Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction.

The ability to derive retinal ganglion cells (RGCs) from human pluripotent stem cells (hPSCs) has led to numerous advances in the field of retinal research, with great potential for the use of hPSC-derived RGCs for studies of human retinal development, in vitro disease modeling, drug discovery, as well as their potential use for cell replacement therapeutics. Of all these possibilities, the use of hPSC-derived RGCs as a human-relevant platform for in vitro disease modeling has received the greatest attention, due to the translational relevance as well as the immediacy with which results may be obtained compared to more complex applications like cell replacement. While several studies to date have focused upon the use of hPSC-derived RGCs with genetic variants associated with glaucoma or other optic neuropathies, many of these have largely described cellular phenotypes with only limited advancement into exploring dysfunctional cellular pathways as a consequence of the disease-associated gene variants.

Transient Seizure Clusters and Epileptiform Activity Following Widespread Bilateral Hippocampal Interneuron Ablation.

Interneuron loss is a prominent feature of temporal lobe epilepsy in both animals and humans and is hypothesized to be critical for epileptogenesis. As loss occurs concurrently with numerous other potentially proepileptogenic changes, however, the impact of interneuron loss in isolation remains unclear. For the present study, we developed an intersectional genetic approach to induce bilateral diphtheria toxin-mediated deletion of Vgat-expressing interneurons from dorsal and ventral hippocampus.

Targeting eIF2α in TBI-induced traumatic optic neuropathy: Effects of Salubrinal and the Integrated Stress Response Inhibitor.

Traumatic brain injury (TBI) can induce traumatic axonal injury in the optic nerve, which is referred to as traumatic optic neuropathy (TON). TON occurs in up to 5% of TBI cases and leads to irreversible visual deficits. TON-induced phosphorylation of eIF2α, a downstream ER stress activator in the PERK pathway presents a potential point for therapeutic intervention.

Early Measures of TBI Severity Poorly Predict Later Individual Impairment in a Rat Fluid Percussion Model.

Background: Multiple measures of injury severity are suggested as common data elements in preclinical traumatic brain injury (TBI) research. The robustness of these measures in characterizing injury severity is unclear. In particular, it is not known how reliably they predict individual outcomes after experimental TBI.

Brief Oxygen Exposure after Traumatic Brain Injury Hastens Recovery and Promotes Adaptive Chronic Endoplasmic Reticulum Stress Responses.

Traumatic brain injury (TBI) is a major public health concern, particularly in adolescents who have a higher mortality and incidence of visual pathway injury compared to adult patients. Likewise, we have found disparities between adult and adolescent TBI outcomes in rodents. Most interestingly, adolescents suffer a prolonged apneic period immediately post-injury, leading to higher mortality; therefore, we implemented a brief oxygen exposure paradigm to circumvent this increased mortality.

Brief oxygen exposure after traumatic brain injury speeds recovery and promotes adaptive chronic endoplasmic reticulum stress responses.

Traumatic brain injury (TBI) is a major public health concern particularly in adolescents who have a higher mortality and incidence of visual pathway injury compared to adult patients. Likewise, we have found disparities between adult and adolescent TBI outcomes in rodents. Most interestingly, adolescents suffer a prolonged apneic period immediately post injury leading to higher mortality; so, we implemented a brief oxygen exposure paradigm to circumvent this increased mortality.

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

Injury to the optic nerve, termed, traumatic optic neuropathy (TON) is a known comorbidity of traumatic brain injury (TBI) and is now known to cause chronic and progressive retinal thinning up to 35 years after injury. Although animal models of TBI have described the presence of optic nerve degeneration and research exploring acute mechanisms is underway, few studies in humans or animals have examined chronic TON pathophysiology outside the retina. We used a closed-head weight-drop model of TBI/TON in 6-week-old male C57BL/6 mice.

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

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.