TBI leads to degeneration of afferent neuronal projections

TBI 导致传入神经元投射退化

• 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
• 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' 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

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.

创伤性脑损伤有许多后遗症，这些后遗症是由最初的损伤引起的， 退化和功能缺陷，这可能会出现在很长一段时间后，最初的 损伤虽然许多研究已经检查了脑缺血半影区的继发性神经元损失， 由于炎性细胞因子的诱导和营养因子的改变而发生的损伤部位 环境中，这些变化在损伤组织的传入轴突，项目的影响， 远侧位置的损伤部位尚未被研究。特别是基底前脑 胆碱能神经元（BFCN）投射在整个皮层和海马，并且这些神经元 对许多认知功能至关重要。这些神经元表达所有的神经营养因子 受体，Trk家族（TrkA、TrkB和TrkC），其促进神经元存活和轴突生长。 生长，以及p75 NTR，其可促进神经元死亡和轴突变性。 因此，这些细胞的靶区域中营养因子水平改变的结果是， 神经元可能严重影响其轴突投射的完整性， 对这些神经元支持的认知功能产生负面影响。使用流体 在小鼠中，我们将研究撞击损伤（FPI）模型诱导中度TBI的即时作用。 以及皮质损伤对基底前脑传入神经元的长期影响。使用 隔室培养策略，我们将研究轴突信号转导的机制，介导 退行性反应了解作为一个整体发生的损害范围 TBI的后果对于制定限制负面影响的治疗策略至关重要 伤害的后果。