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.

项目摘要 创伤性脑损伤（TBI）可导致显著的发病率，这些发病率会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， 神经毒性或神经营养作用。到目前为止，这些影响主要在啮齿动物中进行了研究， 在人类中的平行考虑尚未产生临床可翻译的结果，这表明可能存在不同的 高级哺乳动物的反应。猪是一种理想的临床前转化动物模型， 然而，在细胞结构、代谢率和全身炎症反应方面与人类的相似性仅 一些TBI研究中心正在使用猪的脑损伤模型，目前还没有一个研究中心专注于脑损伤的研究。 小胶质细胞和受损轴突之间的相互作用或丘脑域内的病理学。我们的初步数据 表明小胶质细胞过程会聚到损伤的轴突south（小胶质细胞过程会聚; MPC）在微型猪的丘脑中，在大鼠中不重现。敏感性增加 感觉刺激和焦虑与TBI和炎症有关，不幸的是， TBI猪模型的行为评估留下了损伤后MPC和行为结果之间的联系 不清楚我们的初步数据和以前的研究都表明MPC可能是一个改善过程， 促进损伤后轴突生长，但需要注意的是，异常轴突生长与损伤后轴突生长的增强有关。 行为病态因此，本研究的目的是评估MPC对神经突生长的作用 和行为的发病率在猪模型的弥漫性TBI，并获得洞察的相似性，以人类 病理研究表明，男性有更大的促炎反应，较少的轴突生长， 与女性相比，感觉敏感性和焦虑程度降低。然而，没有已知的研究评估 男性和女性的MPC。因此，本研究将针对以下具体目标： 阐明小胶质细胞突起会聚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， 猪中小胶质细胞-轴突相互作用/MPC的多重免疫组织学样本，以确定 MPC的进展与感觉敏感性和焦虑/社会互动的变化，轴突 在损伤后第一周内，两种性别的生长/收缩变化。这项研究意义重大，因为它 将提供关于1）脑回猪模型中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的性别相关差异。 这些研究将作为未来调查的跳板，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介导的感觉的治疗性调节的研究 敏感和/或焦虑。