Mechanisms of Chronic Progressive Axon Degeneration Following TBI

项目摘要/摘要 中度或严重的颅脑损伤是一个严重的健康问题，除了通常具有破坏性的急性影响外，还可以引发慢性和不断演变的神经病理，这些病理可能是长期功能下降的基础。令人惊讶的是，在人类中重度脑外伤后，观察到了令人惊讶的旷日持久的轴突变性和相关的组织萎缩，并持续了数月和数年，可能导致一些患者的进行性认知能力下降。然而，在脑损伤后的几个月和几年里，驱动轴突继续膨胀和退化的机制尚不清楚，而且可能是可以修改的。此外，急性损伤，包括局灶性脑损伤与弥漫性脑损伤的程度，如何促进轴突变性的性质和进展尚不清楚。 在这里，我们假设中重度脑损伤的慢性轴突变性反映了一种通过顺行和逆行方向的变性而跨越神经网络的进行性脱节综合征，这取决于最初损伤的性质和分布。神经元胞体的死亡，例如由于局灶性病变，可以诱导其传出轴突(以及潜在的突触伙伴)的下游(顺行)变性，长期以来一直被认为是亚急性期轴突丢失的主要驱动因素。相反，神经元突触后伙伴的缺失已被证明通过生存信号的丢失(通过Jun Kinase/c-Jun途径)来驱动逆行变性。在初步数据中，我们利用多种模型和死后人的脑损伤组织，提供了逆行和顺行退变均可导致脑外伤后数月和数年的慢性和进行性轴突退行性变的证据。基于这些令人信服的发现，我们提出了一项综合性翻译设计，目的是1)通过结合病毒追踪和单细胞RNA测序的组织清理技术对神经元网络进行检查，确定脑损伤后小鼠慢性顺行性和退行性变性的相对贡献和机制；2)利用脑损伤的回脑模型验证对小鼠的观察，并评估整个脑回进行性轴突变性如何决定行为结局；3)使用死后标本确定局灶性和弥漫性脑损伤在确定人类脑损伤后进行性轴突变性的范围、分布和性质中的作用。 了解轴突在损伤后慢性阶段退化的机制将为发展脑外伤后随着时间的推移而进行有针对性的治疗干预提供必要的重要数据。

PROJECT SUMMARY/ ABSTRACT Moderate or severe TBI is a substantial health problem that in addition to often-devastating acute effects, can trigger chronic and evolving neuropathologies that may underlie long-term functional decline. Surprisingly protracted axonal degeneration and associated tissue atrophy has be observed following moderate-severe TBI in humans, persisting many months and years after injury and may contribute to progressive cognitive decline in some patients. However, the mechanisms that drive axons to continue to swell and degenerate in the months and years post-TBI are unknown, and potentially modifiable. Moreover, how the acute injury, including the degree of focal versus diffuse brain injury, contributes to the nature and progression of axon degeneration is unexplored. Here we hypothesize that chronic axon degeneration in moderate-severe TBI reflects a progressive disconnection syndrome across neural networks via degeneration in both an anterograde and retrograde direction, which is dependent upon the nature and distribution of the initial injury. The death of neuronal somata, for example due to a focal lesion, can induce downstream (anterograde) degeneration of their efferent axons (and potentially their synaptic partners) and has long been thought as the dominant driver of axon loss in the subacute phase. In contrast, loss of a neuron's post-synaptic partner has been shown to drive retrograde degeneration via the loss of survival signaling (via the Jun Kinase/ c-Jun pathway). In preliminary data we provide evidence that both retrograde and anterograde degeneration drive chronic and progressive axon degeneration for many months and years post-TBI using multiple models and post-mortem human TBI tissue. Based on these compelling findings we propose an integrated translational design to 1) Determine the relative contribution and mechanisms of anterograde and retrograde degeneration chronically post-TBI in mice via examination of the neuronal network through tissue clearing techniques in combination with viral tracing and single cell RNA sequencing; 2) Utilize a gyrencephalic model of TBI to validate observations in mice and evaluate how progressive axon degeneration across the gyrencephalic brain determines behavioral outcome and, 3) Determine the role of focal and diffuse brain injuries in determining the extent, distribution and nature of progressive axon degeneration following human TBI using post-mortem samples. Understanding the mechanisms by which axons degenerate in the chronic phase post-injury will provide important data necessary for the development of targeted therapeutic interventions over time following TBI.