Department of Behavioural and Molecular Neurobiology, Regensburg Center of Neuroscience, University of Regensburg, Regensburg, 93053, Germany.
Regensburg Center for Biochemistry, Laboratory for RNA Biology, University of Regensburg, Regensburg, 93053, Germany.
Mol Psychiatry. 2022 Oct;27(10):4064-4076. doi: 10.1038/s41380-022-01481-2. Epub 2022 Mar 25.
Social anxiety disorder is characterized by a persistent fear and avoidance of social situations, but available treatment options are rather unspecific. Using an established mouse social fear conditioning (SFC) paradigm, we profiled gene expression and chromatin alterations after the acquisition and extinction of social fear within the septum, a brain region important for social fear and social behaviors. Here, we particularly focused on the successful versus unsuccessful outcome of social fear extinction training, which corresponds to treatment responsive versus resistant patients in the clinics. Validation of coding and non-coding RNAs revealed specific isoforms of the long non-coding RNA (lncRNA) Meg3 regulated, depending on the success of social fear extinction. Moreover, PI3K/AKT was differentially activated with extinction success in SFC-mice. In vivo knockdown of specific Meg3 isoforms increased baseline activity of PI3K/AKT signaling, and mildly delayed social fear extinction. Using ATAC-Seq and CUT&RUN, we found alterations in the chromatin structure of specific genes, which might be direct targets of lncRNA Meg3.
社交焦虑障碍的特征是持续的恐惧和回避社交场合，但现有的治疗选择相当不具体。使用已建立的小鼠社交恐惧条件反射（SFC）范式，我们在隔区（对社交恐惧和社交行为很重要的大脑区域）内描述了社交恐惧获得和消退后的基因表达和染色质改变。在这里，我们特别关注社交恐惧消退训练的成功和失败结果，这对应于临床中治疗反应性和抵抗性患者。对编码和非编码 RNA 的验证揭示了长非编码 RNA（lncRNA）Meg3 的特定异构体受到调节，具体取决于社交恐惧消退的成功与否。此外，PI3K/AKT 在 SFC 小鼠中的激活与消退成功有关。体内特异性 Meg3 异构体的敲低增加了 PI3K/AKT 信号的基线活性，并轻度延迟了社交恐惧的消退。使用 ATAC-Seq 和 CUT&RUN，我们发现了特定基因染色质结构的改变，这些基因可能是 lncRNA Meg3 的直接靶点。
