Insulin‐like Growth Factor‐1 Treatment of Experimental Traumatic Brain Injury Increases Newborn Neuron Migration Through the Granular Cell Layer

Abstract

Traumatic brain injuries (TBI) are a tragic yet surprisingly common problem throughout the world. In the United States alone, 2.8 million people a year are diagnosed with a TBI. TBI causes cellular death and dysfunction within the brain that is connected with cognitive and behavioral dysfunction both clinically and experimentally.The controlled cortical impact (CCI) model is a well characterized contusion model of TBI that emulates both motor and cognitive deficits in addition to cell loss within the dentate gyrus of the hippocampus. Following CCI there is an early loss of the immature neuron population in the subgranular zone of the dentate gyrus followed by a compensatory increase in newborn neurons. Additionally, there is increased glial reactivity in response to injury. Of these newborn neurons, only a small portion survive and incorporate into the granular cell layer (GCL) of the dentate gyrus. However, the surviving trauma‐born neurons display stunted growth and reduced arborization, and not many make it to a fully functional form.Previous research shows that treatment with insulin‐like growth factor‐1 (IGF‐1) conveys behavioral improvements and increases the survival of doublecortin (DCX) positive trauma‐born neurons with improved dendritic arborization. In the current study, C57BL/6J mice underwent a CCI or a sham injury and were administered IGF‐1 (3mg/mg) or vehicle by intracerebroventricular injection (nCCI&IGF‐1 = 7 | nCCI&Veh = 8 | nSham&IGF‐1 = 4 | nSham&Veh = 4) for 7 days following injury. Animals were euthanized 7 days after injury, and the brain was collected, processed, and sectioned at a thickness of 40mm for immunohistochemistry. Tissue was then immuno‐labeled for DCX, a marker of immature neurons, and glial fibrillary acidic protein (GFAP), a marker of astrocytes in the brain, and imaged.We observed that the trauma‐born neurons of CCI injured mice treated with IGF‐1 migrate from the subgranular zone and into the outer 2/3rds of the GCL more frequently than do those observed in animals treated with vehicle. During development, GFAP positive cells send processes out that serve as a scaffolding by which immature neurons can migrate. As such, we hypothesized that after TBI, immature neurons migrate through the GCL by utilizing GFAP positive processes, and that IGF‐1 would increase the number of processes projecting through the GCL compared to vehicle treated animals.We assessed the number of GFAP positive processes projecting into the GCL by counting the number of processes per millimeter in three brain sections collected from the epicenter of injury. Our findings suggest that there is an increase in GFAP processes following CCI, but treatment with IGF‐1 did not increase the number of these processes. Our findings suggest that increased migration seen with IGF‐1 treatment does not occur along glial processes, or that this is not the only means by which DCX positive cells are able to migrate after injury.Support or Funding InformationFunded through American Physiological Society 2019 UGSRF Fellowship