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VIP 神经元中的 mTOR 信号调节生物钟同步和嗅觉。

mTOR signaling in VIP neurons regulates circadian clock synchrony and olfaction.

机构信息

Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812.

Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA 30310.

出版信息

Proc Natl Acad Sci U S A. 2018 Apr 3;115(14):E3296-E3304. doi: 10.1073/pnas.1721578115. Epub 2018 Mar 19.

Abstract

Mammalian/mechanistic target of rapamycin (mTOR) signaling controls cell growth, proliferation, and metabolism in dividing cells. Less is known regarding its function in postmitotic neurons in the adult brain. Here we created a conditional knockout mouse model to address this question. Using the Cre-LoxP system, the gene was specifically knocked out in cells expressing (vasoactive intestinal peptide), which represent a major population of interneurons widely distributed in the neocortex, suprachiasmatic nucleus (SCN), olfactory bulb (OB), and other brain regions. Using a combination of biochemical, behavioral, and imaging approaches, we found that mice lacking in VIP neurons displayed erratic circadian behavior and weakened synchronization among cells in the SCN, the master circadian pacemaker in mammals. Furthermore, we have discovered a critical role for mTOR signaling in mediating olfaction. Odor stimulated activation in the OB, anterior olfactory nucleus, as well as piriform cortex. Odor-evoked c-Fos responses along the olfactory pathway were abolished in mice lacking mTOR in VIP neurons, which is consistent with reduced olfactory sensitivity in these animals. Together, these results demonstrate that mTOR is a key regulator of SCN circadian clock synchrony and olfaction.

摘要

哺乳动物/雷帕霉素靶蛋白(mTOR)信号通路控制分裂细胞的细胞生长、增殖和代谢。关于其在成年大脑的有丝分裂后神经元中的功能知之甚少。在这里,我们创建了一个条件性敲除小鼠模型来解决这个问题。使用 Cre-LoxP 系统,该基因在表达 (血管活性肠肽)的细胞中特异性敲除, 表达的细胞代表广泛分布于新皮质、视交叉上核(SCN)、嗅球(OB)和其他脑区的主要中间神经元群体。通过生化、行为和成像方法的结合,我们发现缺乏 VIP 神经元中的 会导致小鼠出现不规则的昼夜节律行为,并削弱了哺乳动物主生物钟 SCN 中细胞之间的同步性。此外,我们还发现 mTOR 信号在介导嗅觉中起着关键作用。气味刺激 OB、前嗅核和梨状皮质中的 激活。在 VIP 神经元中缺乏 mTOR 的小鼠中,嗅探通路中的气味诱发 c-Fos 反应被消除,这与这些动物嗅觉敏感性降低一致。总之,这些结果表明 mTOR 是 SCN 昼夜节律同步和嗅觉的关键调节因子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e4da/5889665/84c868ee4aa0/pnas.1721578115fig01.jpg

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