Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice
Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice
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DOI：
10.1038/s41398-020-0854-2
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发表时间：
2020-05-28
影响因子：
6.8
通讯作者：
Shelkovnikova, Tatyana A.
中科院分区：
文献类型：
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作者：
Kukharsky, Michail S.;Ninkina, Natalia N.;Shelkovnikova, Tatyana A.
NEAT1是一种广泛表达的长非编码RNA(LncRNA)，是细胞应激反应的重要调节因子。然而，NEAT1在中枢神经系统(CNS)中的生理作用仍然知之甚少。在目前的研究中，我们通过结合行为表型、电生理学和表达分析来表征Neat1基因敲除小鼠模型(Neat1(-/-)小鼠)的中枢神经系统功能，从而解决了这一问题。RNAScope(R)原位杂交显示，在野生型小鼠中，Neat1在中枢神经系统区域都有表达，在神经胶质细胞中高表达，在神经元中低表达。在小鼠中，Neat1的缺失导致对生理应激的反应不足，表现为多动和惊恐逃避反应。此外，Neat1(-/-)小鼠在社会互动和活动节奏模式方面表现出缺陷，但保留了正常的运动功能和记忆。Neat1(-/-)小鼠在大脑中不存在神经元丢失、明显的神经炎症或严重的突触功能障碍。然而，培养的Neat1(-/-)神经元具有高度兴奋性和钙稳态失调的特点，在体内，应激诱导的神经元活动也在Neat1(-/-)小鼠中增强。基因表达分析表明，Neat1可能是脑内多个基因的弱正向调节因子。此外，Neat1的缺失影响了对中枢神经系统功能至关重要的基因的选择性剪接，并与神经疾病有关。总体而言，我们的数据表明，Neat1参与了大脑中的压力信号传递，并微调了中枢神经系统的功能，使其能够适应生理压力的行为。
NEAT1 is a highly and ubiquitously expressed long non-coding RNA (lncRNA) which serves as an important regulator of cellular stress response. However, the physiological role of NEAT1 in the central nervous system (CNS) is still poorly understood. In the current study, we addressed this by characterising the CNS function of the Neat1 knockout mouse model (Neat1(-/-) mice), using a combination of behavioural phenotyping, electrophysiology and expression analysis. RNAscope (R) in situ hybridisation revealed that in wild-type mice, Neat1 is expressed across the CNS regions, with high expression in glial cells and low expression in neurons. Loss of Neat1 in mice results in an inadequate reaction to physiological stress manifested as hyperlocomotion and panic escape response. In addition, Neat1(-/-) mice display deficits in social interaction and rhythmic patterns of activity but retain normal motor function and memory. Neat1(-/-) mice do not present with neuronal loss, overt neuroinflammation or gross synaptic dysfunction in the brain. However, cultured Neat1(-/-) neurons are characterised by hyperexcitability and dysregulated calcium homoeostasis, and stress-induced neuronal activity is also augmented in Neat1(-/-) mice in vivo. Gene expression analysis showed that Neat1 may act as a weak positive regulator of multiple genes in the brain. Furthermore, loss of Neat1 affects alternative splicing of genes important for the CNS function and implicated in neurological diseases. Overall, our data suggest that Neat1 is involved in stress signalling in the brain and fine-tunes the CNS functions to enable adaptive behaviour in response to physiological stress.