Mechanisms of Chronic Progressive Axon Degeneration Following TBI

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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.