LincRNAs involved in DCS-induced fear extinction: Shedding light on the transcriptomic dark matter
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PROVIDER: PRJEB36128 | ENA |
REPOSITORIES: ENA
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Project description:There is a growing appreciation of the role of non-coding RNAs in the regulation of gene and protein expression. Long non-coding RNAs can modulate splicing by hybridizing with precursor messenger RNAs (pre-mRNAs) and influence RNA editing, mRNA stability, translation activation and microRNA-mRNA interactions by binding to mature mRNAs. LncRNAs are highly abundant in the brain and have been implicated in neurodevelopmental disorders. Long intergenic non-coding RNAs are the largest subclass of lncRNAs and play a crucial role in gene regulation. We used RNA sequencing and bioinformatic analyses to identify lincRNAs and their predicted mRNA targets associated with fear extinction that was induced by intra-hippocampally administered D-cycloserine in an animal model investigating the core phenotypes of PTSD. We identified 43 differentially expressed fear extinction related lincRNAs and 190 differentially expressed fear extinction related mRNAs. Eight of these lincRNAs were predicted to interact with and regulate 108 of these mRNAs and seven lincRNAs were predicted to interact with 22 of their pre-mRNA transcripts. On the basis of the functions of their target RNAs, we inferred that these lincRNAs bind to nucleotides, ribonucleotides and proteins and subsequently influence nervous system development, and morphology, immune system functioning, and are associated with nervous system and mental health disorders. Quantitative trait loci that overlapped with fear extinction related lincRNAs, included serum corticosterone level, neuroinflammation, anxiety, stress and despair related responses. This is the first study to identify lincRNAs and their RNA targets with a putative role in transcriptional regulation during fear extinction.
2020-03-01 | E-MTAB-8647 | biostudies-arrayexpress
Project description:Trauma-related disorders arise from inefficient fear extinction and have immeasurable social and economic costs. Here, we characterized mouse phenotypes that spontaneously show individual differences in adaptive or maladaptive fear extinction and, before the traumatic experience, we found that specific morphological, electrophysiological and transcriptomic patterns of fear matrix pyramidal neurons predispose to trauma-related disorders. Finally, by using an optogenetic approach we showed the possibility to rescue the inefficient fear extinction activating fear matrix infralimbic pyramidal neurons
2023-06-02 | GSE209572 | GEO
Project description:Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example the expression of an aversive behavior upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinctionare only beginning to emerge. Here we show that fear extinction initiates up-regulation of hippocampal insulin-growth factor 2 (Igf2) and down-regulation of insulin-growth factor binding protein 7 (Igfbp7). In line with this observation we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2-signaling during fear extinction. To this end we show that fear extinction-induced IGF2/IGFBP7-signaling promotes the survival of 17-19 day-old newborn hippocampal neurons. In conclusion, our data suggests that therapeutic strategies that enhance IGF2-signaling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory. We employed mice to investigate fear extinction in the hippocampus-dependent contextual fear conditioning paradigm. To this end, male C57BL/6J mice were exposed to the fear conditioning box (context) followed by an electric foot-shock which elicits the acquisition of conditioned contextual fear. For extinction training animals were repeatedly reexposed to the conditioned context on consecutive days (24h interval) without receiving the footshockagain (extinction trial, E). This procedure eventually results in the decline of the aversive freezing behavior. Mice that were exposed to the conditioning context without receiving fear conditioning training served as control groups. To gain a better understanding of the molecular processes underlying fear extinction we performed a genome-wide analysis of the hippocampal transcriptome during fear extinction. In the employed paradigm fear extinction is a gradual process. To capture the longitudinal course of fear extinction we decided to perform hippocampal microarray analysis at two time points: (1) After the first extinction trial (E1) when animals display high levels of aversive freezing behavior and (2) at the extinction trial on which the freezing behavior was significantly reduced when compared to E1. This extinction trial, in the case of this experiment E5, we termed “extinction trial low freezing” (ELF). Mice that were exposed to the conditioning context without receiving fear conditioning training served as control groups (3). For all three groups we hybridized 5 samples (biological replicates).
2011-08-07 | E-GEOD-31063 | biostudies-arrayexpress
Project description:Social interactions are critical components for the survival of mammalian biology and evolution. Dysregulation of social behavior often leads to psychopathologies such as social anxiety disorder, which is characterized by an intense fear and avoidance of social situations. Using the social fear conditioning (SFC) paradigm, we analyzed expression levels of miR-132-3p and miR-124-3p within the septum, a brain region essential for social behavior and fear, after acquisition and extinction of social fear. Functional in vivo approaches using pharmacology, functional inhibition of miR-132-3p, viral miR-132 overexpression and shRNA-mediated knockdown of miR-132-3p within oxytocin receptor positive neurons confirmed septal miR-132-3p to be involved in social fear extinction and the oxytocin-mediated reversal of social fear. Moreover, Argonaute-RNA-co-immunoprecipitation-microarray analysis and further target mRNA quantification, depicted growth differentiation factor-5 (GDF-5) to be involved in miR-132-3p-mediated regulation of social fear extinction. Local application of GDF-5 resulted in impaired social fear extinction, an effect which seems to be mediated by miR-132-3p. In summary, we show that septal miR-132-3p is functionally involved in social fear extinction learning and oxytocin-mediated reversal of social fear.
