Modulation of Alcohol Effects on Nervous System Function by Social Experience

酒精是我们社会中滥用最严重的毒品，对健康和经济都有毁灭性的影响。这个

Alcohol is the most abused drug in our society with devastating impact on both health and the economy. The aim of the proposed research activity is twofold: To gain a better understanding of the cellular mechanisms underlying the interaction between alcohol and nervous system function, and to elucidate how social experience modifies this interaction. The neurocellular effects of alcohol intoxication are still poorly understood. Unlike other drugs of abuse, alcohol does not act on one specific receptor in the central nervous system but changes neural activity by altering multiple neurotransmitter systems, e.g. by modifying the efficacy of brain receptors, including those for γ-aminobutyric acid (GABA) and serotonin (5-HT). The same neurochemicals have been implicated in the regulation of social behavior in humans and many non-human animals, especially in the context of aggression and social dominance. Social interactions with conspecifics cause differences in behavior and the corresponding neural circuits. However, how these socially mediated changes affect the interaction between alcohol and neural activity is unknown. A better understanding of the interplay between alcohol and neural circuitry that is shaped by social experience is crucial to improve prevention and individualized treatment options for alcohol-related health risks. This study proposes a combination of behavioral, neurophysiological, neurochemical, and neuroanatomical experiments to explore the effects of acute ethanol exposure in animals of different social status. Experiments will be performed in crayfish, an invertebrate model that features an accessible nervous system as well as identified neural circuitry that is known to be shaped by social experience and can be studied with a high level of experimental rigor. Our preliminary results show that crayfish are sensitive to alcohol exposure and display discrete behavioral changes with increasing intoxication (hyperexcitability is followed by inhibition). Surprisingly, we found that the behavioral changes are expressed more quickly in socially experienced animals compared to those previously isolated from conspecifics. In addition, these socially-shaped differences are paralleled in single-cell recordings of individual neurons. We hypothesize that different social experiences cause modifications of neural receptors that are targeted by alcohol, which produces the observed neurobehavioral changes in response to alcohol exposure. The proposed experiments will use animals of discrete social status (i.e., dominants, subordinates, isolates) to investigate the interplay between different neurotransmitter systems, alcohol, and social status. The results of these basic studies are expected to stimulate work in more complex model systems, which could lead to improvements of preventive measures for alcohol-related health risks as well as behavioral and pharmacological treatments for human alcoholism.