Estrogen Receptor β Agonist Attenuates Endoplasmic Reticulum Stress-Induced Changes in Social Behavior and Brain Connectivity in Mice.
Estrogen Receptor β Agonist Attenuates Endoplasmic Reticulum Stress-Induced Changes in Social Behavior and Brain Connectivity in Mice.
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雌激素受体β激动剂减弱内质网应激引起的小鼠社会行为和大脑连通性的变化。
DOI：
10.1007/s12035-018-0929-8
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发表时间：
2018-09
影响因子：
5.1
通讯作者：
Pillai A
中科院分区：
文献类型：
--
作者：
Crider A;Nelson T;Davis T;Fagan K;Vaibhav K;Luo M;Kamalasanan S;Terry AV Jr;Pillai A
社会交往障碍是包括抑郁症、自闭症和精神分裂症在内的几种主要精神疾病的一个关键特征。虽然，在解剖学上，前额叶皮层（PFC）被认为是社会行为的关键调节器，但对社会互动障碍的细胞机制知之甚少。上述精神障碍的病理生理学中涉及的一种病因机制是细胞应激和随后的内质网（ER）中的适应性反应，其可由多种环境和物理因素引起。ER是一种在蛋白质修饰、折叠和蛋白质成熟中起重要作用的细胞器，然而，ER应激在改变社会行为中的具体作用尚不清楚。在这项研究中，与衣霉素，一种ER应激诱导剂治疗增强肌醇需要ER-到-核信号激酶1（IRE 1）的磷酸化水平，并增加X-box-结合蛋白1（XBP 1）mRNA剪接活性在小鼠PFC，而IRE 1/XBP 1途径的抑制在PFC的病毒颗粒的方法减弱由衣霉素治疗引起的社会行为缺陷。衣霉素处理后，雄性小鼠PFC中的雌激素受体β（ERβ）蛋白水平降低。ERB-041能显著抑制衣霉素诱导的小鼠PFC的社会行为缺陷和IRE 1/XBP 1通路的激活，并能抑制衣霉素诱导的雄性小鼠PFC与海马功能连接的增加。总之，这些结果表明，ERβ激动剂通过IRE-1/XBP 1途径减弱ER应激诱导的社会行为缺陷。
Impaired social interaction is a key feature of several major psychiatric disorders including depression, autism and schizophrenia. While, anatomically, the prefrontal cortex (PFC) is known as a key regulator of social behavior, little is known about the cellular mechanisms that underlie impairments of social interaction. One etiological mechanism implicated in the pathophysiology of the aforementioned psychiatric disorders is cellular stress and consequent adaptive responses in the endoplasmic reticulum (ER) that can result from a variety of environmental and physical factors. The ER is an organelle that serves essential roles in protein modification, folding, and maturation of proteins, however, the specific role of ER stress in altered social behavior is unknown. In this study, treatment with tunicamycin, an ER stress inducer enhanced the phosphorylation level of inositol-requiring ER-to-nucleus signal kinase 1 (IRE1) and increased X-box-binding protein 1 (XBP1) mRNA splicing activity in the mouse PFC, whereas inhibition of IRE1/XBP1 pathway in PFC by a viral particle approach attenuated social behavioral deficits caused by tunicamycin treatment. Reduced estrogen receptor beta (ERβ) protein levels were found in the PFC of male mice following tunicamycin treatment. Pretreatment with an ERβ specific agonist, ERB-041 significantly attenuated tunicamycin-induced deficits in social behavior, and activation of IRE1/XBP1 pathway in mouse PFC. Moreover, ERB-041 inhibited tunicamycin-induced increases in functional connectivity between PFC and hippocampus in male mice. Together, these results show that ERβ agonist attenuates ER stress-induced deficits in social behavior through the IRE-1/XBP1 pathway.
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影响因子：
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作者：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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