Memories are central to understanding who we are, knowing where we came from, and planning for our future. A devastating consequence of traumatic brain injury (TBI) is the loss or disruption of memory function. Animal models can provide powerful tools for examining cognitive and behavioral symptomology and brain pathological changes resulting from brain injury. My research in the Hales Lab involves directly examining the cognitive, behavioral, and neurological impact of concussions in a rodent model of mild TBI using the lateral impact procedure. This technique was developed to simulate the velocity of impact, head acceleration, and rotational forces associated with sports-related concussion or motor vehicle accidents. Studies of patients who have experienced TBIs have reported impairments in spatial working memory. Previous research from our lab has found that rats with hippocampal or medial entorhinal cortex (MEC) lesions showed impaired spatial memory when performing a naturalistic spatial foraging task known as the Traveling Salesperson Problem (TSP); however, ecologically valid tasks, such as the TSP, have not commonly been used to examine cognitive function post-TBI. In the TSP, rats travel around an open field arena, retrieving food rewards that have been placed in specified target locations. This spontaneous behavior involves multiple cognitive processes, including spatial memory, route planning, and attention. With the TSP, we can measure the efficiency of navigational strategies. Besides examining the effects of mTBI on TSP performance, we will also be measuring neuroinflammation in the brain via microglia morphological analysis, focusing on the hippocampus, MEC, and prefrontal cortical regions.

Sleep is universal, yet its purpose is still debated. The Synaptic Homeostasis Hypothesis (SHY), introduced by Drs. Cirelli and Tononi, proposes that the price we pay for synaptic plasticity is sleep. During wake, neurons are excited and interact with other neurons through trillions of synapses. During sleep, neuronal firing decreases and we propose that unimportant synapses become weakened compared to those that are significant, increasing the signal/noise ratio. Synaptic renormalization during sleep also has other key advantages, including saving energy and avoiding synaptic saturation, thus allowing new learning the next day. Previous studies on SHY have demonstrated that synapses become stronger during wake and weaker after sleep in areas such as the cerebral cortex, hippocampus, and cerebellum. The goal of this investigation is to test SHY in the striatum, to determine whether similar sleep/wake changes are present. Twelve mice are used, divided into three groups for comparison (4 mice/group): mice allowed to sleep (collected at 3 pm), mice spontaneously awake (3 am), and mice that are sleep deprived, all for ~6-8 hours. Three groups allow us to attribute any differences to behavioral state, rather than stress (sleep deprivation) or time of day (3 am and 3 pm). For each mouse, approximately 500 synapses are measured to determine sleep/wake changes. In my project, I am using FIJI, an image-J extension that allows one to reconstruct dendrites and measure synapses from 3D image stacks acquired using serial-block face scanning electron microscopy. Thus far, I have reconstructed 22 dendrites and measured 773 synapses.

Tolerance to alcohol reflects behavioral plasticity that may underlie shifts towards disordered use, with changes occurring within the first moments of exposure. We know that alcohol’s anxiolytic effects motivate drinking behavior, but how these anxiolytic effects change following the first few exposures to alcohol remains unclear. The current study investigated the impact that factors associated with shifts in endogenous neurosteroid tone, such as sex, estrous status, or isolation, had on the development of rapid tolerance to the anxiolytic effects of alcohol in C57BL/6J mice. Recent work supports the idea that high basolateral amygdala (BLA) neurosteroid levels facilitate anxiolysis. Anxiety-like behavior was evaluated using the elevated plus maze (EPM) in female and male mice following one or two exposures to alcohol and/or saline. Our data suggests that there was a positive effect of estrous stage, sex, and housing condition on whether mice developed rapid tolerance to ethanol. Ongoing analysis is utilizing immunohistochemistry to evaluate whether BLA parvalbumin (PV) interneuron activity mediates this effect. In the BLA, PV-interneurons not only modulate fear learning, but also dynamically respond to neurosteroid tone to facilitate shifts in anxiety state. Brains were harvested following first or second exposure to alcohol and probed for immunoreactivity to cfos and parvalbumin. This work supports an interaction between neurosteroid tone and rapid tolerance, but further research will be needed to improve our understanding of how this interaction moderates the development of disordered alcohol use.