Acute and Chronic Neural and Glial Response to Mild Traumatic Brain Injury in the Hippocampus

Abstract

ABSTRACTTraumatic brain injury (TBI) is an established risk factor for developing neurodegenerative disease. However, how TBI leads from acute injury to chronic neurodegeneration is limited to post-mortem models. There is a lack of connections betweenin vitroandin vivoTBI models that can relate injury forces to both macroscale tissue damage and brain function at the cellular level. Needle-induced cavitation (NIC) is a technique that can produce small cavitation bubbles in soft tissues, which allows us to relate small strains and strain rates in living tissue to ensuing acute and chronic cell death, tissue damage, and tissue remodeling. Here, we applied NIC to mouse brain slices to create a new model of TBI with high spatial and temporal resolution. We specifically targeted the hippocampus, which is a brain region critical for learning and memory and an area in which injury causes cognitive pathologies in humans and rodent models. By combining NIC with patch-clamp electrophysiology, we demonstrate that NIC in the Cornu Ammonis (CA)3 region of the hippocampus dynamically alters synaptic release onto CA1 pyramidal neurons in a cannabinoid 1 receptor (CB1R)-dependent manner. Further, we show that NIC induces an increase in extracellular matrix proteins associated with neural repair that is mitigated by CB1R antagonism. Together, these data lay the groundwork for advanced approaches in understanding how TBI impacts neural function at the cellular level, and the development of treatments that promote neural repair in response to brain injury.SIGNIFICANCECurrent models of mild TBI (mTBI) cannot relate injury forces to both macroscale tissue damage and brain function at the cellular level. We combine a microscale injury model inex vivobrain slices while simultaneously recording glutamatergic inputs onto CA1 hippocampal pyramidal neurons. Post-injury examination of chronic tissue regeneration by astrocytes allow us to connect acute neuronal signaling responses to chronic fibrosis after TBI. These studies provide a new tool for understanding the physiological and molecular responses to TBI and lay the groundwork for future experiments unraveling the synaptic mechanisms that mediate these responses seconds, minutes, and days following injury.