Learning not to fear: neural correlates of learned safety

Abstract

The ability to recognize and properly respond to instances of protection from impending danger is critical for preventing chronic stress and anxiety-central symptoms of anxiety and affective disorders afflicting large populations of people. Learned safety encompasses learning processes, which lead to the identification of episodes of security and regulation of fear responses. On the basis of insights into the neural circuitry and molecular mechanisms involved in learned safety in mice and humans, we describe learned safety as a tool for understanding neural mechanisms involved in the pathomechanisms of specific affective disorders. This review summarizes our current knowledge on the neurobiological underpinnings of learned safety and discusses potential applications in basic and translational neurosciences.

Figure 1

Fear conditioning and conditioned inhibition of fear are based upon associative learning process involving the conditioned stimulus (CS), the unconditioned stimulus, and conditioning context. (a) Classical conditioning paradigms based on associative learning involve the conditioning chamber where the training procedures are carried out which constitutes the conditioning context. During training, the unconditioned stimulus (US), which has an intrinsic valence (here, aversive such as a mild electric footshock) becomes associated with the CS (such as an auditory signal) that is a priori neutral. (b) During fear conditioning, the temporal pairing of the US and the CS induces a transfer of the fear-inducing properties from the US to the CS. Consecutively, the previously neutral stimulus CS and the conditioning context elicit the physiological and behavioral responses (such as freezing) inherent to the US. Conditioned inhibition of fear (or learned safety) is mediated by the temporal dissociations of the US and the CS, in a way that the two stimuli never coincide. Consequently, the presence of the conditioned inhibitor leads to a reduction of the fear response induced by the conditioning context.

Figure 2

Behavioral paradigms and readouts of learned safety in rodents. (a and b) Inescapable shock (off-set pairing) procedure to induce learned safety in rats. (a) Schematic illustration of the different shock and safety signal conditions used. Red filled bars represent the occurrence of tail shock, and green filled boxes indicate the occurrence of a safety CS (5 s chamber blackout) over time. In the Safe group, the CS was presented with the termination of each shock US. In the Random group, the CS was delivered independent of the shock schedule. In the variable group, shocks were delivered at the same schedule as in the Random group, but lights remained on throughout the session. Animals in the Fixed group received 100, 5 s shocks with the house light on throughout the session. Rats in the home cage control group (HC) were left undisturbed in their home cages and animals in HC-Random group remained in the home cage but were exposed to 100, 5 s blackouts in a room adjacent to the stress room. (b). Mean (±SEM) time spent exploring the juvenile conspecific in a 3 min test given 24 h after 100 tail shocks (Christianson et al, 2008). Group designations indicate the conditions of previous tail shocks. Pairwise comparisons identified significant differences between Safe and all other groups receiving shock. (c and d) Explicit unpairing procedure to induce learned safety in mice. (c) Schematic illustration of safety and fear conditioning used. Safety conditioning (upper panel) consisted of a simple conditioned inhibition of learned fear paradigm in which the delivery of four shock US is followed by the presentation of four tone CS. In the fear conditioning protocol (bottom panel), the number of CS and US presentations was matched to the safety conditioning paradigm (ie four paired CS–US). Training was conducted over a period of 3 days, one session per day. A memory recall test, consisting of a single CS presentation, was carried out 24 h after the last training day. (d) Contextual freezing in the presence of the CS in safety conditioned, fear conditioned, and tone alone control mice. *P<0.05, **P<0.01, ***P<0.001. Reproduced, with permission, from Christianson et al (2008) and Pollak et al (2008, 2010a).

Figure 3

Human paradigms and functional consequences of learned safety. (a) An explicit unpairing protocol: experimental paradigm and amygdala responses to the aversive stimulus. training and test phase: The training phase (left) consisted of several explicitly unpaired (bottom row) or paired (top row) presentations of the conditioned stimulus (CS) and the unconditioned stimulus (US) and was followed by a period of rest (middle) during which the structural MRI (magnetic resonance imaging) images were acquired. The test phase (right) consisted of five presentations of the CS alone (Pollak et al, 2010b). (b) A conditional discrimination procedure: diagram of the trial design in the AX+/BX− human paradigm. The training phase (left) consisted of four unpaired CS (B and X) alone (bottom row) and paired CS (A and X) presentations and the US (top row). The test phase (right) consisted of three presentations of the CS (A and B) (Jovanovic et al, 2010). (c) A cluster of differential activation in the left amygdala between safety and fear trained subjects in response to the CS is shown on a standard brain. Color codes indicate the t score=3.56 days. Mean fear-potentiated startle on AX+, BX−, and AB trials across diagnostic groups from three studies. Fear-potentiated startle in a traumatized civilian sample with post-traumatic stress disorders (PTSD) (n=29) and without PTSD (n=61) (Jovanovic et al, 2010). Reproduced, with permission, from Jovanovic et al (2010) and Pollak et al (2010b) (b) and (d).

Figure 4

Model for the potential neural circuitry mediating learned safety. In such a model, which is largely based on rodent studies, the sensory insular (Si) and posterior intralaminar nucleus (PIN) work in concert with the basolateral amygdala (BLA), leading to the inhibition of bed nucleus of the striatum terminals (BNSTIv) and possibly also to other output regions of amygdala (ie, the central gray (CG) and the lateral hypothalamus (LH)) to mediate the behavioral effects of learned safety. The sensory input of the signal used to induce learned safety is received by the thalamus and the sensory cortex, presumably also receiving direct sensory inputs, which project to the PIN and the Si. The Si projects directly to the BLA, which also receives input from the PIN and orchestrates the behavioral output through communications with the central amygdala (CeA). The PIN, furthermore, projects back to the thalamus and also transmits signals to the part of the caudoputamen (CP) lying dorsal to BLA, which may contribute to the emotional regulation of the behavioral output through its connection to the basal ganglia (BG). Cortical control mechanisms are thought to be mediated by the prefrontal cortex (PFC) through direct inhibitory constraints on the BLA but also by its interaction with the hippocampus (HIPP) required for gating the modulatory influences of prefrontal regions, hereby leading to an inhibition of the emotional response orchestrated by the amygdala during learned safety.