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，是由于最初的损伤加重了神经 退化和功能缺陷，可能会在最初的手术后长时间出现 受伤。虽然许多研究已经研究了大脑中动脉半暗带的继发性神经元丢失。 由于炎性细胞因子的诱导和营养改变而发生的损伤部位 环境，损伤组织中这些变化对投射到 远端部位的受伤部位尚未调查。尤其是基底前脑 胆碱能神经元(BFCN)分布于大脑皮层和海马区，这些神经元 对许多认知功能都是至关重要的。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)，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退化。 因此，这些目标区域营养因子水平变化的后果是 神经元可能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。使用流体 采用冲击伤(FPI)模型建立小鼠中度颅脑损伤模型，研究其对急性颅脑损伤的即刻影响 皮质损伤对基底前脑传入神经元的长期影响。vbl.使用 隔室培养策略，我们将研究轴突信号调节的机制 逆行退行性反应。了解发生的损害的全部范围 创伤性脑损伤的后果对于制定治疗策略以限制负面影响至关重要 伤害的后果。