Feichtenbiner Alicia B, Sytsma Karinn, O'Boyle Ryan P, Mittenzwei Rhonda, Maioli Heather, Scherpelz Kathryn P, Child Daniel D, Li Ning, Ariza Torres Jeanelle, Keene Lisa, Kirkland Amanda, Howard Kimberly, Latimer Caitlin, Keene C Dirk, Ransom Christopher, Nolan Amber L
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98104, USA.
Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
J Neuroinflammation. 2025 Jan 16;22(1):9. doi: 10.1186/s12974-024-03328-9.
Traumatic brain injury is a leading cause of chronic neurologic disability and a risk factor for development of neurodegenerative disease. However, little is known regarding the pathophysiology of human traumatic brain injury, especially in the window after acute injury and the later life development of progressive neurodegenerative disease. Given the proposed mechanisms of toxic protein production and neuroinflammation as possible initiators or contributors to progressive pathology, we examined phosphorylated tau accumulation, microgliosis and astrogliosis using immunostaining in the orbitofrontal cortex, a region often vulnerable across traumatic brain injury exposures, in an age and sex-matched cohort of community traumatic brain injury including both mild and severe cases in midlife. We found that microglial response is most prominent after chronic traumatic brain injury, and interactions with neurons in the form of satellite microglia are increased, even after mild traumatic brain injury. Taking our investigation into a mouse model, we identified that these satellite microglia suppress neuronal excitability in control conditions but lose this ability with chronic traumatic brain injury. At the same time, network hyperexcitability is present in both mouse and human orbitofrontal cortex. Our findings support a role for loss of homeostatic control by satellite microglia in the maladaptive circuit changes that occur after traumatic brain injury.
创伤性脑损伤是导致慢性神经功能残疾的主要原因，也是神经退行性疾病发展的危险因素。然而，对于人类创伤性脑损伤的病理生理学，尤其是急性损伤后的窗口期以及进行性神经退行性疾病的后期发展，我们知之甚少。鉴于有毒蛋白质产生和神经炎症的机制被认为可能是进行性病理的启动因素或促成因素，我们在一个年龄和性别匹配的社区创伤性脑损伤队列中，包括中年的轻度和重度病例，使用免疫染色检查了眶额皮质中磷酸化tau蛋白的积累、小胶质细胞增生和星形胶质细胞增生，眶额皮质是一个在各种创伤性脑损伤中经常易受损的区域。我们发现，慢性创伤性脑损伤后小胶质细胞反应最为突出，即使在轻度创伤性脑损伤后，以卫星小胶质细胞形式与神经元的相互作用也会增加。通过对小鼠模型的研究，我们发现这些卫星小胶质细胞在对照条件下会抑制神经元兴奋性，但在慢性创伤性脑损伤后会丧失这种能力。同时，小鼠和人类眶额皮质均存在网络兴奋性过高的情况。我们的研究结果支持卫星小胶质细胞失去稳态控制在创伤性脑损伤后发生的适应不良回路变化中所起的作用。
