TBI leads to degeneration of afferent neuronal projections

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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.