Metabolic depression (MD) occurs during the acute period of TBI and this impairs the ability of neuronal circuits to meet local activity demand, which in turn could limit the success of rehabilitative strategies, and functional outcome. Although most neurons survive mild or moderate TBI, at least acutely, they cannot operate efficiently and this severely compromises brain function, which may lead to persistent behavioral deficits. This manifests as a loss of correlated functional activity using resting state functional magnetic resonance imaging (rsFMRI) and is typically reported using a connectomic analysis of brain network function. There remains much to learn about how to treat the injured brain, how the functional trajectory of neurons evolves with time, and the dependence on the extent and major pathologic subtype of the initial injury. We propose combined rsFMRI, behavior and molecular studies of metabolism and synaptic plasticity that will provide a longitudinal analysis of injury to investigate how MD manifests in altered functional connectivity and brain reorganization chronically. We will use the information gained to provide insight on how the small molecule agonist of TrkB receptors - 7,8- dihydroxyflavone (DHF) will alter the functional trajectory of the injured brain through reduction of MD acutely, followed by enhancement of synaptic plasticity and cognitive outcome chronically. By modelling clinical situations of early post-injury rehabilitation versus rehabilitation that is delayed due to additional injuries, we will determine whether an intervention with DHF will mitigate the effects of acute MD, followed by, or simultaneously with the reinstitution of function using a period of early or delayed exercise. We propose studies that will test whether either intervention, alone or in combination, can be delayed but still provide a significant boost to brain connectivity and functional outcome. We will conduct these studies in both male and female rats, and will use new statistically-driven methods that provide a level of confidence to enable subject-level analysis for discrimination of burden of tissue damage, regardless of the actual injury severity. We will employ these covariates of MD, tissue swelling and atrophy, as well as exercise level, to derive a statistically robust analysis of whether off-setting MD acutely, will potentiate the effects of rehabilitation.
We hypothesize that the period of convalescence after TBI is caused by the loss of the capacity of brain cells to metabolize the energy necessary to sustain brain plasticity and function. We will determine the capacity of a natural BDNF agonist to restore energy balance with subsequent enhancement of physical rehabilitation outcome after concussive brain injury. We will combine functional brain imaging, molecular assessments of synaptic plasticity and metabolism, and behavior to assess the efficacy of the interventions.
