Activity-based anorexia (ABA) is an animal model of anorexia nervosa, a mental illness with highest mortality and with onset that is most frequently during adolescence. We questioned whether vulnerability of adolescent mice to ABA differs between sexes and whether individual differences in resilience are causally linked to α4βδ-GABA_AR expression. C57BL6/J WT and α4-KO adolescent male and female mice underwent ABA induction by combining wheel access with food restriction. ABA vulnerability was measured as the extent of food restriction-evoked hyperactivity on a running wheel and body weight losses. α4βδ-GABA_AR levels at plasma membranes of pyramidal cells in dorsal hippocampus were assessed by electron microscopic immunocytochemistry. Temporal patterns and extent of weight loss during ABA induction were similar between sexes. Both sexes also exhibited individual differences in ABA vulnerability. Correlation analyses revealed that, for both sexes, body weight changes precede and thus are likely to drive suppression of wheel running. However, the suppression was during the food-anticipatory hours for males, while for females, suppression was delayed by a day and during food-access hours. Correspondingly, only females adaptively increased food intake. ABA induced up-regulation of α4βδ-GABA_ARs at plasma membranes of dorsal hippocampal pyramidal cells of females, and especially those females exhibiting resilience. Conversely, α4-KO females exhibited greater food restriction-evoked hyperactivity than WT females. In contrast, ABA males did not up-regulate α4βδ-GABA_ARs, did not exhibit genotype differences in vulnerability, and exhibited no correlation between plasmalemmal α4βδ-GABA_ARs and ABA resilience. Thus, food restriction-evoked hyperactivity is driven by anxiety but can be suppressed through upregulation of hippocampal α4βδ-GABA_ARs for females but not for males. This knowledge of sex-related differences in the underlying mechanisms of resilience to ABA indicates that drugs targeting α4βδ-GABA_ARs may be helpful for treating stress-induced anxiety and anorexia nervosa of females but not males.

活动性厌食症 (ABA) 是神经性厌食症的一种动物模型，神经性厌食症是一种死亡率最高的精神疾病，且最常在青春期发病。我们质疑青春期小鼠对 ABA 的脆弱性是否因性别而异，以及复原力的个体差异是否与 α4βδ-GABA _A R 表达存在因果关系。 C57BL6/J WT 和 α4-KO 青春期雄性和雌性小鼠通过将轮子进入与食物限制相结合进行 ABA 诱导。 ABA 脆弱性通过食物限制引起的跑轮多动和体重减轻的程度来衡量。通过电子显微镜免疫细胞化学评估背侧海马锥体细胞质膜的 α4βδ-GABA _A R 水平。 ABA 诱导期间体重减轻的时间模式和程度在性别之间相似。两性在 ABA 脆弱性方面也表现出个体差异。相关分析显示，对于男女来说，体重变化先于发生，因此可能会抑制车轮行驶。然而，对于雄性来说，抑制是在食物预期时间内进行的，而对于雌性来说，抑制是在食物获取时间内延迟一天。相应地，只有雌性会适应性地增加食物摄入量。 ABA 诱导雌性，尤其是表现出弹性的雌性背侧海马锥体细胞质膜上 α4βδ-GABA _A R 的上调。相反，α4-KO 雌性比 WT 雌性表现出更大的食物限制引起的多动症。 相比之下，ABA 雄性没有上调 α4βδ-GABA _A Rs，在脆弱性方面没有表现出基因型差异，并且质膜 α4βδ-GABA _A Rs 与 ABA 恢复力之间没有相关性。因此，食物限制引起的多动是由焦虑引起的，但可以通过上调女性海马 α4βδ-GABA _A R 来抑制，但男性则不然。对 ABA 恢复力的潜在机制与性别相关的差异的认识表明，针对 α4βδ-GABA _A R 的药物可能有助于治疗女性而非男性的压力引起的焦虑和神经性厌食症。