Tau-independent effects of high frequency head impact on cognition and neurobehavior

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PROJECT SUMMARY (ABSTRACT) An athletic career filled with head impacts (HI) predisposes athletes to chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by behavioral deficits, cognitive impairment, and p-tau pathology in the sulcal depths where the brain is most susceptible to stress and strain. A burning question in the CTE field is to the role of p-tau in behavioral impairments: is it causative, downstream, or incidental? In Alzheimer's disease and other tauopathies considerable p- tau accumulation and neuronal death is required before strong behavioral changes are detected, and it remains debatable if the low levels of p-tau found in Stage I and II CTE are causative factors of the behavioral changes reported in these same athletes. As such, exploration of the causes of behavioral deficits beyond the protein aggregation spectrum is required. Repeat traumatic brain injury (TBI) rodent models are widely used to study CTE. Overall, this work has had partial success – almost all groups report chronic cognitive deficits and neurobehavioral abnormalities. In contrast, immense difficulty remains recapitulating the chronic neuropathology of CTE in rodents, with one major reason being the lisencephalic brain of the rodent. TBI-induced acute accumulations of p-tau and amyloid-β are possible, but these require axonal injury to generate. Repeat HI models without axonal injury do exist, and do not have either an acute or chronic increase in p-tau or amyloid-β. Precisely because of these limitations, repeat HI mice without axonal injury are excellent models to study the tau-independent effects of repetitive injury. In this proposal we use a HI mouse model with high frequency impacts (HI-HF) that does not present with structural damage outside of the optic tract: with no axonal injury, no neuronal cell death, no neuroinflammation, and no p-tau accumulation. We will focus on hippocampal neurons to study their physiological response to HI-HF. The long-term goal of this project is to understand how repeat HI disrupts physiological brain function, why these changes persist after HI exposure has stopped, and to identify molecular targets to reverse these changes. In this proposal we are testing the hypothesis that HI-HF causes chronic synaptic adaptation. The purpose of these adaptations is to reduce calcium influx into neurons in response to HI, but the consequences include chronic behavioral deficits including cognitive impairment. !