CPEB3-dowregulated Nr3c1 mRNA translation confers resilience to developing posttraumatic stress disorder-like behavior in fear-conditioned mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE159731 | GEO | 2021/04/26
REPOSITORIES: GEO
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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:Fear extinction is an adaptive behavioral process critical for organism’s survival, but deficiency in extinction may lead to PTSD. While the amygdala and its neural circuits are critical for fear extinction, the molecular identity and organizational logic of cell types that lie at the core of these circuits remain unclear. Here we report that mice deficient for amygdala-enriched gastrin-releasing peptide gene (Grp-/-) exhibit enhanced neuronal activity in the basolateral amygdala (BLA) and stronger fear conditioning, as well as deficient extinction in stress-enhanced fear learning (SEFL). rAAV2-retro-based tracing combined with visualization of the GFP knocked in the Grp gene showed that BLA receives several GRPergic conditioned stimulus projections: from the indirect auditory thalamus-to-auditory cortex pathway, medial prefrontal cortex, ventral hippocampus and ventral tegmental area. Transcription of dopamine-related genes was decreased in BLA of Grp-/- mice following SEFL extinction recall, suggesting that the GRP may mediate fear extinction regulation by dopamine.
2021-12-01 | GSE164226 | GEO
Project description:The suppression of fear memory in the absence of danger (fear extinction) requires coordinated neural activity within the amygdala and medial prefrontal (prelimbic and infralimbic) cortex. Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear memory and extinction. In the present study, we investigated the effects of optogenetic manipulations of prelimbic pyramidal neurons on amygdala gene expression to analyze the specific transcriptional pathways involved in fear extinction. To this aim, transgenic mice (Thy1-COP4) having cortical and amygdala pyramidal neurons optogenetically excitable were (or not) fear-conditioned. During the extinction phase, the mice received optogenetic (or sham) stimulations to maintain the activation of the prelimbic pyramidal neurons and impair fear extinction. At the end of behavioral testing, electrophysiological (Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the pyramidal neurons of prelimbic cortex. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Results demonstrate that pyramidal neurons of prelimbic cortex are involved in modulation of the fear responses during extinction phase and their optogenetic stimulation in fear-conditioned mice results in strong modifications of the amygdala transcriptome. Understanding the transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.
2021-01-14 | GSE162417 | GEO
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: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:Emerging knowledge suggests that post-traumatic stress disorder (PTSD) is causally associated with epigenetic changes although its molecular underpinnings are still largely elusive. We postulate that differentially methylated probes mined from peripheral whole blood could be candidates for potential PTSD diagnostic signatures. Working within the Systems Biology PTSD Biomarker Consortium (SBPBC), we compared 52 PTSD male veterans (CAPS > 40) and 52 age/ethnicity matched controls (CAPS < 20) and detected ~5,600 differentially methylated CpG islands (CpGI) annotated to ~2,800 differentially methylated genes (DMG). The majority (84.5%) of these DMGs was hypermethylated in PTSD veterans, and nearly 30% of those representing the focus group of the present study were differentially methylated in their promoter regions. These promoter-bound DMGs were significantly enriched in four major network-clusters comprising PTSD-associated complications, PTSD-relevant endocrine signaling, nervous system development and nervous system functions. The severity of some current PTSD symptoms was correlated with the increased risk of medical problems, which was captured in epigenetically perturbed networks associated with insulin resistance, circadian rhythm, innate immunity and telomere management. DMGs involved with addiction, fear sensitization and neurotransmissions were enriched in the networks of long term potentiation, depression and fear memory consolidation, and thereby potentially induced lasting impacts on brain. Finally, we curated a set of DMGs that co-enrich multiple PTSD-relevant networks, and we speculate that these genes are cooperative associated with PTSD risk. The present study emphasizes the need to validate these potential PTSD signatures by probing independent cross-sectional and prospective human cohorts.
2017-08-31 | GSE76401 | 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: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 | GSE76103 | 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
Project description:Long noncoding RNAs (lncRNAs) represent a multidimensional class of regulatory molecules that are involved in many aspects of brain function. Emerging evidence indicates that lncRNAs are localized to the synapse; however, a direct role for their activity in this subcellular compartment in memory formation has yet to be demonstrated. Using lncRNA capture-seq, we identified a Gas5 variant that accumulate in the synaptic compartment within the infralimbic prefrontal cortex of adult male C57/Bl6 mice. Gas5 RNA immunoprecipitation followed by mass spectrometry revealed that this Gas5 isoform, in association with the RNA binding proteins G3BP2 and CAPRIN1, regulates the activity-dependent trafficking and clustering of RNA granules. In addition, we found that cell-type-specific, activity-dependent, and synapse-specific knockdown of this Gas5 variant led to impaired fear extinction memory. These findings identify a new mechanism of fear extinction that involves the dynamic interaction between local lncRNA activity and RNA condensates in the synaptic compartment.
2023-11-20 | PXD046479 | Pride