Travis D. Goode

Animal Models of Fear Relapse

Whereas fear memories are rapidly acquired and enduring over time, extinction memories are slow to form and are susceptible to disruption. Consequently, behavioral therapies that involve extinction learning (e.g., exposure therapy) often produce only temporary suppression of fear and anxiety. This review focuses on the factors that are known to influence the relapse of extinguished fear. Several phenomena associated with the return of fear after extinction are discussed, including renewal, spontaneous recovery, reacquisition, and reinstatement. Additionally, this review describes recent work, which has focused on the role of psychological stress in the relapse of extinguished fear. Recent developments in behavioral and pharmacological research are examined in light of treatment of pathological fear in humans.

Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear

The medial prefrontal cortex (mPFC) has been implicated in the extinction of emotional memories, including conditioned fear. We found that ventral hippocampal (vHPC) projections to the infralimbic (IL) cortex recruited parvalbumin-expressing interneurons to counter the expression of extinguished fear and promote fear relapse. Whole-cell recordings ex vivo revealed that optogenetic activation of vHPC input to amygdala-projecting pyramidal neurons in the IL was dominated by feed-forward inhibition. Selectively silencing parvalbumin-expressing, but not somatostatin-expressing, interneurons in the IL eliminated vHPC-mediated inhibition. In behaving rats, pharmacogenetic activation of vHPC→IL projections impaired extinction recall, whereas silencing IL projectors diminished fear renewal. Intra-IL infusion of GABA receptor agonists or antagonists, respectively, reproduced these effects. Together, our findings describe a previously unknown circuit mechanism for the contextual control of fear, and indicate that vHPC-mediated inhibition of IL is an essential neural substrate for fear relapse.Neurons in the ventral hippocampus project to parvalbumin inhibitory interneurons in the infralimbic (IL) region of medial prefrontal cortex. Activation of this projection produces feed-forward inhibition of IL and causes relapse of extinguished fear.

Enhancement of striatum-dependent memory by conditioned fear is mediated by beta-adrenergic receptors in the basolateral amygdala.

Emotional arousal can have a profound impact on various learning and memory processes. For example, unconditioned emotional stimuli (e.g., predator odor or anxiogenic drugs) enhance dorsolateral striatum (DLS)-dependent habit memory. These effects critically depend on a modulatory role of the basolateral complex of the amygdala (BLA). Recent work indicates that, like unconditioned emotional stimuli, exposure to an aversive conditioned stimulus (CS) (i.e., a tone previously paired with shock) can also enhance consolidation of DLS-dependent habit memory. The present experiments examined whether noradrenergic activity, particularly within the BLA, is required for a fear CS to enhance habit memory consolidation. First, rats underwent a fear conditioning procedure in which a tone CS was paired with an aversive unconditioned stimulus. Over the course of the next five days, rats received training in a DLS-dependent water plus-maze task, in which rats were reinforced to make a consistent body-turn response to reach a hidden escape platform. Immediately after training on days 1–3, rats received post-training systemic (Experiment 1) or intra-BLA (Experiment 2) administration of the β-adrenoreceptor antagonist, propranolol. Immediately after drug administration, half of the rats were re-exposed to the tone CS in the conditioning context (without shock). Post-training CS exposure enhanced consolidation of habit memory in vehicle-treated rats, and this effect was blocked by peripheral (Experiment 1) or intra-BLA (Experiment 2) propranolol administration. The present findings reveal that noradrenergic activity within the BLA is critical for the enhancement of DLS-dependent habit memory as a result of exposure to conditioned emotional stimuli.

Reversible Inactivation of the Bed Nucleus of the Stria Terminalis Prevents Reinstatement But Not Renewal of Extinguished Fear

Abstract The extinction of conditioned fear is labile. For example, fear to an extinguished conditioned stimulus (CS) returns after presentation of an aversive stimulus (“reinstatement”) or a change in context (“renewal”). Substantial research implicates the bed nucleus of the stria terminalis (BNST) in the stress-induced relapse of extinguished behaviors, such as in instrumental drug seeking, but its role in the relapse of extinguished fear responses is not clear. Here, we explored the role of the BNST in both the reinstatement and renewal of fear, two forms of relapse that are differentially triggered by stress. In Experiment 1, rats received pairings of an auditory CS and footshock unconditioned stimulus (US) followed by an extinction procedure. After extinction, rats received an unsignaled US to reinstate fear to the extinguished CS. Twenty-four hours later, they were infused with either muscimol or vehicle into the BNST immediately prior to a CS retrieval test. In Experiment 2, rats were conditioned and extinguished in two distinct contexts. Twenty-four hours after extinction, the rats were infused with muscimol, NBQX, or vehicle immediately prior to a CS retrieval test in either the extinction context or a different (but familiar) context. In both experiments, freezing behavior served as the index of conditioned fear. The results revealed that BNST inactivation prevented reinstatement (Experiment 1), but not renewal (Experiment 2), of conditioned freezing to the extinguished CS. Hence, the BNST is critical for the reinstatement of extinguished fear in an aversive context, but not for the contextual retrieval processes that mediate fear renewal.

