Microglia Dysregulation and Altered Responses to Stress after Traumatic Brain Injury

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PROJECT SUMMARY More than 5.3 million individuals suffer from a traumatic brain injury (TBI) related disability in the United States. Mounting clinical and experimental evidence shows a common co-morbidity of TBI is hypothalamic-pituitary- adrenal (HPA) axis dysfunction that results in the suppression of the stress hormone - cortisol in humans or the equivalent corticosterone (CORT) in rodents. Suppressed CORT is associated with aberrant neuronal responses in stress circuitry and can exacerbate post-TBI impairments, including cognitive and behavioral deficits. Sleep fragmentation is a frequent consequence of stress, thus we predict that post-injury sleep fragmentation engages a vulnerable biological pathway that substantially influences outcome by modulating neuroinflammation. For example, increasing data demonstrates that microglia mediate chronic TBI-induced recovery by perpetuating maladaptive inflammation, cytotoxicity, and altering neuronal viability and plasticity. Importantly, this microglial response may be worsened by post-TBI stressors. For example, microglia highly express glucocorticoid receptor (GR), which binds CORT to induce potent anti-inflammatory signaling. We hypothesize that TBI-induced suppression of CORT may compromise the anti-inflammatory action of GR in microglia, thus CORT production in response to stressors after TBI is vital to ensure control of inflammation. Due to the interplay of the stress and immune axes, the effect of chronic stress on TBI outcome must be better understood. This proposal aims to determine how neuronal activation and stress circuitry is altered in response to post-TBI sleep fragmentation, and how microglial GR may influence inflammation, neuronal activation, and cognition with post-TBI sleep fragmentation. Aim 1 will determine how microglia influence stress circuitry and hippocampal neuronal function with post-TBI sleep fragmentation. To do this, Pt. 3 we will rapidly deplete microglia through CSF1R antagonism and expose animals with and without microglia to post-TBI sleep fragmentation to define the cell specific role of microglia on neuronal activation in stress circuitry. We will further determine the RNA profile of the hippocampus following microglia depletion with post-TBI sleep fragmentation and perform electrophysiology to distinguish whether differences in hippocampal activity are due to changes in neuronal function and viability or microglial signaling. Aim 2 will test if microglial GR activation mediates inflammation, neuronal activation, and behavior following post-TBI sleep fragmentation. To do this, we will use Pt. 3 an inducible knockout of GR in microglia and determine differences in RNA sequencing profile, immunohistochemistry, and hippocampal-dependent behavioral tasks with sleep fragmentation after TBI. We hypothesize that reactive microglia mediate neuronal deficits in response to post-TBI sleep fragmentation through suppressed GR anti-inflammatory action. Ultimately, this proposed study will shed light on stress-immune dysfunction after TBI and better understand how to improve long-term quality of life and outcome for TBI survivors.