Chronic ethanol exposure and withdrawal induces lasting alterations in brain function which in turn contribute to the addiction state and confer susceptibility to relapse in abstinent individuals. These changes affect a variety of interrelated processes such as sleep and cognitive control that are believed to contribute to the propensity for relapse. Preliminary data presented here strongly suggest chronic ethanol exposure in rats leads to impaired sleep, which likely contributes to cognitive impairments during protracted withdrawal. A potential mechanism for these behavioral impairments is altered network function. Recent studies have observed the replay of waking neuronal assemblies during states of rest and sleep which are believed to be fundamental to learning processes. The present proposal will examine the effects of alcohol related insomnia on rule learning, behavioral flexibility, and replay in a rat model of alcohol addiction by employing multielectrode recordings from the hippocampus and prefrontal cortex of awake and behaving rats.
In Aim 1, animals will be tasked on their rule learning and behavioral flexibility in a multisession operant box procedure. Recordings will be taken during task performance to define activity dependent network states (templates) from single-unit firing within the prefrontal cortex. Using these template states, we will look for replay of task dependent activity during resting wakefulness. Periods likely to contain replay activity will be identified by searching for sharp-wave ripple activity in the hippocampal field recordings. These hippocampal oscillations are highly correlated with replay events both during sleep and resting wakefulness.
In Aim 2, zolpidem (Ambien) will be administered during protracted withdrawal to recover sleep impairments, behavioral deficits, and network function. Zolpidem is one of several recently developed non-benzodiazepine sleep enhancers which similar clinical efficacy but fewer side-effects compared to traditional benzodiazepines. Of particular importance, zolpidem shows minimal risk of physical dependency, has limited effect on normal sleep architecture, and does not impair sleep dependent enhancements in learning. For these reasons, zolpidem is ideal for the study of learning processes in sleep deprived animals and is also of potential clinical relevance. The experiments performed in Aim 1 and Aim 2 will provide new insights into the effects of alcohol exposure on brain function, and potentially identify a new clinical target for treating these impairments. This proposal was designed to expand upon the trainee's technical abilities, scientific knowledgebase, and analytical skills in order to foster his growth as a scientist in preparation for a career in alcohol research.
Sleep impairments are commonly observed in abstinent alcoholics and increase the risk for relapse within these individuals. These sleep deficits cause impairments in cognitive control and memory formation that may play an important role in relapse to uncontrolled drinking. Studies in this project will examine cognitive and network function in relation to alcohol related sleep impairments, and determine if these functions can be restored by pharmacologically treating insomnia.
|Cui, Changhai; Noronha, Antonio; Warren, Kenneth R et al. (2015) Brain pathways to recovery from alcohol dependence. Alcohol 49:435-52|
|Gass, Justin T; Glen Jr, William Bailey; McGonigal, Justin T et al. (2014) Adolescent alcohol exposure reduces behavioral flexibility, promotes disinhibition, and increases resistance to extinction of ethanol self-administration in adulthood. Neuropsychopharmacology 39:2570-83|
|Gass, Justin T; Trantham-Davidson, Heather; Kassab, Amanda S et al. (2014) Enhancement of extinction learning attenuates ethanol-seeking behavior and alters plasticity in the prefrontal cortex. J Neurosci 34:7562-74|