The goal of this research is to study the effects of withdrawal from prolonged exposure to alcohol on inhibition mediated by GABAAR receptors in the thalamus. Withdrawal from chronic alcohol drinking is a serious public health problem with a wide spectrum of adverse effects on the brain. Among the main symptoms of alcohol withdrawal (AW) are hyperexcitability, increased anxiety and increased susceptibility to seizure generation. The thalamus is a central interface between sensory organs and the cerebral cortex and one of the brain areas that may be vulnerable to prolonged exposure to alcohol. It plays a variety of essential physiological roles that are often disrupted in chronic alcoholics, including sleep regulation and co-ordination of motor activity. The thalamus can also be involved in motor seizures. It has been suggested that prolonged exposure to alcohol may cause an imbalance in inhibitory (GABA) and excitatory (glutamate) neurotransmission, as well as changes in the expression of their receptors such as GABAARs. The inhibitory function of these receptors, especially those containing the alpha4 GABAAR subunit, is highly sensitive to alcohol in several areas of the brain including the thalamus. However, the effects of AW on inhibition in the thalamus have remained relatively unexplored. In addition, the factors that could regulate thalamic Gabra4 gene expression in response to AW are not yet identified. The regulatory elements known as microRNAs (miRNAs) have emerged recently as key players in regulating gene expression at the post-transcriptional or translational levels. They have also been linked to many disorders, including alcohol addiction. In this research study, we ask whether a specific subset of physiologically relevant miRNAs can target thalamic Gabra4 gene expression and/or protein levels resulting in altered neuronal excitability. The findings from this research will not only provide new information on the role of thalamic excitability in alcohol-related pathologies, but may also reveal the role of specific miRNAs in regulation of Gabra4 expression and function. This could help in the identification of therapeutic targets for the treatment of alcohol withdrawa-related pathologies such as hyperexcitability.
Prolonged exposure to alcohol is a serious public health problem in the U.S., and abrupt withdrawal from alcohol (AW) in a chronic alcoholic is associated with a wide spectrum of behavioral effects and negative outcomes, including extreme anxiety, sleeplessness, rapid breathing, seizures and death. The main objective of the proposed study is to study the effects of AW on the excitability of brain cells in an important mid brain structure known as the thalamus that is involved in the control of processing information from the senses. The study will also identify alterations in brain function that can result from AW and lead to seizures and will help to identify brain molecules such as microRNAs that can serve as targets for new drugs to treat AW and its associated health hazards.
|Bekdash, Rola A; Harrison, Neil L (2015) Downregulation of Gabra4 expression during alcohol withdrawal is mediated by specific microRNAs in cultured mouse cortical neurons. Brain Behav 5:e00355|