Center for Neural Science, New York University, USA.
Neuroscience. 2013 Jun 25;241:250-67. doi: 10.1016/j.neuroscience.2013.03.020. Epub 2013 Mar 21.
Anorexia nervosa (AN) is an eating disorder characterized by self-imposed severe starvation and often linked with excessive exercise. Activity-based anorexia (ABA) is an animal model that reproduces some of the behavioral phenotypes of AN, including the paradoxical increase in voluntary exercise following food restriction (FR). Although certain rodents have been used successfully in this animal model, C57BL/6 mice are reported to be less susceptible to ABA. We re-examined the possibility that female C57BL/6 mice might exhibit ABA vulnerability during adolescence, the developmental stage/sex among the human population with particularly high AN vulnerability. After introducing the running wheel to the cage for 3 days, ABA was induced by restricting food access to 1h per day (ABA1, N=13) or 2 h per day (ABA2, N=10). All 23 exhibited increased voluntary wheel running (p<0.005) and perturbed circadian rhythm within 2 days. Only one out of five survived ABA1 for 3 days, while 10 out of 10 survived ABA2 for 3 days and could subsequently restore their body weight and circadian rhythm. Exposure of recovered animals to a second ABA2 induction revealed a large range of vulnerability, even within littermates. To look for the cellular substrate of differences in vulnerability, we began by examining synaptic patterns in the hippocampus, a brain region that regulates anxiety as well as plasticity throughout life. Quantitative EM analysis revealed that CA1 pyramidal cells of animals vulnerable to the second ABA2 exhibit less GABAergic innervation on cell bodies and dendrites, relative to the animals resilient to the second ABA (p<0.001) or controls (p<0.05). These findings reveal that C57BL/6J adolescent females can be used to capture brain changes underlying ABA vulnerability, and that GABAergic innervation of hippocampal pyramidal neurons is one important cellular substrate to consider for understanding the progression of and resilience to AN.
神经性厌食症（AN）是一种以自我施加的严重饥饿为特征的饮食失调症，通常与过度运动有关。基于活动的厌食症（ABA）是一种动物模型，它再现了 AN 的一些行为表型，包括在食物限制（FR）后自愿运动的反常增加。尽管某些啮齿动物在这种动物模型中被成功使用，但据报道 C57BL/6 小鼠对 ABA 的敏感性较低。我们重新检查了 C57BL/6 雌性小鼠在青春期可能表现出 ABA 易感性的可能性，青春期是人类中 AN 易感性特别高的发育阶段/性别。在将跑步轮引入笼子 3 天后，通过每天限制进食 1 小时（ABA1，N=13）或 2 小时（ABA2，N=10）来诱导 ABA。所有 23 只动物都表现出自愿轮跑的增加（p<0.005），并在 2 天内扰乱了昼夜节律。只有五分之一的动物在 ABA1 中存活了 3 天，而 10 只动物在 ABA2 中存活了 3 天，并且能够随后恢复体重和昼夜节律。对恢复动物进行第二次 ABA2 诱导的暴露表明，即使在同窝仔中，易感性也有很大差异。为了寻找易感性差异的细胞基础，我们首先检查了海马体中的突触模式，海马体是调节焦虑以及终生可塑性的大脑区域。定量 EM 分析显示，相对于对第二次 ABA2 具有抗性的动物（p<0.001）或对照（p<0.05），对第二次 ABA2 敏感的动物的 CA1 锥体神经元的 GABA 能神经支配在细胞体和树突上较少。这些发现表明，C57BL/6J 青春期雌性小鼠可用于捕获 ABA 易感性的大脑变化，并且海马体锥体神经元的 GABA 能神经支配是理解 AN 进展和抗性的一个重要细胞基础。
