Sex differences in neuroimmune function and developmental vulnerability to early life traumatic brain injury

神经免疫功能的性别差异和早期创伤性脑损伤的发育脆弱性

• 批准号: 10578379
• 负责人: Kathryn M. Lenz
• 金额: $ 41.96万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578379
• 关键词: 10 year old; 4 year old; Acute; Adolescent; Adult; Affect; Alcohol abuse; Anxiety; Astrocytes; Attention deficit hyperactivity disorder; Behavioral; Blood - brain barrier anatomy; Brain; CSF1R gene; Cells; Child; Childhood; Chronic; Cognitive deficits; Data; Development; Drug abuse; Elderly; Elements; Emergency department visit; Environment; FDA approved; Female; Future; Gene Expression; Genes; Gliosis; Hippocampus; Histology; Hormones; Human; Hypothalamic structure; Immune; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Knowledge; Lateral; Learning; Life; Mediating; Mediator; Mental Depression; Mental disorders; Microglia; Modeling; Moods; Neuroimmune; Neurological outcome; Neurons; Outcome; Patients; Pattern; Phase; Public Health; Rattus; Risk; Risk Taking; Rodent; Role; Sex Differences; Shapes; Signal Transduction; Social Behavior; Social Functioning; Source; Stress; Stress and Coping; Substance abuse problem; Synapses; Testing; Time; Toddler; Traumatic Brain Injury; Vascular Permeabilities; Withdrawal; Work; age group; behavior change; behavioral health; behavioral outcome; biological sex; blood-brain barrier disruption; blood-brain barrier permeabilization; brain cell; cell type; comparison group; early childhood; early experience; experience; experimental study; first responder; fluid percussion injury; improved; inhibitor; injured; male; mast cell; nano-string; nervous system disorder; neural circuit; neurobehavioral; neurodevelopment; neuroinflammation; neuropathology; novel; novel therapeutics; pediatric emergency; pediatric traumatic brain injury; pharmacologic; postnatal; preclinical study; public health relevance; response; response to brain injury; response to injury; sex; social; social deficits; social stress; transcriptome sequencing; transcriptomics; treatment strategy; verbal

Project summary: Traumatic brain injury (TBI) in childhood is the leading cause of pediatric emergency room visits, with over 800,000 children visiting the ER each year according to the CDC. Pediatric TBI can have lifelong consequences for behavioral health, increases rates of ADHD, drug and alcohol abuse, long-term cognitive and social deficits, depression and anxiety. This suggests that early childhood is a period of particular vulnerability to long-term, deleterious neurological outcomes after TBI. Despite the clear evidence of a significant public health problem, the proximal mechanisms leading up to those long term TBI-related outcomes are poorly understood. TBI induces robust neuroinflammation and brain-resident innate immune cells, such as microglia, regulate normal brain development, including synaptic patterning. The impact of TBI on microglia-synaptic interactions is poorly understood. We have demonstrated dramatic developmental biases in activation and sex differences in the profile of neuroimmune cells in the immature rat brain, both microglia and the less studied mast cells. Mast cells are abundant in the developing brain and sparse in adults, suggesting that mast cells could contribute uniquely to the neuroimmune milieu after pediatric TBI. Mast cells are ‘first responders’ to immune insults and coordinate subsequent immune cell (microglia and astrocyte) activation as well as vascular permeability but their role in TBI has not been well studied. In our project, we will use lateral fluid percussion injury on juvenile rats to model pediatric TBI, which our preliminary data suggest elicits robust mast cell activation in the hippocampus, acute gliosis, and long-term, sex-dependent shifts in social behavior and stress hormones. Because so little is known about the unique pediatric response to injury, we will compare the pediatric versus adult injury response of male and female rats via RNAseq and Nanostring profiling of isolated immune cells in a comprehensive time course study (Aim 1). To test for a contribution of mast cells to pediatric TBI, we will use an acute mast cell inhibition using an FDA-approved pharmacological agent and comprehensively profile neuroinflammatory responses, alterations in blood brain barrier (BBB) permeability to narrow in on a potential mechanism through which mast cells are acting after TBI, and correlate BBB changes with social and stress-related behavior outcomes (Aim 2). To determine whether microglia are important for long-term neurodevelopmental programming of behavioral outcomes and sculpting neural circuits after pediatric TBI, we will perform microglia depletion/forced turnover experiments post-TBI (Aim 3). We will compare sexes in all studies, and we predict that males more robust basal neuroimmune tone in the developing brain may render them more vulnerable to TBI-related outcomes. Our studies have the potential to improving long-term outcomes following pediatric traumatic brain injury and uncover potential new therapeutic options targeted to the unique neuroimmune environment of the developing brain.

项目概要：儿童期创伤性脑损伤（TBI）是儿科急诊室的主要原因 根据 CDC 的数据，每年有超过 800,000 名儿童前往急诊室就诊。 对行为健康产生终生影响，增加多动症、药物和酒精滥用的发生率，长期 认知和社交缺陷、抑郁和焦虑这表明幼儿期是一个特殊的时期。 尽管有明确的证据表明，TBI 后仍容易遭受长期、有害的神经系统后果。 重大公共卫生问题，导致长期 TBI 相关问题的近端机制 创伤性脑损伤（TBI）会引发强烈的神经炎症和大脑固有免疫，但人们对它的结果知之甚少。 小胶质细胞等细胞调节正常的大脑发育，包括 TBI 的影响。 我们对小胶质细胞-突触相互作用知之甚少。 未成熟大鼠大脑中神经免疫细胞的激活和性别差异，两种小胶质细胞 研究较少的肥大细胞在发育中的大脑中丰富，而在成人中则稀疏， 这表明肥大细胞可能对儿童 TBI 后的神经免疫环境做出独特的贡献。 是免疫损伤的“第一反应者”并协调随后的免疫细胞（小胶质细胞和星形胶质细胞） 激活以及血管通透性，但它们在 TBI 中的作用尚未得到充分研究。 使用幼年大鼠的侧面液体冲击损伤来模拟儿科 TBI，我们的初步数据表明 引起海马体中肥大细胞的强烈激活、急性神经胶质增生以及长期的、性别依赖性的变化 由于我们对儿科对伤害的独特反应知之甚少， 我们将通过 RNAseq 和 Nanostring 比较雄性和雌性大鼠的儿童与成人损伤反应 在综合时间过程研究中对分离的免疫细胞进行分析（目标 1）。 肥大细胞治疗儿科 TBI，我们将使用 FDA 批准的药理学药物进行急性肥大细胞抑制 剂并全面分析神经炎症反应、血脑屏障 (BBB) 的变化 渗透性缩小了肥大细胞在 TBI 后发挥作用的潜在机制，并将其关联起来 BBB 随社会和压力相关行为结果而变化（目标 2）。 对于行为结果的长期神经发育规划和塑造神经回路很重要 儿科 TBI 后，我们将进行 TBI 后小胶质细胞耗竭/强制周转实验（目标 3）。 比较所有研究中的性别，我们预测男性的基础神经免疫基调更强健 发育中的大脑可能使他们更容易受到 TBI 相关后果的影响。 改善儿科创伤性脑损伤后的长期结果并发现潜在的新疗法 针对发育中大脑独特的神经免疫环境的选择。