Extinction after fear memory reactivation fails to eliminate renewal in rats

HighlightsConditioned stimulus (CS) retrieval 1 h prior to extinction did not prevent fear renewal.Pre‐extinction exposure to the conditioning context did not disrupt fear renewal.Unconditioned stimulus (US) exposure prior to extinction enhanced baseline fear but did not eliminate renewal.A conditioning trial prior to extinction enhanced fear across training but did not block renewal. Abstract Retrieving fear memories just prior to extinction has been reported to effectively erase fear memories and prevent fear relapse. The current study examined whether the type of retrieval procedure influences the ability of extinction to impair fear renewal, a form of relapse in which responding to a conditional stimulus (CS) returns outside of the extinction context. Rats first underwent Pavlovian fear conditioning with an auditory CS and footshock unconditional stimulus (US); freezing behavior served as the index of conditioned fear. Twenty‐four hours later, the rats underwent a retrieval‐extinction procedure. Specifically, 1 h prior to extinction (45 CS‐alone trials; 44 for rats receiving a CS reminder), fear memory was retrieved by either a single exposure to the CS alone, the US alone, a CS paired with the US, or exposure to the conditioning context itself. Over the next few days, conditional freezing to the extinguished CS was tested in the extinction and conditioning context in that order (i.e., an ABBA design). In the extinction context, rats that received a CS + US trial before extinction exhibited higher levels of conditional freezing than animals in all other groups, which did not differ from one another. In the renewal context, all groups showed renewal, and none of the reactivation procedures reduced renewal relative to a control group that did not receive a reactivation procedure prior to extinction. These data suggest retrieval‐extinction procedures may have limited efficacy in preventing fear renewal.

Bed nucleus of the stria terminalis mediates fear to ambiguous threat signals

Anxiety is characterized by a fear of potential future threats. The bed nucleus of the stria terminalis (BNST) has been implicated in anxiety, but its role in processing ambiguous threats is unclear. Here we examined whether the BNST mediates conditioned freezing to conditioned stimuli (CSs) that poorly predict the onset of aversive unconditioned stimuli (USs) in rats. Reversible inactivation of the BNST selectively reduced freezing to CSs that poorly predicted US onset (e.g., a backward CS that followed the US), but did not affect freezing to forward CSs even when they predicted USs of variable intensity. Importantly, backward (but not forward) CSs selectively increased Fos in the ventral BNST and in BNST-projecting neurons in the infralimbic region of the medial prefrontal cortex (mPFC), but not in the hippocampus or amygdala. These data reveal that BNST circuits process ambiguous threat signals central to the etiology and expression of anxiety. IMPACT STATEMENT The bed nucleus of the stria terminalis (BNST) is required for the expression of defensive behavior to uncertain threats, a function that is central to pathological anxiety.

Neural Circuits for Fear Relapse

Abstract Humans and other animals rapidly associate environmental cues with aversive outcomes. However, learned fear responses are slow to attenuate, and the fear memory itself may be difficult or impossible to erase. Indeed the relapse of previously extinguished fear is a widespread phenomenon and poses a great challenge to the long-term efficacy of therapies for fear-related pathologies in humans. This chapter provides an updated account of the neurobiological basis of fear relapse, with particular emphasis on circuits within and among the amygdala, bed nucleus of the stria terminalis, hippocampus, and prefrontal cortex.

Common neurocircuitry mediating drug and fear relapse in preclinical models

BackgroundComorbidity of anxiety disorders, stressor- and trauma-related disorders, and substance use disorders is extremely common. Moreover, therapies that reduce pathological fear and anxiety on the one hand, and drug-seeking on the other, often prove short-lived and are susceptible to relapse. Considerable advances have been made in the study of the neurobiology of both aversive and appetitive extinction, and this work reveals shared neural circuits that contribute to both the suppression and relapse of conditioned responses associated with trauma or drug use.ObjectivesThe goal of this review is to identify common neural circuits and mechanisms underlying relapse across domains of addiction biology and aversive learning in preclinical animal models. We focus primarily on neural circuits engaged during the expression of relapse.Key findingsAfter extinction, brain circuits involving the medial prefrontal cortex and hippocampus come to regulate the expression of conditioned responses by the amygdala, bed nucleus of the stria terminalis, and nucleus accumbens. During relapse, hippocampal projections to the prefrontal cortex inhibit the retrieval of extinction memories resulting in a loss of inhibitory control over fear- and drug-associated conditional responding.ConclusionsThe overlapping brain systems for both fear and drug memories may explain the co-occurrence of fear and drug-seeking behaviors.

Distinct Activity Patterns of the Human Bed Nucleus of the Stria Terminalis and Amygdala during Fear Learning

The amygdala and, more recently, also the bed nucleus of the stria terminalis, have been widely implicated in fear and anxiety. Much of our current knowledge is derived from animal studies and suggests an intricate convergence and divergence in functions related to defensive responding. In a recent paper, Klumpers and colleagues set out to examine these functions in a human fear learning procedure using functional magnetic resonance imaging. Their main findings were a role for the bed nucleus of the stria terminalis in threat anticipation, and for the amygdala in threat confrontation. Here, we provide a critical summary of this interesting study and point out some important issues that were not addressed by its authors. In particular, we first take a closer look at the striking differences between both samples that were combined for the study, and, secondly, we provide an in-depth discussion of their findings in relation to existing neurobehavioral models.