery Xijing Hospital Air Force Military Medical University Xi'an Shaanxi 710032 ChinaDepartment of Neurosurgery Xijing Hospital Air Force Military Medical University Xi'an Shaanxi 710032 ChinaDepartment of Neurosurgery Xijing Hospital Air Force Military Medical University Xi'an Shaanxi 710032 ChinaDepartment of Neurosurgery Xijing Hospital Air Force Military Medical University Xi'an Shaanxi 710032 ChinaDepartment of Neurosurgery Xijing Hospital Air Force Military Medical University Xi'an Shaanxi 710032 ChinaDepartment of Neurosurgery Xijing Hospital Air Force Military Medical University Xi'an Shaanxi 710032 ChinaDepartment of Neurosurgery Xijing Hospital Air Force Military Medical University Xi'an Shaanxi 710032 ChinaDepartment of Neurosurgery Xijing Hospital Air Force Military Medical University Xi'an Shaanxi 710032 ChinaDepartment of Neurosurgery Xijing Hospital Air Force Military Medical University Xi'an Shaanxi 710032 ChinaAbstract Shockwave‐induced traumatic brain injury (TBI) results in the onset of post‐traumatic stress disorder (PTSD), triggered either by the TBI itself or other stressors. However, the interplay and underlying mechanisms of how these factors synergistically induce PTSD remain inadequately elucidated. Here, mice in the TBI (induced by biological shock tube blast injury) and PTSD (induced by single prolonged stress method) groups both displayed symptoms of PTSD behaviors, with the TBI+PTSD (composite model) group exhibiting more severe manifestations. The result of snRNA‐seq demonstrated a noticeable increase in the population of Gabra6+ neurons in the prefrontal cortex region of mice in the TBI+PTSD group. Knocking down cortical Gabra6 mitigated PTSD‐related behavioral outcomes. Mechanistically, the Smad3/4 complex activation led to the upregulation of Gabra6 expression in cortical neurons. Interaction of Gabra6 with Homer1 activated downstream cAMP signaling pathways. Homer1KO‐Nestin mice show reduced susceptibility to PTSD. Subsequently, the efficacy of monoclonal antibody intervention at the 218 site of Gabra6 in ameliorating PTSD development is verified. This study suggests that TBI and stressors act as independent components in PTSD development, with Gabra6+ neurons pivotal in synergistically facilitating PTSD formation. Strategies geared toward minimizing exposure to singular or combined stressors may effectively diminish the risk of developing PTSD.https://doi.org/10.1002/advs.202407000cAMP signalingGabra6PTSDsingle‐nucleus RNA sequencingTBI |
| spellingShingle | Xiaowei Fei Zehan Zhang Ya‐nan Dou Weihao Lv Hongqing Chen Li Wang Xin He Wangshu Chao Peng Luo Zhou Fei Single‐Nucleus RNA Sequencing Reveals That Gabra6+ Neurons in Prefrontal Cortex Promote the Progression of PTSD After Shockwave‐Induced TBI Advanced Science cAMP signaling Gabra6 PTSD single‐nucleus RNA sequencing TBI |
| title | Single‐Nucleus RNA Sequencing Reveals That Gabra6+ Neurons in Prefrontal Cortex Promote the Progression of PTSD After Shockwave‐Induced TBI |
| title_full | Single‐Nucleus RNA Sequencing Reveals That Gabra6+ Neurons in Prefrontal Cortex Promote the Progression of PTSD After Shockwave‐Induced TBI |
| title_fullStr | Single‐Nucleus RNA Sequencing Reveals That Gabra6+ Neurons in Prefrontal Cortex Promote the Progression of PTSD After Shockwave‐Induced TBI |
| title_full_unstemmed | Single‐Nucleus RNA Sequencing Reveals That Gabra6+ Neurons in Prefrontal Cortex Promote the Progression of PTSD After Shockwave‐Induced TBI |
| title_short | Single‐Nucleus RNA Sequencing Reveals That Gabra6+ Neurons in Prefrontal Cortex Promote the Progression of PTSD After Shockwave‐Induced TBI |
| title_sort | single nucleus rna sequencing reveals that gabra6 neurons in prefrontal cortex promote the progression of ptsd after shockwave induced tbi |
| topic | cAMP signaling Gabra6 PTSD single‐nucleus RNA sequencing TBI |
| url | https://doi.org/10.1002/advs.202407000 |
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