Molecular and neural mechanisms associated with injury and recovery from traumatic brain injury

Optimal reward-guided behavior relies on intact connections between prefrontal cortex and striatum: circuitry that is disrupted by frontal brain injury1,2. Sustaining a brain injury increases risk for developing depression, anxiety, attention deficits, mood disorders and problems with impulse control3,4. The symptoms of frontal traumatic brain injury (TBI) strongly resemble psychiatric disorders with regards to disruptions in reward-guided behavior, and therefore may share common mechanisms driving behavioral impairments. Mechanisms may include a combination of inflammatory, molecular, and cellular changes that are triggered by injury. Determining which factors mediate persistent effects of behavior is necessary to understand chronic impacts of TBI and develop treatments addressing the often debilitating symptoms enduring after injury. The proposed research will examine how severe and mild frontal TBI impacts neural communication with its distributed striatal network to influence reward-guided behavior. Identifying a neurophysiology signature associated with reward deficits would provide a new target for brain-based treatment options. Neuromodulation, altering the electrical potentials of the brain, may serve as a potential intervention to remediate behavioral deficits by restoring rhythmic brain patterns and structural integrity of their underlying connections following injury. Preclinical testing in translational animal models is critical to better understand the structural and functional mechanisms driving behavioral impairments, and to test repetitive brain stimulation as a method to remediate effects of injury. The first goal of this proposal is to quantify behavioral consequences of severe and mild frontal TBI made using a controlled cortical impact (CCI) in rodents. TBI causes axonal shearing of white matter tracts and chronic inflammation resulting in long-term changes to the brain’s microstructure. Abnormalities in corticostriatal connectivity is being implicated in the onset of psychiatric-like symptoms, yet the relationship with TBI-induced impairments remains unclear. As one of the most widely used injury models in animals, CCI produces focal damage in rats that mirrors concussion, contusion, and hemorrhage in humans by driving an impactor directly into the brain through a surgical opening in the skull30. The injury severity and location are controlled by the experimenter and highly reproducible across animals. After injury, rats will perform a probabilistic reversal learning task which requires reward-guided decision making, behavioral inhibition, flexible behavior, and conditional discrimination: cognitive functions that all depend on intact prefrontal cortex. Reward-related behavioral impairments on the reversal learning task will be related to microstructural changes. To capture disturbances in the cortico-striatal network after TBI, brain activity will be recorded as rats run the probabilistic reversal learning task. Neural activity is not random, it oscillates at periodic frequencies to coordinate communication within and between distributed brain areas. Each of these frequency bands are predicted to coordinate different aspects of behavior through long-range coupling in functional networks. Large-scale local field potential probes will be used to record from 32 brain areas simultaneously capturing these oscillatory dynamics during reward-guided behavior. Identifying frequency-specific activity that is disrupted by TBI, would offer insight into the neural mechanisms of reward-guided behavior and point to a new therapeutic target. Lastly, brain stimulation targeting the cortico-striatal network will be used to assess its effectiveness at inducing neuroplasticity changes to remediate effects of TBI. We will follow neuromodulation procedures known to be successful in humans with the goal of studying the structural and functional mechanisms associated with restored reward-guided behavior. The proposal will examine if stimulation to lateral orbitofrontal cortex can improve reward-guided behavior, restore cortico-striatal network activity, and induce long-term structural changes. This research is critical to identify mechanisms of TBI and remediate reward-related impairments.