Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

Michail S Kukharsky,Vsevolod Telezhkin,Johnathan Cooper-Knock,Shinichi Nakagawa,Tatyana A Shelkovnikova,Tetsuro Hirose,Camille Rabesahala De Meritens,Haiyan An,Wenbin Wei,Natalia N Ninkina,Vladimir L Buchman

doi:10.1038/s41398-020-0854-2

Abstract

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® 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.

Highlights

Introduction Long noncodingRNAs are an arbitrary group comprising non-protein coding transcripts longer than 200 nucleotides
LncRNAs play an important role in fine-tuning the functions specific for different cell types, and their activity might be especially important in the adult nervous system
Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) is an abundant long non-coding RNA (lncRNA) known to be expressed in the mammalian central nervous system (CNS) its role in the CNS under basal conditions and under conditions of physiological stress remained largely unknown

Summary

Introduction

RNAs (lncRNAs) are an arbitrary group comprising non-protein coding transcripts longer than 200 nucleotides. The prominent member of the latter group is Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), a nuclear-retained lncRNA with important roles in cellular (patho)physiology and one of the most intensely studied lncRNAs. NEAT1 contributes to various cellular. The longer NEAT1 isoform, NEAT1_2, is essential for the assembly of nuclear bodies termed paraspeckles[2,3], whereas NEAT1_1, albeit a paraspeckle component, is dispensable for their formation and likely plays various paraspeckle-independent roles[4]. NEAT1 expression is elevated in stressed cells[5], such as those subjected to hypoxia[6], viral infection[7], heat shock[8], mitochondrial stress[9] or proteasome inhibition[10]. Changes in NEAT1 levels is a recurrent theme in neoplasias, and the gene is a hotspot for mutations in several types of cancer[1]

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Results

Conclusion