Inhibition of Fear by Learned Safety Signals: A Mini-Symposium Review

Christianson, John P.; Fernando, Anushka B. P.; Kazama, Andrew M.; Jovanović, Tanja; Ostroff, Linnaea E.; Sangha, Susan

doi:10.1523/jneurosci.3340-12.2012

Cited by 156 publications

(139 citation statements)

References 81 publications

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“…Our rodent model safety signal conforms to safety-signal mechanisms involving modulation of BLA activity to reduce behavioral and physiological responses to stressors (30,31,34). Our findings suggest that the mechanism underlying the complex interplay between infant trauma-linked cues and later-life depressive-like behavior involves an amygdala 5-HT/CORT interaction that positively modulates the neurobehavioral dysregulation stemming from early-life trauma (Fig.…”

Section: Mechanisms Underlying Modulation Of Adult Neurobehavioral Fusupporting

confidence: 62%

“…The amygdala is a principal target of safety signals (35,37), which inhibit amygdala output to provide relief from fearful states (30,34,38).…”

Section: Significancementioning

confidence: 99%

“…Intriguingly, these effects converge with the safety-signal literature. A safety signal is a learned sensory cue that can reduce stress and attenuate amygdala-dependent fear learning by being negatively correlated to an aversive event (30,31) or positively correlated with an attachment formed in infancy or adulthood (32,33). Indeed, safety signals attenuate fear learning and expression in humans, nonhuman primates, and rodents (18,31,34,35) and reduce depressive-like behaviors in rodents (12,19,36).…”

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confidence: 99%

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Enduring good memories of infant trauma: Rescue of adult neurobehavioral deficits via amygdala serotonin and corticosterone interaction

Rincón-Cortés

Barr

Mouly

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Children form a strong attachment to their caregiver-even when that caretaker is abusive. Paradoxically, despite the trauma experienced within this relationship, the child develops a preference for trauma-linked cues-a phenomenon known as trauma bonding. Although infant trauma compromises neurobehavioral development, the mechanisms underlying the interaction between infant trauma bonding (i.e., learned preference for trauma cues) and the long-term effects of trauma (i.e., depressive-like behavior, amygdala dysfunction) are unknown. We modeled infant trauma bonding by using odor-shock conditioning in rat pups, which engages the attachment system and produces a life-long preference for the odor that was paired with shock. In adulthood, this trauma-linked odor rescues depressive-like behavior and amygdala dysfunction, reduces corticosterone (CORT) levels, and exerts repair-related changes at the molecular level. Amygdala microarray after rescue implicates serotonin (5-HT) and glucocorticoids (GCs), and a causal role was verified through microinfusions. Blocking amygdala 5-HT eliminates the rescue effect; increasing amygdala 5-HT and blocking systemic CORT mimics it. Our findings suggest that infant trauma cues share properties with antidepressants and safety signals and provide insight into mechanisms by which infant trauma memories remain powerful throughout life.E arly-life trauma is associated with compromised neurobehavioral development and vulnerability to later-life psychiatric disorders like depression (1-5). Long-lasting effects of infant trauma relevant to depression include disruptions in social behavior, alterations in the serotonin (5-HT) system, and amygdala dysfunction (2, 5-8), which have been replicated by animal models (9-15). Paradoxically, trauma-linked cues-even those associated with abusive attachment-can elicit strong attraction and feelings of comfort in humans (16,17). Furthermore, a lifelong attraction to trauma-linked cues has also been demonstrated in rodent models of infant trauma, which suggests that sensory cues learned during infancy alter adult behaviors and amygdala activity (12,18,19).To explore the enduring effects of infant trauma and the mechanisms underlying their modulation by infant trauma-linked cues, we used an odor-learning paradigm during the sensitive period for attachment learning in rat pups, postnatal (PN) days 8-12, which is characterized by rapid and robust odor-preference learning that extends to aversive stimuli (14,(20)(21)(22). Specifically, we used infant olfactory classical conditioning in which a novel peppermint odor is paired with a mild shock (0.5 mA, 1s) to produce a preferred odor that functions behaviorally as a maternal odor and results in neural activation comparable with that induced by natural maternal odor (20,(23)(24)(25). During the sensitive period, low endogenous levels of corticosterone (CORT) and attenuated shock-induced CORT release prevent the infant amygdala from exhibiting the learning-induced plasticity required for avoidance learning (1...

