Inbred Substrain Differences Influence Neuroimmune Response and Drinking Behavior.

BACKGROUND The inbred mouse strain C57BL/6 is widely used in both models of addiction and immunological disease. However, there are pronounced phenotypic differences in ethanol consumption and innate immune response between B6 substrains. The focus of this study was to examine the effects of substrain on innate immune response and neuroimmune-induced escalation of voluntary ethanol consumption. The main goal was to identify if substrain differences in immune response can account for differences in ethanol behavior. METHODS We compared acute innate immune response to a viral dsRNA mimic, polyinosinic:polycytidylic acid (poly(I:C)), in brain using qRT-PCR in both C57BL/6N and C57BL/6J mice. Next, we used a neuroimmune model of escalation using poly(I:C) to compare drinking behavior between substrains. Finally, we compared brain neuroimmune response to both ethanol and repeated poly(I:C) in both strains as a way to account for differences in ethanol behavior. RESULTS We found that C57BL/6 strains have differing immune response and drinking behaviors. C57BL/6N mice have a shorter but more robust inflammatory response to acute poly(I:C). In contrast, C57BL/6J mice have a smaller but longer lasting acute immune response to poly(I:C). In our neuroimmune-induced escalation model, C57BL/6J mice but not C57BL/6N mice escalate ethanol intake after poly(I:C). Finally, only C57BL/6J mice show enhanced proinflammatory transcript abundance after poly(I:C) and ethanol, suggesting that longer lasting immune responses are critical to neuroimmune drinking phenotypes. CONCLUSIONS Altogether, this work has elucidated additional influences that substrain has on both innate immune response and drinking phenotypes. Our observations highlight the importance of considering and reporting the source and background used for production of transgenic and knockout mice. This data provides further evidence that genetic background must be carefully considered when investigating the role of neuroimmune signaling in ethanol abuse.