Prater Katherine E, Aurbach Elyse L, Larcinese Hanna K, Smith Taylor N, Turner Cortney A, Blandino Peter, Watson Stanley J, Maren Stephen, Akil Huda
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA.
Neuropsychopharmacology. 2017 Jul;42(8):1706-1714. doi: 10.1038/npp.2017.37. Epub 2017 Feb 16.
Individuals respond differently to traumatic experiences, including their propensity to develop posttraumatic stress disorder (PTSD). Understanding individual differences in PTSD vulnerability will allow the development of improved prevention and treatment options. Here we characterized fear conditioning and extinction in rats selectively bred for differences in their locomotor response to a novel environment. Selectively bred high-responder (bHR) and low-responder (bLR) male rats are known to differ in their emotional reactivity on a range of measures of spontaneous anxiety- and depressive-like behaviors. We demonstrate that bHRs have facilitated extinction learning and retention compared with outbred Sprague Dawley rats, whereas bLRs show reduced extinction learning and retention. This indicates that bLRs are more vulnerable to PTSD-like behavior. Fibroblast growth factor 2 (FGF2) has previously been implicated in the development of these behavioral phenotypes and facilitates extinction learning in outbred animals, therefore we examined the effects of early-life FGF2 on bHR and bLR behavior. FGF2 administered on the day after birth facilitated extinction learning and retention in bHRs, but not in bLRs or control rats, during adulthood. This indicates that, under the current fear conditioning paradigm, early-life FGF2 has protective effects only in resilient animals. This stands in contrast to FGF2's ability to protect vulnerable animals in milder tests of anxiety. These results provide a unique animal model of individual differences in PTSD-like behavior, allowing the study of genetic, developmental, and environmental factors in its expression.
个体对创伤经历的反应各不相同，包括他们患创伤后应激障碍（PTSD）的倾向。了解PTSD易感性的个体差异将有助于开发更好的预防和治疗方案。在此，我们对因对新环境的运动反应不同而选择性培育的大鼠的恐惧条件反射和消退进行了表征。已知选择性培育的高反应者（bHR）和低反应者（bLR）雄性大鼠在一系列自发焦虑样和抑郁样行为测量中的情绪反应性存在差异。我们证明，与远交系Sprague Dawley大鼠相比，bHRs的消退学习和记忆得到了促进，而bLRs的消退学习和记忆则有所减少。这表明bLRs更容易出现类似PTSD的行为。成纤维细胞生长因子2（FGF2）此前被认为与这些行为表型的发展有关，并促进远交系动物的消退学习，因此我们研究了早期FGF2对bHR和bLR行为的影响。出生后一天给予FGF2可促进成年期bHRs的消退学习和记忆，但对bLRs或对照大鼠则无此作用。这表明，在当前的恐惧条件反射范式下，早期FGF2仅对有恢复力的动物具有保护作用。这与FGF2在较温和的焦虑测试中保护易受伤害动物的能力形成对比。这些结果提供了一个独特的类似PTSD行为个体差异的动物模型，有助于研究其表达中的遗传、发育和环境因素。
