Pediatric traumatic brain injury and early life stress effects on prefrontal cortex development and cognition: A role for microglia

Project Summary Pediatric Traumatic Brain Injury (pTBI) impacts half a million children each year, leaving over 20% with long- lasting cognitive deficits that negatively impact their quality of life. Children are especially vulnerable to pTBI because their brains are still developing at the time of injury. A major factor associated with poor outcomes following pTBI is a life history of early life stress (ELS), such as poverty, abuse, and natural disasters. ELS increases the risk for pTBI and increases chronic attentional, impulsive, and social deficits. Despite this established association, the mechanisms underlying how ELS and pTBI generate these neurocognitive impairments remain poorly understood, leaving these kids with few therapeutic options to improve symptoms. My laboratory uses lateral fluid percussion injury (LFPI) to model pTBI in rats at postnatal day (P)15, which is developmentally equivalent to toddler age. Early life injury generates behavioral phenotypes in adult rats that resemble pTBI symptoms in humans, specifically cognitive alterations and social impairment. Given that cognitive deficits are the most common lasting symptom of pTBI, this proposal builds upon these findings to further investigate how pTBI impacts brain development and resulting cognition. I will combine this model with maternal separation stress and assess development of the medial prefrontal cortex (mPFC), as it is a major hub for cognitive function. Microglia are the brain’s resident immune cells, regulate brain development, including synaptic patterning, and are highly sensitive to stress and injury. Thus, microglia may be key to programming stress and pTBI outcomes. I hypothesize that ELS primes mPFC microglia, enhancing their response to pTBI, and leading to excessive synaptic pruning in mPFC, reduced structural complexity, and impaired cognition. The objectives of this proposal are to define acute neuroimmune changes in the mPFC following ELS+pTBI, determine how these early life insults impact cognitive function in adulthood, and investigate the association between these acute molecular and chronic behavioral phenotypes. In Specific Aim 1 I will use a) engulfment analysis and Golgi staining to examine microglial pruning and resulting mPFC neuronal organization, and b) the 5-choice serial reaction time task to assess complex cognitive phenotypes, including executive function, impulsivity, and attention. In Specific Aim 2 I will use a) transcriptomics to interrogate the role of microglia in these phenotypes and b) pharmacological intervention to shift microglia towards a more homeostatic phenotype following pTBI in an attempt to block the development of neurocognitive deficits later in life. Overall, the findings of these studies will clarify the role of the mPFC and microglia in ELS and pTBI interactions and provide possible insights into novel treatment options for the long- term cognitive consequences of these early life insults.