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A mouse model of stress-enhanced fear learning demonstrates extinction-sensitive and extinction-resistant effects of footshock stress.

ABSTRACT: Stressful experiences can cause long-lasting sensitization of fear and anxiety that extends beyond the circumstances of the initial trauma. The neural mechanisms of these stress effects have been studied extensively in rats using the stress-enhanced fear learning (SEFL) paradigm, in which exposure to footshock stress potentiates subsequent fear conditioning. Here we establish a mouse version of the SEFL paradigm. Male and female 129s6 mice received four 1-mA footshocks or equivalent context exposure without shock. Shock exposure induced Pavlovian fear conditioning to the shock context and produced three more general effects: (1) suppression of open field exploration, (2) potentiated unconditioned fear of a novel tone stimulus, and (3) enhanced fear conditioning in a novel context. To determine whether these effects of footshock stress reflect generalized Pavlovian fear conditioning versus nonassociative fear sensitization, some mice received extinction training in the footshock stress context, which reduced contextual fear to the levels of unstressed control mice. Extinction restored normal open field exploration, suggesting that this effect of stress reflects generalized Pavlovian fear. In contrast, extinction failed to attenuate stress-enhanced fear, indicating that stress-enhanced fear is nonassociative and mechanistically distinct from Pavlovian fear conditioning. The effects of footshock stress were similar in male and female mice, although female mice displayed larger acute responses to fear-inducing stimuli than did males. The results demonstrate that footshock stress influences emotional behavior through distinct associative and nonassociative mechanisms, which likely involve unique neural underpinnings.

SUBMITTER: Hassien AM

PROVIDER: S-EPMC7006373 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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A mouse model of stress-enhanced fear learning demonstrates extinction-sensitive and extinction-resistant effects of footshock stress.

Hassien Alexa M AM Shue Francis F Bernier Brian E BE Drew Michael R MR

Behavioural brain research 20191127

Stressful experiences can cause long-lasting sensitization of fear and anxiety that extends beyond the circumstances of the initial trauma. The neural mechanisms of these stress effects have been studied extensively in rats using the stress-enhanced fear learning (SEFL) paradigm, in which exposure to footshock stress potentiates subsequent fear conditioning. Here we establish a mouse version of the SEFL paradigm. Male and female 129s6 mice received four 1-mA footshocks or equivalent context expo ...[more]

PMID: 31785363

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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:Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota1. In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases2. Alterations in the microbiota can also modulate host behaviours-such as social activity, stress, and anxiety-related responses-that are linked to diverse neuropsychiatric disorders3. However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders.

Dataset Information

A mouse model of stress-enhanced fear learning demonstrates extinction-sensitive and extinction-resistant effects of footshock stress.

Publications

A mouse model of stress-enhanced fear learning demonstrates extinction-sensitive and extinction-resistant effects of footshock stress.

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