ATF6β Deficiency Elicits Anxiety-like Behavior and Hyperactivity Under Stress Conditions
ATF6β Deficiency Elicits Anxiety-like Behavior and Hyperactivity Under Stress Conditions
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DOI：
10.1007/s11064-023-03900-4
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发表时间：
2023-02-28
影响因子：
4.4
通讯作者：
Hori，Osamu
中科院分区：
文献类型：
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作者：
Tanaka，Takashi;Nguyen，Dinh Thi;Hori，Osamu
转录激活因子6（ATF 6）是一种内质网（ER）应激调节的转录因子，可诱导ER中主要分子伴侣的表达。我们最近报道，ATF 6 β，ATF 6的一个亚型，促进海马神经元暴露于ER应激和兴奋性毒性，至少部分通过诱导钙网蛋白的表达，一个ER分子伴侣具有高钙离子结合能力。在本研究中，我们证明了小鼠中的ATF 6 β缺乏也降低了钙网蛋白表达，并增加了另一种ER分子伴侣葡萄糖调节蛋白78在情感脑区域（如前额叶皮层（PFC），下丘脑，海马和杏仁核）的表达。综合行为分析显示，Atf 6 b −/−小鼠在亮/暗转换测试中表现出焦虑样行为，在强迫游泳测试中表现出多动。与这些结果一致，PFC和下丘脑促肾上腺皮质激素释放激素（CRH）的表达在Atf 6 b −/−小鼠中增加，循环皮质酮也是如此。此外，CRH受体1拮抗剂减轻了Atf 6 b −/−小鼠的焦虑样行为。这些发现表明，ATF 6 β缺乏通过CRH受体1依赖性机制产生焦虑样行为和多动。ATF 6 β可能在大脑情感中心的精神疾病中发挥作用。
Activating transcription factor 6 (ATF6) is an endoplasmic reticulum (ER) stress-regulated transcription factor that induces expression of major molecular chaperones in the ER. We recently reported that ATF6β, a subtype of ATF6, promoted survival of hippocampal neurons exposed to ER stress and excitotoxicity, at least in part by inducing expression of calreticulin, an ER molecular chaperone with high Ca2+-binding capacity. In the present study, we demonstrate that ATF6β deficiency in mice also decreases calreticulin expression and increases expression of glucose-regulated protein 78, another ER molecular chaperone, in emotional brain regions such as the prefrontal cortex (PFC), hypothalamus, hippocampus, and amygdala. Comprehensive behavioral analyses revealed thatAtf6b−/−mice exhibit anxiety-like behavior in the light/dark transition test and hyperactivity in the forced swim test. Consistent with these results, PFC and hypothalamic corticotropin-releasing hormone (CRH) expression was increased inAtf6b−/−mice, as was circulating corticosterone. Moreover, CRH receptor 1 antagonism alleviated anxiety-like behavior inAtf6b−/−mice. These findings suggest that ATF6β deficiency produces anxiety-like behavior and hyperactivity via a CRH receptor 1-dependent mechanism. ATF6β could play a role in psychiatric conditions in the emotional centers of the brain.