Behavioral and axonal impacts of thalamic microglial process convergence following diffuse brain injury

弥漫性脑损伤后丘脑小胶质细胞过程收敛的行为和轴突影响

• 批准号: 10590783
• 负责人: Audrey D Lafrenaye
• 金额: $ 42.69万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10590783
• 关键词: 3-Dimensional; Acute; Address; Adult; Animal Model; Animals; Anxiety; Autopsy; Axon; Behavior assessment; Behavioral; Brain; Brain Injuries; Clinical; Data; Diffuse; Diffuse Axonal Injury; Diffuse Brain Injury; Ear; Encephalitis; Family suidae; Female; Foundations; Functional disorder; Future; Goals; Human; Human Pathology; Immune; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Inherited; Injury; Investigation; Knowledge; Lead; Limb structure; Link; Mammals; Mediating; Mediator of activation protein; Microglia; Microscopic; Modeling; Molecular; Morbidity - disease rate; Nerve Growth Factors; Neurites; Neuroimmune; Neurons; Nociception; Outcome; Pathology; Persons; Population; Preparation; Process; Property; Proteins; Publishing; Rattus; Research; Rodent; Rodent Model; Role; Sampling; Sensory; Services; Social Interaction; Suggestion; Swelling; TBI treatment; Testing; Thalamic structure; Therapeutic; Time; Tissue Sample; Tissues; Traumatic Brain Injury; Universities; Work; anxiety sensitivity; anxiety-like behavior; axon injury; behavioral outcome; biobank; brain cell; clinically translatable; cofilin; cohort; fluid percussion injury; functional outcomes; injured; insight; male; metabolic rate; neuroinflammation; neurotoxic; pain sensation; physical process; porcine model; pre-clinical; protein expression; reconstruction; repaired; response; sex; social anxiety; systemic inflammatory response

Project Summary Traumatic brain injury (TBI) can lead to significant morbidities that are altered by changes in inflammatory state. Microglia, the innate immune cells of the brain, are critical mediators of neuroinflammation that can have either neurotoxic or neurotrophic effects. To date, these effects have been examined primarily in rodents, while their parallel consideration in humans has not yielded clinically translatable findings, suggesting potentially different responses in higher order mammals. The pig is an ideal pre-clinical translational animal model, due to its similarities to humans in cytoarchitecture, metabolic rates and systemic inflammatory responses, however, only a handful of TBI research centers are using pig models of brain injury and currently none are focused on the interaction between microglia and injured axons or pathology within the thalamic domain. Our preliminary data demonstrated that microglial processes converge onto injured axonal swellings (microglial process convergence; MPC) in the thalamus of micro pigs, that is not recapitulated in rats, following diffuse TBI. Increased sensitivity to sensory stimulation and anxiety are associated with TBI and inflammation, unfortunately, the limited use of behavioral assessments in pig models of TBI leaves the link between post-injury MPC and behavioral outcomes unclear. Both our preliminary data and previous studies indicate that MPC may be an ameliorative process, promoting axonal outgrowth post-injury with the caveat that aberrant axonal outgrowth is linked to heightened behavioral morbidity. Therefore, the goal of this study is to assess the role of MPC on neurite outgrowth and behavioral morbidity in a pig model of diffuse TBI and gain insight into the similarity to human pathology. Studies indicate that males have greater pro-inflammatory responses, less axonal outgrowth, and reduced sensory sensitivity and anxiety compared to females. However, there are no known studies evaluating MPC in both males and females. Accordingly, the current study will address the following specific aim 1) To elucidate the extent and role of microglial process convergence on axonal outgrowth and behavioral morbidity following diffuse TBI. To address this aim we will complete quantitative 3D assessments of multiplexed immunohistological samples for microglial-axonal interactions/MPC in pigs to determine the degree and progression of MPC in relation to sensory sensitivity and anxiety/social interaction changes, axonal outgrowth/retraction changes in both sexes within the first week post-injury. This study is significant because it will provide valuable preliminary data regarding 1) the duration and extent of MPC in a gyrencephalic pig model, 2) the behavioral dysfunction(s) associated with thalamic MPC, and 3) the sex-associated differences in MPC. These studies will serve as a springboard for future investigations into 1) the potential adaptive and/or maladaptive role of various degrees of MPC 2) the molecular mechanisms involved in and potential therapeutic modulation of MPC and 3) investigations regarding the therapeutic modulation of TBI-mediated sensory sensitivity and/or anxiety.

项目概要 创伤性脑损伤 (TBI) 可导致显着的发病率，并因炎症状态的变化而改变。 小胶质细胞是大脑的先天免疫细胞，是神经炎症的关键介质，可以具有以下任一作用： 神经毒性或神经营养作用。迄今为止，这些影响主要在啮齿动物中进行了研究，而它们的 在人类中的平行考虑尚未产生可临床转化的结果，表明可能存在不同的结果 高等哺乳动物的反应。猪是理想的临床前转化动物模型，因为它 然而，在细胞结构、代谢率和全身炎症反应方面与人类相似 一些 TBI 研究中心正在使用猪脑损伤模型，但目前没有一个研究中心专注于 小胶质细胞与丘脑域内受损轴突或病理之间的相互作用。我们的初步数据 证明小胶质细胞过程会聚到受伤的轴突肿胀上（小胶质细胞过程会聚； MPC）存在于微型猪的丘脑中，但在弥漫性 TBI 后的大鼠中并未重现。灵敏度提高 感觉刺激和焦虑与 TBI 和炎症有关，不幸的是，有限的使用 TBI 猪模型的行为评估留下了受伤后 MPC 和行为结果之间的联系 不清楚。我们的初步数据和之前的研究都表明 MPC 可能是一个改善过程， 促进损伤后轴突生长，但需注意异常轴突生长与轴突生长加剧有关 行为发病率。因此，本研究的目的是评估 MPC 对神经突生长的作用 弥漫性 TBI 猪模型中的行为发病率和行为发病率，并深入了解与人类的相似性 病理。研究表明，男性有更强的促炎症反应、更少的轴突生长，并且 与女性相比，感官敏感性和焦虑感降低。然而，目前还没有已知的研究评估 男性和女性都有 MPC。因此，当前的研究将解决以下具体目标 1) 阐明小胶质细胞过程收敛对轴突生长和行为的程度和作用 弥漫性 TBI 后的发病率。为了实现这一目标，我们将完成定量 3D 评估 猪小胶质细胞-轴突相互作用/MPC 的多重免疫组织学样本以确定其程度 MPC 的进展与感觉敏感性和焦虑/社交互动变化、轴突 受伤后第一周内两性的生长/回缩变化。这项研究意义重大，因为它 将提供有关以下方面的有价值的初步数据：1) 环脑猪模型中 MPC 的持续时间和程度， 2) 与丘脑 MPC 相关的行为功能障碍，以及 3) MPC 中与性别相关的差异。 这些研究将作为未来研究的跳板：1）潜在的适应性和/或 不同程度的MPC的适应不良作用2)参与的分子机制和潜在的治疗 MPC 的调节和 3) 关于 TBI 介导的感觉治疗调节的研究 敏感和/或焦虑。