Somatostatin, neuronal vulnerability and behavioral emotionality.
Somatostatin, neuronal vulnerability and behavioral emotionality.
复制标题
生长抑素，神经元脆弱性和行为情绪。
DOI：
10.1038/mp.2014.184
复制
发表时间：
2015-03
影响因子：
11
通讯作者：
Sibille, E.
中科院分区：
文献类型：
--
作者：
Lin, L. C.;Sibille, E.
生长抑素（SST）缺陷是抑郁症和其他神经系统疾病伴心境障碍的常见病理特征，但对SST缺陷对心境症状的贡献或这些缺陷的原因知之甚少。在这里，我们发现，缺乏Sst（SstKO）的小鼠表现出升高的行为情绪，高基础血浆皮质酮和减少的BDNF，皮质抑素和Gad 67的基因表达，共同概括了人类抑郁症的行为，神经内分泌和分子特征。在SstKO和杂合子（SstHZ）小鼠中的研究表明，皮质酮升高不足以重现行为表型，这表明Sst细胞特异性分子变化的推定作用。使用激光捕获显微切割，我们表明，皮质SST阳性中间神经元显示显着更大的转录组失调慢性应激后相比，锥体神经元。通过真核起始因子2（EIF 2）信号传导的蛋白质翻译，以前涉及神经退行性疾病的途径，在应激暴露的SST神经元中受到最大的影响和抑制。然后，我们表明，激活EIF 2信号通过EIF 2激酶抑制减轻小鼠应激诱导的行为情绪。总之，我们的数据表明：（1）低SST在情绪相关表型中发挥因果作用，（2）EIF 2介导的蛋白质翻译失调可能代表SST神经元脆弱性的机制，以及（3）全球EIF 2信号传导具有抗抑郁/抗焦虑潜力。
Somatostatin (SST) deficits are common pathological features in depression and other neurological disorders with mood disturbances, but little is known about the contribution of SST deficits to mood symptoms or causes of these deficits. Here we show that mice lacking Sst (SstKO) exhibit elevated behavioral emotionality, high basal plasma corticosterone and reduced gene expression of Bdnf, Cortistatin, and Gad67, together recapitulating behavioral, neuroendocrine and molecular features of human depression. Studies in SstKO and heterozygous (SstHZ) mice show that elevated corticosterone is not sufficient to reproduce the behavioral phenotype, suggesting a putative role for Sst cell-specific molecular changes. Using laser-capture microdissection, we show that cortical SST-positive interneurons display significantly greater transcriptome deregulations after chronic stress compared to pyramidal neurons. Protein translation through eukaryotic initiation factor 2 (EIF2) signaling, a pathway previously implicated in neurodegenerative diseases, was most affected and suppressed in stress-exposed SST neurons. We then show that activating EIF2 signaling through EIF2 kinase inhibition mitigated stress-induced behavioral emotionality in mice. Together, our data suggest that (1) low SST plays a causal role in mood-related phenotypes, (2) deregulated EIF2-mediated protein translation may represent a mechanism for vulnerability of SST neurons, and (3) that global EIF2 signaling has antidepressant/anxiolytic potential.
登录
查看更多内容
影响因子：
4.8
作者：
BROWN, MR;RIVIER, C;VALE, W
通讯作者：
VALE, W
影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
Ron, D
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D
影响因子：
3.7
作者：
AGREN, H;LUNDQVIST, G
通讯作者：
LUNDQVIST, G
影响因子：
3.7
作者：
Albrecht A;Thiere M;Bergado-Acosta JR;Poranzke J;Müller B;Stork O
通讯作者：
Stork O