Functional consequences of repeated alcohol withdrawals on the electroencephalogram of mice

Abstract

Alcohol use disorder (AUD) is a chronic, relapsing brain disease characterized by the impaired ability to stop or control alcohol consumption to the point of adverse consequences in multiple facets of a person’s life. Alcohol withdrawal (WD) is a clinical syndrome that affects those with a regular alcohol intake who suddenly decrease or stop consuming alcohol. Symptoms include neural hyperexcitability that can promote seizures and, potentially death. These seizures show similarities to kindling-like phenomena observed in epilepsy. Studying alcohol-withdrawal kindling is useful not only for the world of alcohol research but also for the development of new drugs and treatments. In this thesis, I performed continuous electrophysiological recordings from C57BL/6J mice undergoing chronic, intermittent ethanol exposure (CIE) and withdrawal in order to determine how multiple withdrawals increase epileptiform activity in tandem with increased numbers of withdrawal. Multiple withdrawals produced interictal spontaneous epileptiform spikes that intensified with increasing numbers of withdrawal, with statistically significant increase in after three cycles of WD out of a total of 4 WDs. A second round of CIE replicated the effect in a subset of mice. Theta rhythms are important oscillations implicated in significant state-dependent hippocampal temporal processing, including coding and decoding of memories. During CIE, I found that while overall theta power did not change, theta frequency, measured in the dentate gyrus, shifted to lower values. Disruption of theta has been associated with compromised cognitive function in epilepsy. In summary, my work supports the idea that alcohol withdrawal produces a hyperexcitable state in a non-seizure prone mouse strain, with electrographic markers consistent with epileptiform activity and impaired cognition.