2023-11-08 | GSE211449 | GEO
Project description:Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example the expression of an aversive behavior upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinctionare only beginning to emerge. Here we show that fear extinction initiates up-regulation of hippocampal insulin-growth factor 2 (Igf2) and down-regulation of insulin-growth factor binding protein 7 (Igfbp7). In line with this observation we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2-signaling during fear extinction. To this end we show that fear extinction-induced IGF2/IGFBP7-signaling promotes the survival of 17-19 day-old newborn hippocampal neurons. In conclusion, our data suggests that therapeutic strategies that enhance IGF2-signaling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory.
2011-08-08 | GSE31063 | GEO
Project description:Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example the expression of an aversive behavior upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinctionare only beginning to emerge. Here we show that fear extinction initiates up-regulation of hippocampal insulin-growth factor 2 (Igf2) and down-regulation of insulin-growth factor binding protein 7 (Igfbp7). In line with this observation we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2-signaling during fear extinction. To this end we show that fear extinction-induced IGF2/IGFBP7-signaling promotes the survival of 17-19 day-old newborn hippocampal neurons. In conclusion, our data suggests that therapeutic strategies that enhance IGF2-signaling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory.
2011-08-08 | GSE31063 | GEO
Project description:In this study, we systematically observed the expression of mRNAs, microRNAs (miRNA), long non-coding RNAs (lncRNAs), and circRNAs in the basolateral amygdala of mice after fear memory formation, extinction, and updating by whole-transcriptional sequencing, then a variety of inter-group comparison and bioinformatics analysis were used to find the differential expressed RNAs, enrich the function of them, and construct the molecular interaction networks. Moreover, competing endogenous RNA (ceRNA) molecular networks and transcriptional regulatory networks for the candidate circRNAs were constructed. Through these analyses, we found that about 10% of molecules were both involved in the fear memory extinction and formation, but the molecules and their signaling pathways were almost completely different between fear memory extinction and updating. This study describes a relatively detailed molecular network for fear memory updating, which might provide some novel directions for further mechanism research, and help to develop a specific physical method for fear memory intervention, based on the regulation of these key molecules.
2022-01-07 | GSE185808 | GEO
Project description:In this study, we systematically observed the expression of mRNAs, microRNAs (miRNA), long non-coding RNAs (lncRNAs), and circRNAs in the basolateral amygdala of mice after fear memory formation, extinction, and updating by whole-transcriptional sequencing, then a variety of inter-group comparison and bioinformatics analysis were used to find the differential expressed RNAs, enrich the function of them, and construct the molecular interaction networks. Moreover, competing endogenous RNA (ceRNA) molecular networks and transcriptional regulatory networks for the candidate circRNAs were constructed. Through these analyses, we found that about 10% of molecules were both involved in the fear memory extinction and formation, but the molecules and their signaling pathways were almost completely different between fear memory extinction and updating. This study describes a relatively detailed molecular network for fear memory updating, which might provide some novel directions for further mechanism research, and help to develop a specific physical method for fear memory intervention, based on the regulation of these key molecules.
2022-01-07 | GSE185807 | GEO
Project description:circRNA sequencing for 6 samples. In this study, we systematically observed the expression of mRNAs, microRNAs (miRNA), long non-coding RNAs (lncRNAs), and circRNAs in the basolateral amygdala of mice after fear memory formation, extinction, and updating by whole-transcriptional sequencing, then a variety of inter-group comparison and bioinformatics analysis were used to find the differential expressed RNAs, enrich the function of them, and construct the molecular interaction networks. Moreover, competing endogenous RNA (ceRNA) molecular networks and transcriptional regulatory networks for the candidate circRNAs were constructed. Through these analyses, we found that about 10% of molecules were both involved in the fear memory extinction and formation, but the molecules and their signaling pathways were almost completely different between fear memory extinction and updating. This study describes a relatively detailed molecular network for fear memory updating, which might provide some novel directions for further mechanism research, and help to develop a specific physical method for fear memory intervention, based on the regulation of these key molecules.
2022-01-07 | GSE185806 | GEO
Project description:Background: Extinction-based exposure therapy is used in treating anxiety- and trauma-related disorders, however there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to facilitate the inadequate protection against return-of-fear phenomena. Methods: Spontaneous recovery and fear renewal tests, assessed persistence and context-independence of treatments rescuing deficient fear extinction in 129S1/SvImJ mice. To reveal neurobiological mechanisms supporting long-lasting extinction rescue, whole-genome expression profiling, qRT-PCR, immunohistochemistry and chromatin immunoprecipitation were used. Results: Persistent and context-independent rescue of deficient fear extinction induced by dietary zinc-restriction was associated with enhanced expression of dopamine-related genes, such as genes encoding the dopamine- D1 (Drd1a) and -D2 (Drd2) receptor in the medial prefrontal cortex (mPFC) and amygdala. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a possibly involved gene regulatory mechanism. While enhancing histone acetylation, via administering the HDAC inhibitor MS275, does not induce successful fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated. This was associated with enhanced neuronal histone acetylation in the mPFC and amygdala. Finally, as a proof of principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. Conclusion: Current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear inhibitory memory.
2016-12-21 | GSE76108 | GEO