Microglia Dysregulation and Altered Responses to Stress after Traumatic Brain Injury

创伤性脑损伤后小胶质细胞失调和对压力的反应改变

• 批准号: 10756431
• 负责人: Zoe M. Tapp
• 金额: $ 1.02万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-05-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10756431
• 关键词: Adult; Animals; Anti-Inflammatory Agents; Area; Attenuated; Behavior; Behavioral; Binding; Biological; CSF1R gene; Cells; Central Nervous System; Chronic; Chronic stress; Clinical; Cognition; Cognitive; Cognitive deficits; Corticosterone; Data; Electrophysiology (science); Ensure; Functional disorder; Gene Expression Profile; Genes; Glucocorticoid Receptor; Glucocorticoids; Goals; Hippocampus; Hormones; Human; Hydrocortisone; Immune; Immune System Diseases; Immunohistochemistry; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Injury; Ipsilateral; Knock-out; Lateral; Learning; Lesion; Life; Liquid substance; Long-Term Potentiation; Mediating; Mental disorders; Microglia; Modeling; Mus; NR3C1 gene; Neuronal Plasticity; Neurons; Outcome; Pathology; Pathway interactions; Percussion; Persons; Production; Quality of life; RNA; Receptor Activation; Recovery; Reporter; Reporting; Rodent; Role; Signal Transduction; Sleep Fragmentations; Sleep disturbances; Stress; Survivors; Testing; Traumatic Brain Injury; United States; Visualization; antagonist; biological adaptation to stress; comorbidity; cytotoxic; cytotoxicity; disability; experimental study; hypothalamic-pituitary-adrenal axis; improved; injury stressor; insight; neuroinflammation; neuron loss; neuroprotection; neurotransmission; response; stressor; transcriptome sequencing

PROJECT SUMMARY More than 5.3 million individuals suffer from a traumatic brain injury (TBI) related disability in the United States. Mounting clinical and experimental evidence shows a common co-morbidity of TBI is hypothalamic-pituitary- adrenal (HPA) axis dysfunction that results in the suppression of the stress hormone - cortisol in humans or the equivalent corticosterone (CORT) in rodents. Suppressed CORT is associated with aberrant neuronal responses in stress circuitry and can exacerbate post-TBI impairments, including cognitive and behavioral deficits. Sleep fragmentation is a frequent consequence of stress, thus we predict that post-injury sleep fragmentation engages a vulnerable biological pathway that substantially influences outcome by modulating neuroinflammation. For example, increasing data demonstrates that microglia mediate chronic TBI-induced recovery by perpetuating maladaptive inflammation, cytotoxicity, and altering neuronal viability and plasticity. Importantly, this microglial response may be worsened by post-TBI stressors. For example, microglia highly express glucocorticoid receptor (GR), which binds CORT to induce potent anti-inflammatory signaling. We hypothesize that TBI-induced suppression of CORT may compromise the anti-inflammatory action of GR in microglia, thus CORT production in response to stressors after TBI is vital to ensure control of inflammation. Due to the interplay of the stress and immune axes, the effect of chronic stress on TBI outcome must be better understood. This proposal aims to determine how neuronal activation and stress circuitry is altered in response to post-TBI sleep fragmentation, and how microglial GR may influence inflammation, neuronal activation, and cognition with post-TBI sleep fragmentation. Aim 1 will determine how microglia influence stress circuitry and hippocampal neuronal function with post-TBI sleep fragmentation. To do this, Pt. 3 we will rapidly deplete microglia through CSF1R antagonism and expose animals with and without microglia to post-TBI sleep fragmentation to define the cell specific role of microglia on neuronal activation in stress circuitry. We will further determine the RNA profile of the hippocampus following microglia depletion with post-TBI sleep fragmentation and perform electrophysiology to distinguish whether differences in hippocampal activity are due to changes in neuronal function and viability or microglial signaling. Aim 2 will test if microglial GR activation mediates inflammation, neuronal activation, and behavior following post-TBI sleep fragmentation. To do this, we will use Pt. 3 an inducible knockout of GR in microglia and determine differences in RNA sequencing profile, immunohistochemistry, and hippocampal-dependent behavioral tasks with sleep fragmentation after TBI. We hypothesize that reactive microglia mediate neuronal deficits in response to post-TBI sleep fragmentation through suppressed GR anti-inflammatory action. Ultimately, this proposed study will shed light on stress-immune dysfunction after TBI and better understand how to improve long-term quality of life and outcome for TBI survivors.

项目摘要 在美国，超过530万人患有脑损伤（TBI）相关的残疾。 安装的临床和实验证据表明，TBI的共同多发性是下丘脑 - 垂体 - 肾上腺（HPA）轴功能障碍导致人类或人类中的压力激素 - 皮质醇抑制 啮齿动物中的等效皮质酮（Cort）。抑制Cort与异常的神经元反应有关 在应力电路中，可能会加剧TBI后的障碍，包括认知和行为缺陷。睡觉 碎裂是压力的常见后果，因此我们预测伤害后睡眠碎片散布 一种脆弱的生物学途径，通过调节神经炎症会影响结果。为了 例如，增加数据表明，小胶质细胞介导了慢性TBI诱导的恢复 适应不良的炎症，细胞毒性和改变神经元的活力和可塑性。重要的是，这个小胶质细胞 TBI后压力源可能会恶化反应。例如，小胶质细胞高度表达糖皮质激素受体 （GR），它结合Cort诱导有效的抗炎信号传导。我们假设TBI引起了 抑制CORT可能会损害GR在小胶质细胞中的抗炎作用，因此Cort产生 响应于TBI后的压力源，对于确保控制炎症至关重要。由于压力的相互作用和 免疫轴，必须更好地理解慢性应激对TBI结果的影响。该建议旨在 确定神经元激活和应力电路如何因TBI睡眠片段化而改变， 以及小胶质细胞如何影响TBI睡眠后的炎症，神经元激活和认知 分散。 AIM 1将确定小胶质细胞如何影响应力回路和海马神经元功能 带有TBI后睡眠破裂。为此，PT。 3我们将通过CSF1R拮抗迅速耗尽小胶质细胞 并暴露于有或没有小胶质细胞的动物，以在TBI睡眠破裂后定义细胞的特异性作用 应力回路中神经元激活的小胶质细胞。我们将进一步确定海马的RNA轮廓 通过TBI睡眠后碎片化进行小胶质细胞耗竭，并进行电生理学以区分 海马活性的差异是否是由于神经元功能和生存力或小胶质细胞的变化所致 信号。 AIM 2将测试小胶质细胞激活是否介导炎症，神经元激活和行为 TBI睡眠后分裂后。为此，我们将使用PT。 3小胶质细胞中GR的诱导型敲除 并确定RNA测序谱，免疫组织化学和海马依赖性的差异 TBI后睡眠碎片的行为任务。我们假设反应性小胶质细胞介导神经元 通过抑制GR的抗炎作用来应对TBI后睡眠破裂的缺陷。最终， 这项拟议的研究将阐明TBI后的应力免疫功能障碍，并更好地了解如何改进 TBI幸存者的长期生活质量和结果。