Dataset Information

Behavioral tagging of extinction learning.

ABSTRACT: Extinction of contextual fear in rats is enhanced by exposure to a novel environment at 1-2 h before or 1 h after extinction training. This effect is antagonized by administration of protein synthesis inhibitors anisomycin and rapamycin into the hippocampus, but not into the amygdala, immediately after either novelty or extinction training, as well as by the gene expression blocker 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole administered after novelty training, but not after extinction training. Thus, this effect can be attributed to a mechanism similar to synaptic tagging, through which long-term potentiation can be enhanced by other long-term potentiations or by exposure to a novel environment in a protein synthesis-dependent fashion. Extinction learning produces a tag at the appropriate synapses, whereas novelty learning causes the synthesis of plasticity-related proteins that are captured by the tag, strengthening the synapses that generated this tag.

SUBMITTER: de Carvalho Myskiw J

PROVIDER: S-EPMC3549103 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Behavioral tagging of extinction learning.

de Carvalho Myskiw Jociane J Benetti Fernando F Izquierdo Iván I

Proceedings of the National Academy of Sciences of the United States of America 20121231 3

Extinction of contextual fear in rats is enhanced by exposure to a novel environment at 1-2 h before or 1 h after extinction training. This effect is antagonized by administration of protein synthesis inhibitors anisomycin and rapamycin into the hippocampus, but not into the amygdala, immediately after either novelty or extinction training, as well as by the gene expression blocker 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole administered after novelty training, but not after extinction trai ...[more]

PMID: 23277583

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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).

Project description:BackgroundFear responding in posttraumatic stress disorder (PTSD) is sexually heterogeneous and varies with hormonal fluctuations throughout the menstrual cycle. While research suggests that estrogen levels affect PTSD symptoms among women, there is a dearth of research on modulatory effects of estrogen on fear responding among women with PTSD, and neural outcome measures are lacking.MethodsA sample of 42 women with PTSD underwent 2 consecutive alternating blocks of fear conditioning and extinction training, during which a CS+ conditioned stimulus, but not a CS-, predicted the occurrence of an electric shock in an acquisition context but not in an extinction context. Assayed saliva determined estradiol levels. Skin conductance response and whole-brain voxelwise activity during functional magnetic resonance imaging were outcome variables in linear mixed-effects models, with estradiol level, PTSD severity, and task contrasts as predictors.ResultsSkin conductance response exhibited a significant estradiol × PTSD severity × habituation interaction (t = 3.180, p = .002), such that PTSD severity was correlated with increased arousal responding between training blocks among women with lower estradiol (t = -3.985, p < .001) but not higher estradiol (t = 0.550, p = .583). Voxelwise activity also demonstrated an identical three-way interaction within dorsomedial prefrontal cortex and anterior insula clusters. The skin conductance response and imaging interactions between PTSD severity and estradiol were not specific to conditioned stimulus type or context.ConclusionsEstradiol moderated the relationship between PTSD severity and arousal response habituation between fear conditioning and extinction training sessions, such that high estradiol protected against the negative impact of severe PTSD symptoms on fear habituation. These findings suggest that estrogen enhances habituation among women with severe PTSD, potentially influencing the efficacy of extinction-based therapies.

Dataset Information

Behavioral tagging of extinction learning.

Publications

Behavioral tagging of extinction learning.

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