Weill Cornell/Rockefeller/Sloan Kettering Tri-Insitutional MD-PhD Program, Weill Cornell Medical College, New York, NY 10065, USA.
Neuropsychopharmacology. 2013 May;38(6):930-7. doi: 10.1038/npp.2012.268. Epub 2013 Jan 3.
Fear extinction learning, the ability to reassess a learned cue of danger as safe when it no longer predicts aversive events, is often dysregulated in anxiety disorders. Selective serotonin reuptake inhibitors (SSRI's) enhance neural plasticity and their ability to enhance fear extinction learning may explain their anxiolytic properties. Caloric restriction (CR) has SSRI-like effects on neural plasticity and anxiety-related behavior. We implemented CR in mice to determine its effects on conditioned-fear responses. Wild type and serotonin transporter (SERT) knockout mice underwent CR for 7 days leading to significant weight loss. Mice were then tested for cued fear learning and anxiety-related behavior. CR markedly enhanced fear extinction learning and its retention in adolescent female mice, and adults of both sexes. These effects of CR were absent in SERT knockout mice. Moreover, CR phenocopied behavioral and molecular effects of chronic fluoxetine, but there was no additive effect of CR in fluoxetine-treated mice. These results demonstrate that CR enhances fear extinction learning through a SERT-dependent mechanism. These results may have implications for eating disorders such as anorexia nervosa (AN), in which there is a high prevalence of anxiety before the onset of dietary restriction and support proposals that in AN, CR is a motivated effort to control dysregulated fear responses and elevated anxiety.
恐惧消退学习，即当一个曾经预示着不愉快事件的危险线索不再预示危险时，重新评估该线索安全的能力，在焦虑障碍中常常失调。选择性 5-羟色胺再摄取抑制剂（SSRIs）增强神经可塑性，它们增强恐惧消退学习的能力可能解释了它们的抗焦虑特性。热量限制（CR）对神经可塑性和焦虑相关行为具有类似 SSRI 的作用。我们在小鼠中实施了 CR，以确定其对条件性恐惧反应的影响。野生型和 5-羟色胺转运体（SERT）敲除小鼠进行了 7 天的 CR，导致体重明显减轻。然后，对小鼠进行了条件性恐惧学习和焦虑相关行为测试。CR 显著增强了青春期雌性小鼠以及成年雌雄小鼠的恐惧消退学习及其保留能力。SERT 敲除小鼠则没有这种 CR 作用。此外，CR 模拟了慢性氟西汀的行为和分子作用，但在氟西汀处理的小鼠中没有 CR 的附加作用。这些结果表明，CR 通过 SERT 依赖的机制增强了恐惧消退学习。这些结果可能对饮食失调症（如神经性厌食症）有影响，因为在饮食限制之前，这种疾病常常伴有很高的焦虑发生率，并支持这样的观点，即 CR 是一种有动机的努力，以控制失调的恐惧反应和升高的焦虑。
