Inbred Substrain Differences Influence Neuroimmune Response and Drinking Behavior

• Published in: Alcoholism, clinical and experimental research Vol. 44; no. 9; pp. 1760 - 1768
• Main Authors: Warden, Anna S., DaCosta, Adriana, Mason, Sonia, Blednov, Yuri A., Mayfield, Roy Dayne, Harris, Robert Adron
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.09.2020
• Subjects: Abuse; Addictions; Addictive behaviors; Alcohol; Alcohol use; Alcoholism; C57BL/6J; C57BL/6N; Double-stranded RNA; Drinking behavior; Ethanol; Immune response; Immune system; Immunological diseases; Inbreeding; Inflammation; Innate immunity; Neuroimmune; Phenotypes; Poly I:C; Polyinosinic:polycytidylic acid; Rodents; TLR3; Transcription; Transgenic mice; C57BL/6N; Alcohol; Poly I:C; C57BL/6J; Neuroimmune; TLR3
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/acer.14410

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 (EtOH) consumption and innate immune response between C57BL/6 substrains. The focus of this study was to examine the effects of substrain on innate immune response and neuroimmune‐induced escalation of voluntary EtOH consumption. The main goal was to identify whether substrain differences in immune response can account for differences in EtOH behavior. Methods We compared acute innate immune response with 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 with both EtOH and repeated poly(I:C) in both substrains as a way to account for differences in EtOH behavior. Results We found that C57BL/6 substrains 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 EtOH intake after poly(I:C). Finally, only C57BL/6J mice show enhanced proinflammatory transcript abundance after poly(I:C) and EtOH, 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. These data provide further evidence that genetic background must be carefully considered when investigating the role of neuroimmune signaling in EtOH abuse. 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. Here we detail how differences in immune response between C57BL/6 substrains regulates drinking behavior. Importantly, we observed that longer lasting immune responses are critical to neuroimmune drinking phenotypes. Taken together this study highlights the importance of reporting the source and background of transgenic and knockout mice used in neuroimmune research.