Mechanisms and relevance of the ethanol-induced suppression of inhibitory signaling in the basolateral amygdala

点击翻译按钮获取中文摘要

Project Summary There is an emerging consensus that addiction is a form of maladaptive learning, wherein exposure to drugs such as ethanol (EtOH) promotes continued drug use by altering the structure and/or function of learning- related brain regions. The premise of this proposal is that the identification of molecular and cellular mechanisms by which EtOH alters associative learning will clarify critical aspects of EtOH addiction and may lead to improved therapeutic approaches for the treatment of alcoholism. Recent work, including studies from the candidate, has suggested that EtOH may modulate associative learning via its effect on G protein-gated inwardly rectifying K+ (GIRK) channels. Preliminary data show that GIRK channels are expressed in the basolateral nucleus of the amygdala (BLA), a critical structure for associative learning, and that repeated in vivo EtOH exposure suppresses GIRK-dependent signaling in pyramidal/projection neurons in this region. This proposal will combine an array of interdisciplinary approaches to test the hypothesis that the EtOH-induced suppression of GIRK channel activity in BLA pyramidal neurons contributes to the complex effects of repeated EtOH exposure, including changes in reward signaling and behavior. In AIM 1, the candidate will utilize slice electrophysiology to probe the salient characteristics and underlying mechanisms of the EtOH-induced suppression of GIRK signaling. In AIM 2, the candidate will combine viral-mediated GIRK suppression with behavioral measures of preference and reward, as well as slice electrophysiology and fast scan cyclic voltammetry (FSCV), to assess the impact of GIRK suppression in the BLA on reward-related neurotransmission and behavior. This project will offer the opportunity for advanced research training that will assist the candidate in her future endeavors, including approaches to measuring excitatory neurotransmission and plasticity in brain slices, neuron-specific manipulation of gene expression, measuring dopamine release by fast-scan cyclic voltammetry (FSCV), and the use of voluntary EtOH consumption models in mice. Mentorship and training will be provided by Dr. Kevin Wickman and Dr. Anna Lee. Additional support for the project and the professional development of the candidate will come from Dr. Jeffery Weiner (Consultant), an expert in the effects of EtOH on amygdala physiology, and a local Advisory Committee composed of experts in addiction research with a strong track record of training independent investigators (Drs. Marilyn Carroll, Stan Thayer, and Robert Meisel). All facets of this proposal are designed to assist the candidate in achieving her goal of transitioning to an independent research position, where she intends to develop a research program that investigates the impact of EtOH across an interconnected network of regions involved in the learning processes that support addiction.