Dissertation Defense: Daniel Chapman

Candidate: Daniel Chapman

Major: Neuroscience

Advisors: Mark Burns, Ph.D. and Stefano Vicini, Ph.D.

Title: From Neurons to Behavior: A Path Towards Brain Stimulation as a Treatment for Repetitive Head Impacts

Traumatic brain injury is the most common neurological disorder and 80% consist of mild traumatic brain injury (mTBI). The severity and persistence of cognitive symptoms is increased with additional repeat mTBIs (rmTBI). A high frequency head impact (HFHI) mouse model of repeat head impacts developed by the Burns lab displays decreased learning and changes in transcriptomic profiles related to synaptic signaling accompanied by decreased plasticity and synaptic changes in CA1 pyramidal neurons. This would suggest that synaptic modifications underlie the anterograde cognitive symptoms following head impacts. It is still unknown how repeat head impacts directly effect an already established memory. Engrams, defined as lasting physical or chemical changes in neurons, are the neural substrate underlying episodic memory and previous studies have shown that activating this population of neurons can recover amnesia. In this study, we use advances in engram cell labeling to interrogate the mechanisms behind cognitive dysfunction in the repat head impact brain and whether they are treatable. Using a contextual fear conditioning model, we found that the HFHI model confers a retrograde amnesia phenotype but does not result in loss of memory bearing engram cells. Sham animals displayed an engram cell specific increase in spine volume, AMPA/NMDA ratio, and AMPA decay tau that was abolished by HFHI. Upon optogenetic reactivation of the engram, the freezing response was recovered in HFHI, suggesting that memories are silenced, not lost. These data provide mechanistic insights into retrograde amnesia in the repeat head impact brain and warrant a further investigation into functional treatments for cognitive recovery.