Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Akiva S. Cohen

Abstract

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States, with an estimated 2.8 million new cases annually resulting from falls, motor vehicle accidents, sports, and other traumatic events. About 75-80% of new cases are considered to be mild (mTBI). Of the sequelae of neurological symptoms that result from mTBI, memory impairments are among the most prevalent and long-lasting consequences. The encoding and consolidation of episodic memories relies on spatial information processing within the hippocampus. The dentate gyrus hippocampal sub-region is one of the primary entryways of cortical input to the hippocampus and is thought to act as a gate or filter of incoming excitation, as well as play a role in specific cognitive processes such as pattern separation. After brain injury, the dentate gyrus exhibits increased network hyperexcitability, however the underlying mechanisms and impact of this circuit alteration on downstream hippocampal function are poorly understood. In this body of work, we evaluated the physiological effects of TBI on dentate gyrus function in a mouse model of lateral fluid percussion injury. One week after injury, our results indicate that network hyperexcitability leads to diminished dentate filtering efficacy and consequently, increased network excitation in downstream area CA3. Additionally, we evaluated the effects of brain injury on the intrinsic and synaptic properties of GABAergic, parvalbumin-expressing inhibitory interneurons in the dentate gyrus. The data demonstrate that increased synaptic inhibition onto these interneurons decreased their likelihood of firing action potentials and suggests a potential mechanism contributing to dentate network hyperexcitability. These findings have important implications for understanding hippocampal vulnerability and associated memory impairments following TBI.

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