Abstract：
OBJECTIVE: Anorexia nervosa (AN) is characterized by hyperactivation of the hypothalamic-pituitary-adrenal axis and cognitive deficits. However, little is known about the rapid non-genomic stress response involvement. This study investigates the molecular, structural and behavioral signatures of the anorexic phenotype induction in female rats on stress-related mechanisms in the hippocampus.
METHODS: Female adolescent rats, exposed to the combination of food restriction and wheel access, i.e., the activity-based anorexia (ABA) protocol, were sacrificed in the acute phase of the pathology (postnatal day [P]42) or following a 7-day recovery period (P49).
RESULTS: ABA rats, in addition to body weight loss and increased wheel activity, alter their pattern of activity over days, showing increased food anticipatory activity, a readout of their motivation to engage in intense physical activity. Corticosterone plasma levels were enhanced at P42 while reduced at P49 in ABA rats. In the membrane fraction of the hippocampus, we found reduced glucocorticoid receptor levels together with reduced expression of caldesmon, n-cadherin and neuroligin-1, molecular markers of cytoskeletal stability and glutamatergic homeostasis. Accordingly, structural analyses revealed reduced dendritic spine density, a reduced number of mushroom-shaped spines, together with an increased number of thin-shaped spines. These events are paralleled by impairment in spatial memory measured in the spatial order object recognition test. These effects persisted even when body weight of ABA rats was restored.
CONCLUSIONS: Our findings indicate that ABA induction orchestrates hippocampal maladaptive structural and functional plasticity, contributing to cognitive deficits, providing a putative mechanism that could be targeted in AN patients.
METHODS: Female adolescent rats, exposed to the combination of food restriction and wheel access, i.e., the activity-based anorexia (ABA) protocol, were sacrificed in the acute phase of the pathology (postnatal day [P]42) or following a 7-day recovery period (P49).
RESULTS: ABA rats, in addition to body weight loss and increased wheel activity, alter their pattern of activity over days, showing increased food anticipatory activity, a readout of their motivation to engage in intense physical activity. Corticosterone plasma levels were enhanced at P42 while reduced at P49 in ABA rats. In the membrane fraction of the hippocampus, we found reduced glucocorticoid receptor levels together with reduced expression of caldesmon, n-cadherin and neuroligin-1, molecular markers of cytoskeletal stability and glutamatergic homeostasis. Accordingly, structural analyses revealed reduced dendritic spine density, a reduced number of mushroom-shaped spines, together with an increased number of thin-shaped spines. These events are paralleled by impairment in spatial memory measured in the spatial order object recognition test. These effects persisted even when body weight of ABA rats was restored.
CONCLUSIONS: Our findings indicate that ABA induction orchestrates hippocampal maladaptive structural and functional plasticity, contributing to cognitive deficits, providing a putative mechanism that could be targeted in AN patients.
摘要：
目的：神经性厌食症（AN）的特征是下丘脑-垂体-肾上腺轴过度激活和认知缺陷。然而,对快速非基因组应激反应的参与知之甚少。这项研究调查了分子，雌性大鼠厌食表型诱导对海马应激相关机制的结构和行为特征。
方法：雌性青春期大鼠，暴露于食物限制和车轮通行的组合，即，基于活动的厌食症（ABA）协议，在病理急性期（出生后第42天）或7天恢复期（P49）后处死。
结果：ABA大鼠，除了减肥和增加车轮活动，改变他们几天的活动模式，显示食物预期活性增加，读出他们从事激烈体力活动的动机。在ABA大鼠中，皮质酮血浆水平在P42时升高，而在P49时降低。在海马的膜部分，我们发现糖皮质激素受体水平降低以及Caldesmon的表达降低，n-cadherin和neuroligin-1，细胞骨架稳定性和谷氨酸能稳态的分子标记。因此，结构分析显示树突棘密度降低，蘑菇状刺的数量减少，加上数量增加的薄形刺。这些事件与空间顺序对象识别测试中测得的空间记忆受损平行。即使ABA大鼠的体重恢复，这些作用仍然存在。
结论：我们的发现表明，ABA诱导协调海马适应不良的结构和功能可塑性，导致认知缺陷，提供了一种可能针对AN患者的推定机制。
方法：雌性青春期大鼠，暴露于食物限制和车轮通行的组合，即，基于活动的厌食症（ABA）协议，在病理急性期（出生后第42天）或7天恢复期（P49）后处死。
结果：ABA大鼠，除了减肥和增加车轮活动，改变他们几天的活动模式，显示食物预期活性增加，读出他们从事激烈体力活动的动机。在ABA大鼠中，皮质酮血浆水平在P42时升高，而在P49时降低。在海马的膜部分，我们发现糖皮质激素受体水平降低以及Caldesmon的表达降低，n-cadherin和neuroligin-1，细胞骨架稳定性和谷氨酸能稳态的分子标记。因此，结构分析显示树突棘密度降低，蘑菇状刺的数量减少，加上数量增加的薄形刺。这些事件与空间顺序对象识别测试中测得的空间记忆受损平行。即使ABA大鼠的体重恢复，这些作用仍然存在。
结论：我们的发现表明，ABA诱导协调海马适应不良的结构和功能可塑性，导致认知缺陷，提供了一种可能针对AN患者的推定机制。
