Region-specific microRNA alterations in marmosets carrying SLC6A4 polymorphisms are associated with anxiety-like behavior.
Region-specific microRNA alterations in marmosets carrying SLC6A4 polymorphisms are associated with anxiety-like behavior.
复制标题
携带SLC6A4多态性的果果中的区域特异性microRNA改变与焦虑样行为有关。
DOI：
10.1016/j.ebiom.2022.104159
复制
发表时间：
2022-08
期刊：
影响因子：
11.1
通讯作者：
Gascon, Eduardo
中科院分区：
文献类型：
--
作者：
Popa, Natalia;Bachar, Dipankar;Roberts, Angela C.;Santangelo, Andrea M.;Gascon, Eduardo
抑郁症和焦虑症等精神疾病是多因素造成的，在西方社会非常普遍。人类研究已经确定了这些疾病的许多高风险遗传变异。其中，血清素转运蛋白基因（SLC6A4）启动子区的多态性备受关注。然而，由于缺乏实验模型，这些遗传变异引起的分子改变以及它们与行为缺陷的关系尚未得到研究。在这方面，狨猴已成为转化神经科学领域的强大模型，用于研究复杂行为的分子基础。在这里，我们利用了狨猴 SLC6A4 基因中自然发生的遗传多态性，这些多态性与焦虑样行为有关。使用 FACS 分选，我们分析了基因型和行为表型狨猴不同大脑区域的 microRNA 含量。我们发现，携带不同 SLC6A4 变体的狨猴在前额皮质区域表现出不同的 microRNA 特征，该区域的活性在抑郁/焦虑患者中持续发生变化。我们还发现结直肠癌 (DCC) 中的缺失基因（一种先前与这些疾病相关的基因）作为不同表达的 microRNA 的下游靶标。值得注意的是，我们发现该区域的 microRNA 和 DCC 水平与焦虑样行为高度相关。我们的研究结果建立了遗传变异、特定皮质区域的分子修饰和复杂行为反应之间的联系，为人类精神病理学背后的基因-行为关系提供了新的见解。这项工作得到了法国国家机构、NRJ 基金会、Celphedia 和法国基金会以及 Wellcome Trust 的支持。
Psychiatric diseases such as depression and anxiety are multifactorial conditions, highly prevalent in western societies. Human studies have identified a number of high-risk genetic variants for these diseases. Among them, polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4) have attracted much attention. However, due to the paucity of experimental models, molecular alterations induced by these genetic variants and how they correlate to behavioral deficits have not been examined. In this regard, marmosets have emerged as a powerful model in translational neuroscience to investigate molecular underpinnings of complex behaviors. Here, we took advantage of naturally occurring genetic polymorphisms in marmoset SLC6A4 gene that have been linked to anxiety-like behaviors. Using FACS-sorting, we profiled microRNA contents in different brain regions of genotyped and behaviorally-phenotyped marmosets. We revealed that marmosets bearing different SLC6A4 variants exhibit distinct microRNAs signatures in a region of the prefrontal cortex whose activity has been consistently altered in patients with depression/anxiety. We also identified Deleted in Colorectal Cancer (DCC), a gene previously linked to these diseases, as a downstream target of the differently expressed microRNAs. Significantly, we showed that levels of both microRNAs and DCC in this region were highly correlated to anxiety-like behaviors. Our findings establish links between genetic variants, molecular modifications in specific cortical regions and complex behavioral responses, providing new insights into gene-behavior relationships underlying human psychopathology. This work was supported by France National Agency, NRJ Foundation, Celphedia and Fondation de France as well as the Wellcome Trust.
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DOI：
10.1073/pnas.2006515117
发表时间：
2020-09-29
影响因子：
11.1
作者：
Feng G;Jensen FE;Greely HT;Okano H;Treue S;Roberts AC;Fox JG;Caddick S;Poo MM;Newsome WT;Morrison JH
通讯作者：
Morrison JH
影响因子：
4.6
作者：
Brent LJ;Heilbronner SR;Horvath JE;Gonzalez-Martinez J;Ruiz-Lambides A;Robinson AG;Skene JH;Platt ML
通讯作者：
Platt ML
影响因子：
14.9
作者：
Chang, Le;Zhou, Guangyan;Xia, Jianguo
通讯作者：
Xia, Jianguo
影响因子：
3.7
作者：
Egner, Tobias;Etkin, Amit;Hirsch, Joy
通讯作者：
Hirsch, Joy
DOI：
10.1093/cercor/bhy249
发表时间：
2019-01-01
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
--
作者：
James GM;Gryglewski G;Vanicek T;Berroterán-Infante N;Philippe C;Kautzky A;Nics L;Vraka C;Godbersen GM;Unterholzner J;Sigurdardottir HL;Spies M;Seiger R;Kranz GS;Hahn A;Mitterhauser M;Wadsak W;Bauer A;Hacker M;Kasper S;Lanzenberger R
通讯作者：
Lanzenberger R