Traumatic Optic Neuropathy Is Associated with Visual Impairment, Neurodegeneration, and Endoplasmic Reticulum Stress in Adolescent Mice

Abstract

Traumatic brain injury (TBI) results in a number of impairments, often including visual symptoms. In some cases, visual impairments after head trauma are mediated by traumatic injury to the optic nerve, termed traumatic optic neuropathy (TON), which has few effective options for treatment. Using a murine closed-head weight-drop model of head trauma, we previously reported in adult mice that there is relatively selective injury to the optic tract and thalamic/brainstem projections of the visual system. In the current study, we performed blunt head trauma on adolescent C57BL/6 mice and investigated visual impairment in the primary visual system, now including the retina and using behavioral and histologic methods at new time points. After injury, mice displayed evidence of decreased optomotor responses illustrated by decreased optokinetic nystagmus. There did not appear to be a significant change in circadian locomotor behavior patterns, although there was an overall decrease in locomotor behavior in mice with head injury. There was evidence of axonal degeneration of optic nerve fibers with associated retinal ganglion cell death. There was also evidence of astrogliosis and microgliosis in major central targets of optic nerve projections. Further, there was elevated expression of endoplasmic reticulum (ER) stress markers in retinas of injured mice. Visual impairment, histologic markers of gliosis and neurodegeneration, and elevated ER stress marker expression persisted for at least 30 days after injury. The current results extend our previous findings in adult mice into adolescent mice, provide direct evidence of retinal ganglion cell injury after head trauma and suggest that axonal degeneration is associated with elevated ER stress in this model of TON.

Chronic Histological Outcomes of Indirect Traumatic Optic Neuropathy in Adolescent Mice: Persistent Degeneration and Temporally Regulated Glial Responses

“…Examination of optic nerve injury through a TAI model is also important because visual impairment occurs in roughly 20% of children with TBI [ 11 ]. We previously described an adolescent murine closed-head trauma model characterized by axonal degeneration and gliosis in the optic nerve and its projection targets, retinal ganglion cell death, and behavioral visual impairment [ 12 , 13 , 14 ]. This injury model appears to produce damage to the optic nerve via force transmission through the optic canal and reproduces key features of indirect traumatic optic neuropathy (iTON).…”

Traumatic Brain Injury: An Age-Dependent View of Post-Traumatic Neuroinflammation and Its Treatment

“…Microglial activation appears as early as 1 dpi and has been found up to 35 dpi [ 160 , 162 , 163 , 164 , 165 , 166 , 167 , 176 ]. It starts in structures close to the impact and extends to remote regions [ 166 ].…”

“…Astrocyte activation is absent before 1 dpi [ 138 , 158 , 165 , 166 , 170 , 171 ]. It begins at 1 dpi and lasts until 35 dpi [ 138 , 158 , 159 , 162 , 163 , 165 , 166 , 167 , 170 , 171 , 175 , 178 ], starting to spread to remote and contralateral regions from 7 dpi [ 159 ]. Astrogliosis is no longer present at 180 dpi [ 158 ].…”

“…Neuronal death appears from 6 hpi in the cortex [ 171 ] and spreads to the thalamus and contralateral hemisphere at 3 dpi [ 181 ] and to remote brain areas at 7 dpi [ 170 , 181 ]. This neuronal death persists into the long term [ 79 , 158 , 167 , 171 , 183 , 188 ] and is still visible at 6 mpi [ 185 ].…”

“…Specifically, adolescent TBI increases the sensitivity to the rewarding effects of cocaine in adulthood [ 168 ]. A study also reported visual and optokinetic response deficits, correlated to microglia and astrocyte activation in the optical tract [ 167 ].…”