Traumatic brain injury (TBI) is the primary cause of death and disability in children and young adults. TBI afflicts approximately two million people annually in the United States and no effective therapy exists. The neurological impairments associated with TBI include learning and memory deficits and increased risk of seizures. The hippocampus is critically involved in both of these phenomena and highly susceptible to damage by traumatic brain injury. Normal hippocampus-dependent cognition requires normal hippocampal output. TBI both diminishes hippocampal output and impairs hippocampus-dependent cognition. In area CA1 of the hippocampus the reduction in output after injury is due primarily to an increase in inhibition. In particular, inhibition from a subset of inhibitory neuros, the cholecystokinin (CCK) positive interneurons, was recently shown to increase after injury. CCK basket cell interneurons provide perisomatic inhibition and are instrumental in regulating action potential firing in CA1 pyramidal neurons, the output cells of the hippocampus. Stimulus-evoked action potentials in pyramidal neurons are significantly reduced after injury, and suppressing inhibition from CCK interneurons with the cannabinoid WIN55,212-2 was recently shown to restore normal stimulus-evoked action potentials in CA1 pyramidal neurons. The current proposal is designed to test the following CENTRAL HYPOTHESIS: Traumatic brain injury causes augmented inhibition from CCK interneurons in hippocampal area CA1. This increased inhibition diminishes hippocampal output and contributes to cognitive impairment. Selectively suppressing CCK interneurons in CA1 will restore normal hippocampal output and mitigate injury- induced cognitive impairment. We will test this hypothesis by measuring hippocampal output both in vitro and in vivo before and after activating the chemogenetic neuronal silencer hM4Di in CCK interneurons.. The development of effective therapeutic strategies for TBI will require a clear understanding of which cell types are affected, and a way to correct their underlying dysfunction. The current proposal is designed to meet these objectives, and will lay the groundwork for translational methods to target and repair TBI damaged neurons.
Traumatic brain injury (TBI) is a major public health issue and has a significant impact on our healthcare system. Economic analyses of the annual cost of TBI-related disabilities range from $4.5 billion in direct expenditure (medical care and services) to $20.6 billion in injury-related work loss and disability. Our long-range goal is to determine the underlying mechanism(s) that cause injury induced cognitive impairment and continue to develop efficacious, safe and well tolerated interventions that can be rapidly translated from the bench to the clinic to ameliorate cognitive dysfunction in TBI patients.
