Cortical Brain Injury Causes Retrograde Degeneration of Afferent Basal Forebrain Cholinergic Neurons via the p75NTR.
Academic Article
Overview
abstract
Traumatic brain injury elicits neuronal loss at the site of injury and progressive neuronal loss in the penumbra. However, the consequences of TBI on afferent neurons projecting to the injured tissue from distal locations is unknown. Basal forebrain cholinergic neurons (BFCNs) extend long projections to multiple brain regions including the cortex, regulate many cognitive functions and are compromised in numerous neurodegenerative disorders. To determine the consequence of cortical injury on these afferent neurons, we used the Fluid Percussion Injury (FPI) model of traumatic brain injury and assessed the effects on BFCN survival and axon integrity in male and female mice. Survival or death of BF neurons can be regulated by neurotrophins or proneurotrophins, respectively. The injury elicited an induction of proNGF and proBDNF in the cortex, and a loss of BFCNs ipsilateral to the injury compared to sham uninjured mice. p75NTR knockout mice did not show loss of BFCN neurons, indicating a retrograde degenerative effect of the cortical injury on the afferent BFCNs mediated through p75NTR. In contrast, locus coeruleus (LC) neurons which also project throughout the cortex were unaffected by the injury, suggesting specificity in retrograde degeneration after cortical TBI. Proneurotrophins (proNTs) provided directly to basal forebrain axons in microfluidic cultures triggered retrograde axonal degeneration and cell death, which did not occur in the absence of p75NTR. This study shows that after traumatic brain injury, proNTs induced in the injured cortex promote BFCN axonal degeneration and retrograde neuron loss through p75NTR.Significance StatementTBI is well-known to elicit direct neuronal loss at the site of injury and secondary loss in the penumbra, however the effect on afferent neuronal populations that project axons from distal locations such as the basal forebrain, has not been elucidated. Basal forebrain cholinergic neurons (BFCNs) project to a myriad of brain regions and regulate cognitive processes such as learning, attention, and memory, and are compromised in neurodegenerative diseases such as Alzheimer's disease. These neurons constitutively express p75NTR, a receptor that can promote neuronal degeneration following injury. We demonstrate here that cortical injury promotes degeneration of afferent BFCNs, mediated by p75NTR, indicating that TBI causes neuronal loss in brain regions distal to the site of injury via retrograde axonal degeneration.
