TBI leads to degeneration of afferent neuronal projections

TBI 导致传入神经元投射退化

基本信息

批准号：
10660379
负责人：
WILMA J FRIEDMAN
金额：
$ 39.25万
依托单位：
RUTGERS THE STATE UNIV OF NJ NEWARK
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660379
关键词：
Affect Afferent Neurons Alzheimer&apos s Disease Apoptosis Apoptotic Area Axon Behavioral Brain Brain Injuries Brain region Cells Characteristics Data Dependence Development Distal Environment Exposure to Family Functional disorder Growth Factor Hippocampus Impaired cognition In Vitro Inflammatory Injury Learning Life Location Maintenance Mediating Memory Modeling Mus NGFR Protein Nerve Degeneration Nerve Growth Factor Receptors Neurodegenerative Disorders Neurons Pathway interactions Play Presynaptic Terminals Process Production Protein Biosynthesis Proteins Proteomics Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Retrograde Degeneration Role Signal Transduction Site Therapeutic Time Tissues Traumatic Brain Injury axon growth axonal degeneration basal forebrain basal forebrain cholinergic neurons cognitive function cytokine fluid percussion injury injured insight millimeter neural circuit neuron apoptosis neuron loss neuronal survival neurotransmission neurotrophic factor polarized cell receptor response therapeutic target

项目摘要

Traumatic brain injury has many sequelae resulting from the initial injury that exacerbate neural degeneration and functional deficits, which may emerge over long times following the initial injury. While many studies have examined secondary neuronal loss in the penumbra of the injury site that occurs due to the induction of inflammatory cytokines and an altered trophic environment, the impact of these changes in the injured tissue on afferent axons that project to the injury site from distal locations has not been investigated. In particular, basal forebrain cholinergic neurons (BFCN) project throughout the cortex and hippocampus, and these neurons are critical for numerous cognitive functions. These neurons express all the neurotrophin receptors, the Trk family (TrkA, TrkB, and TrkC) which promote neuronal survival and axonal growth, as well as p75NTR, which can promote neuronal death and axon degeneration. Therefore, the consequence of altered levels of trophic factors in the target regions of these neurons may critically impact the integrity of their axonal projections and ultimately have negative consequences for the cognitive functions supported by these neurons. Using the fluid percussion injury (FPI) model to induce moderate TBI in mice, we will investigate the immediate and long-term consequences of cortical injury on the afferent basal forebrain neurons. Using compartment culture strategies, we will investigate mechanisms of axonal signaling that mediate retrograde degenerative responses. Understanding the full scope of damage that occurs as a consequence of TBI is critical to developing therapeutic strategies to limit the negative consequences of the injury.

创伤性脑损伤会因最初的损伤而产生许多后遗症，从而加剧神经损伤退化和功能缺陷，可能会在最初的很长一段时间内出现受伤。虽然许多研究已经检查了半暗带的继发性神经元损失由于炎症细胞因子的诱导和营养物质的改变而发生的损伤部位环境中，受伤组织的这些变化对投射到的传入轴突的影响远端损伤部位尚未调查。特别是基底前脑胆碱能神经元 (BFCN) 投射到整个皮层和海马体，这些神经元对于许多认知功能至关重要。这些神经元表达所有神经营养蛋白受体，Trk 家族（TrkA、TrkB 和 TrkC）促进神经元存活和轴突生长，以及 p75NTR，它可以促进神经元死亡和轴突变性。因此，这些目标区域中营养因子水平改变的结果神经元可能会严重影响其轴突投射的完整性，并最终对这些神经元支持的认知功能产生负面影响。使用液体敲击损伤（FPI）模型在小鼠中诱导中度 TBI，我们将研究立即发生的情况以及皮质损伤对传入基底前脑神经元的长期影响。使用隔室培养策略，我们将研究介导的轴突信号传导机制逆行性退行性反应。了解发生的损害的全部范围 TBI 的后果对于制定限制负面影响的治疗策略至关重要受伤的后果。