PINK1 deficiency is associated with increased deficits of adult hippocampal neurogenesis and lowers the threshold for stress-induced depression in mice
PINK1 deficiency is associated with increased deficits of adult hippocampal neurogenesis and lowers the threshold for stress-induced depression in mice
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DOI：
10.1016/j.bbr.2019.02.006
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发表时间：
2019-05-02
影响因子：
2.7
通讯作者：
Bueler, Hansruedi
中科院分区：
文献类型：
--
作者：
Agnihotri, Sandeep K.;Sun, Liuke;Bueler, Hansruedi
帕金森病（PD）的特征是运动障碍和几个非运动功能，包括频繁的抑郁和焦虑。应激诱导的成年海马神经发生（AHN）缺陷与动物的异常情感行为有关。据推测，AHN缺陷可能有助于PD的情感症状，但这一假设仍然没有得到充分的动物模型测试。缺乏PD相关激酶PINK 1的小鼠显示海马中成年出生的神经元分化受损。在这里，我们研究了AHN缺陷和情感行为的PINK 1（-/-）小鼠在基础（无压力）条件下和暴露于慢性压力后的关系。PINK 1丢失和皮质酮对AHN产生负面影响，导致皮质酮处理的PINK 1（-/-）小鼠齿状回中神经干细胞和新生神经元数量减少。尽管基础AHN缺陷增加，PINK 1缺陷小鼠表现出正常的情感行为。然而，在悬尾试验中，在野生型小鼠不受影响的剂量下，缺乏PINK 1使小鼠对皮质酮诱导的行为绝望敏感。此外，在两周的慢性束缚应激后，雄性PINK 1（-/-）小鼠在强迫游泳试验中表现出增加的不动性，并且海马中糖皮质激素受体的蛋白表达减少。因此，虽然受损的AHN本身不足以在该PD模型中引起情感功能障碍，但PINK 1缺陷可能降低PD中慢性应激诱导的抑郁症的阈值。最后，PINK 1缺陷小鼠表现出减少的基础自愿轮运行，但正常的转棒性能，其机制仍有待确定的发现。
Parkinson's disease (PD) is characterized by motor impairments and several non-motor features, including frequent depression and anxiety. Stress-induced deficits of adult hippocampal neurogenesis (AHN) have been linked with abnormal affective behavior in animals. It has been speculated that AHN defects may contribute to affective symptoms in PD, but this hypothesis remains insufficiently tested in animal models. Mice that lack the PD-linked kinase PINK1 show impaired differentiation of adult-born neurons in the hippocampus. Here, we examined the relationship between AHN deficits and affective behavior in PINK1(-/-) mice under basal (no stress) conditions and after exposure to chronic stress. PINK1 loss and corticosterone negatively and jointly affected AHN, leading to lower numbers of neural stem cells and newborn neurons in the dentate-gyrus of corticosterone-treated PINK1(-/-) mice. Despite increased basal AHN deficits, PINK1-deficient mice showed normal affective behavior. However, lack of PINK1 sensitized mice to corticosterone-induced behavioral despair in the tail suspension test at a dose where wildtype mice were unaffected. Moreover, after two weeks of chronic restraint stress male PINK1(-/-) mice displayed increased immobility in the forced swim test, and protein expression of the glucocorticoid receptor in the hippocampus was reduced. Thus, while impaired AHN as such is insufficient to cause affective dysfunction in this PD model, PINK1 deficiency may lower the threshold for chronic stress-induced depression in PD. Finally, PINK1-deficient mice displayed reduced basal voluntary wheel running but normal rotarod performance, a finding whose mechanisms remain to be determined.