FKBP5 and early life stress affect the hippocampus by an age-dependent mechanism.
FKBP5 and early life stress affect the hippocampus by an age-dependent mechanism.
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DOI：
10.1016/j.bbih.2020.100143
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Blair LJ
中科院分区：
文献类型：
--
作者：
Criado-Marrero M;Smith TM;Gould LA;Kim S;Penny HJ;Sun Z;Gulick D;Dickey CA;Blair LJ
早期生活压力(ELS)对大脑有不利影响，通常与精神健康障碍的病因有关，如抑郁症。除了与情绪有关的症状外，抑郁症患者还表现出下丘脑-垂体-肾上腺(HPA)轴调节失调，外周炎症增加，以及大脑结构性改变。尽管潜在的原因尚不清楚，但作为糖皮质激素受体(GR)活性调节器的FK506结合蛋白5(FKBP5)基因的多态与儿童时期的逆境相互作用，增加了抑郁障碍的易感性。我们假设，高水平的FKBP5蛋白结合早期生活压力(ELS)会改变HPA轴和大脑，促进抑郁样行为。为了测试这一点，我们让大脑中高表达FKBP5的小鼠模型(rTgFKBP5小鼠)的雄性和雌性，或产仔对照组，在出生后14天内接受母体分离。然后，我们评估了年轻成年和老年小鼠的神经内分泌、行为和脑变化。我们观察到rTgFKBP5小鼠的基础皮质酮(CORT)水平较低，这在雌性小鼠中加剧。老年但不年轻的rTgFKBP5小鼠表现出更多的抑郁样行为。此外，FKBP5的过表达降低了老年小鼠海马神经元的密度，同时促进了小胶质细胞的表达，但这些作用被ELS逆转。综上所述，这些结果表明，高FKBP5以一种年龄依赖的方式影响基础皮质醇水平、抑郁样症状以及海马神经元和小胶质细胞的数量。高FKBP5会降低小鼠的基础皮质酮水平，特别是对雌性小鼠。ELS可预防FKBP5诱导的老年小鼠抑郁样行为的易感性。FKBP5的过度表达降低了老龄小鼠的海马神经元密度，同时增加了小胶质细胞标志物。
Early life stress (ELS) adversely affects the brain and is commonly associated with the etiology of mental health disorders, like depression. In addition to the mood-related symptoms, patients with depression show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increased peripheral inflammation, and structural brain alterations. Although the underlying causes are unknown, polymorphisms in the FK506-binding protein 5 (FKBP5) gene, a regulator of glucocorticoid receptor (GR) activity, interact with childhood adversities to increase vulnerability to depressive disorders. We hypothesized that high FKBP5 protein levels combined with early life stress (ELS) would alter the HPA axis and brain, promoting depressive-like behaviors. To test this, we exposed males and females of a mouse model overexpressing FKBP5 in the brain (rTgFKBP5 mice), or littermate controls, to maternal separation for 14 days after birth. Then, we evaluated neuroendocrine, behavioral, and brain changes in young adult and aged mice. We observed lower basal corticosterone (CORT) levels in rTgFKBP5 mice, which was exacerbated in females. Aged, but not young, rTgFKBP5 mice showed increased depressive-like behaviors. Moreover, FKBP5 overexpression reduced hippocampal neuron density in aged mice, while promoting markers of microglia expression, but these effects were reversed by ELS. Together, these results demonstrate that high FKBP5 affects basal CORT levels, depressive-like symptoms, and numbers of neurons and microglia in the hippocampus in an age-dependent manner. High FKBP5 reduces basal corticosterone levels in mice, especially in females. ELS prevents FKBP5-induced susceptibility to depressive-like behavior in aged mice. FKBP5 overexpression reduces hippocampal neuron density in aged mice, while increasing microglial markers.
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DOI：
10.1016/j.bbi.2015.11.001
发表时间：
2016-07
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
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影响因子：
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