Goals and Aims of INIA

To more fully understand neural responses to stress and alcohol, and the combination thereof, this INIA will characterize stress and alcohol effects on the nervous system at all levels, and in organisms ranging from mice to monkeys and humans. We have put together this research consortium to gain much needed information about the neural effects of stress, alcohol and stress/alcohol interactions on the level of expression and function of key neuronal molecules, neuronal activity and synaptic efficacy, the neurophysiology of key systems involved in stress and alcohol interactions, genetic factors that contribute to alcohol-stress interactions, as well as stress-related conditioning and other behaviors related to stress.

To achieve this goal we employ a wide range of technologies including genetic analysis and measurement of alterations in gene expression, neurophysiological measurements of ion channel function, synaptic activity and activity of neurons within active circuits in vivo, as well as analysis of stress-related behaviors and alcohol intake. We expect that these coordinated studies will lead to a better understanding of the ways in which alcohol intake interacts with the neural systems involved in stress responding with consequences that contribute strongly to excessive alcohol intake. We expect to gain a much better understanding of the molecular, cellular and systems-based neuroadaptive changes that take place in the brain as a consequence of alcohol/stress interactions. Finally, we hope that our studies will lead to new therapeutic approaches to treatment of individuals with excessive drinking problems.

Our INIA is based on the following hypotheses:

  1. Stress leads to alcohol intake that provides subjective relief from anxiety. Ethanol effects on the function of neurotransmitter receptors and transporters, neurotransmitter release and ion channel function contributes to this anxiolytic action.
     
  2. Chronic alcohol exposure and withdrawal after chronic alcohol leads to stress disequlibrium and subsequent neuroadaptive processes. This stress disequilibrium contributes to enhanced intake by bringing about plastic changes n inputs to amygdala, hippocampus, and prefrontal cortex and from these structures to the Nucleus Accumbens.
     
  3. Alcohol may dampen plasticity related to non-stressful information (e.g. spatial location), and alcohol might interfere with proper fear conditioning and related plasticity to alter normal responses to stressful stimuli.
     
  4. Genetic factors that contribute to increased risk of excessive alcohol intake may involve alterations in responses to stress, or in alcohol effects on such responses.

The cornerstone of our proposal is that alcohol actions on regions within neural circuitry involved in stress responses. We hypothesize that alcohol actions on amygdala physiology and molecular expression/function, as well as effects on amygdala interactions with the hippocampus, Nucleus Accumbens and prefrontal cortex alter key synaptic efficacy to reduce anxiety and other stress-related responses, blunt normal fear conditioning, and reinforce excessive alcohol intake.

Figure 1

This Figure depicts the interrelationships between the approaches we are using and the basic themes of our INIA consortium. Out experimental approaches include analyses of the genetic contributions to the cellular and systems adaptations that take place as a result of alcohol-stress interactions that contribute to excessive drinking. As well, we use animal models to examine stress and effects of chronic alcohol exposure and withdrawal, with particular emphasis on alcohol intake as a final outcome of stress-alcohol interactions. These approaches are examined within the context of the neurochemistry and neural circuitry involved in behaviors related to stress and alcohol effects. All of work is integrated by data and resource sharing through the Informatics Core.

Our approaches to understanding the basis of alcohol/stress interactions is largely represented by:

  1. Examination of the effects of acute and chronic alcohol exposure on the physiology of the prefrontal cortex, amygdala, septum, nucleus accumbens, and hippocampus in mouse models.
     
  2. Examination of the effects of acute and chronic alcohol on anxiety-related behaviors and alcohol drinking in mouse models.
     
  3. Examination of the effects of acute stress on the physiology of prefrontal cortex, amygdala, septum, nucleus accumbens, and hippocampus with anxiety-related behaviors in mouse models.
     
  4. Examination of alcohol-stress interactions in drinking and stress-induced reinstatement of alcohol drinking in mouse models.
     
  5. Discovery of genes involved in alcohol-stress interactions in mice, monkeys and humans.
     
  6. The relationship between stress responses and alcohol self-administration in non-human primates.
     
  7. Examination of stress-related behaviors and alcohol drinking in mice that have undergone random mutagenesis on chromosomes 10, 15, 19 and X as a part of the Tennessee Mouse Genome Consortium (TMGC) mouse mutagenesis program.