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Section: Mechanisms Underlying Modulation Of Adult Neurobehavioral Fusupporting

confidence: 62%

“…The amygdala is a principal target of safety signals (35,37), which inhibit amygdala output to provide relief from fearful states (30,34,38).…”

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

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Enduring good memories of infant trauma: Rescue of adult neurobehavioral deficits via amygdala serotonin and corticosterone interaction

Rincón-Cortés

Barr

Mouly

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Lesions of the posterior (i.e., parietal) insular cortex impair fear learning as measured by fear potentiated startle (Shi and Davis 1999) but not when measured via freezing (Lanuza et al 2004), whereas lesions of the anterior insular, that encompassed the RAIC, significantly augment fear learning when assessed via freezing (Lacroix et al 2000). More recently, lesions of the posterior insular region reduced the anxiety-relieving properties of a safety signal (Christianson et al 2011(Christianson et al , 2012. In these experiments, the group differences in pMAPK-IR and also the effects of PD098059 infusion were largest during counterconditioning, as opposed to normal fear conditioning.…”

Section: Discussionmentioning

confidence: 99%

Neural correlates of appetitive–aversive interactions in Pavlovian fear conditioning

Nasser

McNally

2013

Learn. Mem.

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We used Pavlovian counterconditioning in rats to identify the neural mechanisms for appetitive -aversive motivational interactions. In Stage I, rats were trained on conditioned stimulus (CS) -food (unconditioned stimulus [US]) pairings. In Stage II, this appetitive CS was transformed into a fear CS via pairings with footshock. The development of fear responses was retarded in rats that had received Stage I appetitive training. This counterconditioning was associated with increased levels of phosphorylated mitogen activated protein kinase immunoreactivity (pMAPK-IR) in several brain regions, including midline thalamus, rostral agranular insular cortex (RAIC), lateral amygdala, and nucleus accumbens core and shell, but decreased expression in the ventrolateral quadrant of the midbrain periaqueductal gray. These brain regions showing differential pMAPK-IR have previously been identified as part of the fear prediction error circuit. We then examined the causal role of RAIC MAPK in fear learning and showed that Stage II fear learning was prevented by RAIC infusions of the MEK inhibitor PD098059 (0.5 mg/hemisphere). Taken together, these results show that there are opponent interactions between the appetitive and aversive motivational systems during fear learning and that the transformation of a reward CS into a fear CS is linked to heightened activity in the fear prediction error circuit.

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“…However, typically when cues are repeatedly paired with unconditioned aversive stimuli, they are avoided or the cue itself starts to induce fear or anxiety responses (Maren and Quirk, 2004;Thielen and Shekhar, 2002). As the presence of the FP reduces anxiety-like behavior, the partner rat may be acting as a safety cue, in which case SFiA could be considered a form of safety learning (Christianson et al, 2012). In support of this concept, it was observed that the context during the repeated exposures to a conspecific determined the extent to which anxiolysis would result upon subsequent exposures.…”

Section: Social Familiarity and Safety Cuesmentioning

confidence: 99%

The Role of the Medial Prefrontal Cortex in Regulating Social Familiarity-Induced Anxiolysis

Lungwitz

Stuber

Johnson

et al. 2013

Neuropsychopharmacol

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Overcoming specific fears and subsequent anxiety can be greatly enhanced by the presence of familiar social partners, but the neural circuitry that controls this phenomenon remains unclear. To overcome this, the social interaction (SI) habituation test was developed in this lab to systematically investigate the effects of social familiarity on anxiety-like behavior in rats. Here, we show that social familiarity selectively reduced anxiety-like behaviors induced by an ethological anxiogenic stimulus. The anxiolytic effect of social familiarity could be elicited over multiple training sessions and was specific to both the presence of the anxiogenic stimulus and the familiar social partner. In addition, socially familiar conspecifics served as a safety signal, as anxiety-like responses returned in the absence of the familiar partner. The expression of the social familiarity-induced anxiolysis (SFiA) appears dependent on the prefrontal cortex (PFC), an area associated with cortical regulation of fear and anxiety behaviors. Inhibition of the PFC, with bilateral injections of the GABA A agonist muscimol, selectively blocked the expression of SFiA while having no effect on SI with a novel partner. Finally, the effect of D-cycloserine, a cognitive enhancer that clinically enhances behavioral treatments for anxiety, was investigated with SFiA. D-cycloserine, when paired with familiarity training sessions, selectively enhanced the rate at which SFiA was acquired. Collectively, these outcomes suggest that the PFC has a pivotal role in SFiA, a complex behavior involving the integration of social cues of familiarity with contextual and emotional information to regulate anxiety-like behavior.

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Inhibition of Fear by Learned Safety Signals: A Mini-Symposium Review

Cited by 156 publications

References 81 publications

Enduring good memories of infant trauma: Rescue of adult neurobehavioral deficits via amygdala serotonin and corticosterone interaction

Enduring good memories of infant trauma: Rescue of adult neurobehavioral deficits via amygdala serotonin and corticosterone interaction

Neural correlates of appetitive–aversive interactions in Pavlovian fear conditioning

The Role of the Medial Prefrontal Cortex in Regulating Social Familiarity-Induced Anxiolysis

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