Traumatic brain injury (TBI) persists as the leading cause of death among young and elderly populations despite massive advancements in medical care, which is why the primary objective of my laboratory is to understand the sex-dependent mechanisms responsible for network disruptions underlying traumatic brain injury. TBI survivors are often profoundly affected by long-term increases in brain excitability; however, the slow progression from acute injury to chronic brain dysfunction presents an opportunity to examine the mechanisms beneath these brain changes. Thus, a fundamental understanding of temporal mechanistic changes caused by brain injury is critical for developing rational approaches for targeted treatments during the critical hours and days following TBI.
This laboratory aims to answer critical questions surrounding the mechanisms of neuronal edema at the cellular resolution and its impact on excitability after TBI. Edema is one of the most prominent secondary injuries associated with TBI, one that can be observed within minutes and persist for days; because it is the principal cause of death following TBI, it is a crucially important target for intervention that unfortunately is still confronted with decades-old primary treatments that yield little success. Our recently published work in the Journal of Clinical Investigations shows that edema may not be harmful under all circumstances and can actually increase excitability when suppressed at certain time points. This has potentially major clinical implications, as the current clinical priority still centers around eliminating edema at all costs. This work is the basis for my NIH R01 grant (1.92 million received for five years starting July 1, 2022). In addition to these findings, we also observed noncanonical glutamate release events in the neuropil of both layer 1 and layer 2/3 sensory cortex, known as glutamatergic plumes, after TBI. Glutamate plumes, which have not been reported in TBI, may have a significant influence on network excitability. We received NIH R21 grant totaling $423,500 for two years beginning on September 15th, 2022, so we can begin exploring the mechanisms responsible for plumes after TBI and the effects of plumes on synaptic plasticity and network excitability.
We leverage a multifaceted approach to our research in the laboratory, including in vivo whole-cell electrophysiology, two-photon microscopy, and brain slice electrophysiology. Our lab is the first ever to deploy in vivo whole-cell recording following brain injury, enabling a mechanistic assessment of intrinsic, synaptic, and network behaviors in intact animals—work that was previously impossible in TBI models. My laboratory is one of the few that possesses the expertise, cutting-edge techniques, and animal model necessary to thoroughly answer important questions regarding cellular mechanisms underlying brain network excitability such as epilepsy and spreading depolarization (SD) seen after brain injury, both of which are associated with worsened clinical outcomes. We have yet to understand the relationship between these two entities and edema, despite the fact that both coincide with a period of tissue edema.