Associative learning and extinction of conditioned threat predictors across sensory modalities.
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ABSTRACT:
SUBMITTER: Koenen LR
PROVIDER: S-EPMC8113515 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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).
2011-08-07 | E-GEOD-31063 | biostudies-arrayexpress
Project description:Social groups are organized along dominance hierarchies, which determine how we respond to threats posed by dominant and subordinate others. The persuasive impact of these dominance threats on mental and physical well-being has been well described but it is unknown how dominance rank of others bias our experience and learning in the first place. We introduce a model of conditioned social dominance threat in humans, where the presence of a dominant other is paired with an aversive event. Participants first learned about the dominance rank of others by observing their dyadic confrontations. During subsequent fear learning, the dominant and subordinate others were equally predictive of an aversive consequence (mild electric shock) to the participant. In three separate experiments, we show that participants' eye-blink startle responses and amygdala reactivity adaptively tracked dominance of others during observation of confrontation. Importantly, during fear learning dominant vs subordinate others elicited stronger and more persistent learned threat responses as measured by physiological arousal and amygdala activity. Our results characterize the neural basis of learning through observing conflicts between others, and how this affects subsequent learning through direct, personal experiences.
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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.
2011-08-08 | GSE31063 | GEO
Project description:A reminder can render consolidated memory labile and susceptible to amnesic agents during a reconsolidation window. For the case of threat memory (also termed fear memory), it has been suggested that extinction training during this reconsolidation window has the same disruptive impact. This procedure could provide a powerful therapeutic principle for treatment of unwanted aversive memories. However, human research yielded contradictory results. Notably, all published positive replications quantified threat memory by conditioned skin conductance responses (SCR). Yet, other studies measuring SCR and/or fear-potentiated startle failed to observe an effect of a reminder/extinction procedure on the return of fear. Here we sought to shed light on this discrepancy by using a different autonomic response, namely, conditioned pupil dilation, in addition to SCR, in a replication of the original human study. N = 71 humans underwent a 3-d threat conditioning, reminder/extinction, and reinstatement, procedure with 2 CS+, of which one was reminded. Participants successfully learned the threat association on day 1, extinguished conditioned responding on day 2, and showed reinstatement on day 3. However, there was no difference in conditioned responding between the reminded and the nonreminded CS, neither in pupil size nor SCR. Thus, we found no evidence that a reminder trial before extinction prevents the return of threat-conditioned responding.
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Project description:Neurons in the visual cortex sharpen their orientation tuning as humans learn aversive contingencies. A stimulus orientation (CS+) that reliably predicts an aversive noise (unconditioned stimulus: US) is selectively enhanced in lower-tier visual cortex, while similar unpaired orientations (CS-) are inhibited. Here, we examine in male volunteers how sharpened visual processing is affected by fear extinction learning (where no US is presented), and how fear and extinction memory undergo consolidation one day after the original learning episode. Using steady-state visually evoked potentials from electroencephalography in a fear generalization task, we found that extinction learning prompted rapid changes in orientation tuning: Both conditioned visuocortical and skin conductance responses to the CS+ were strongly reduced. Next-day re-testing (delayed recall) revealed a brief but precise return-of-tuning to the CS+ in visual cortex accompanied by a brief, more generalized return-of-fear in skin conductance. Explorative analyses also showed persistent tuning to the threat cue in higher visual areas, 24 h after successful extinction, outlasting peripheral responding. Together, experience-based changes in the sensitivity of visual neurons show response patterns consistent with memory consolidation and spontaneous recovery, the hallmarks of long-term neural plasticity.
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