Cortico-striatal activity characterizes human safety learning via Pavlovian conditioned inhibition

Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviours. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (UHF) fMRI to examine the neural basis of inhibitory safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat-omission when paired with a known threat signal (A+/AX-), and a standard safety signal that generally predicted threat-omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation. The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular and dorsolateral prefrontal cortex compared to the standard safety signal, whereas the latter evoked greater activation of the ventromedial prefrontal cortex, posterior cingulate and hippocampus, among other regions. Further analyses of the conditioned inhibitor indicated that its initial learning was characterized by consistent engagement of dorsal striatal, midbrain, thalamic, premotor, and prefrontal subregions. These findings suggest that safety learning via conditioned inhibition involves a distributed cortico-striatal circuitry, separable from broader cortical regions involved with processing standard safety signals (e.g., CS-). This cortico-striatal system could represent a novel neural substrate of safety learning, underlying the initial generation of stimulus-safety associations, distinct from wider cortical correlates of safety processing, which facilitate the behavioral outcomes of learning.

Assessing the inhibitory properties of a latent inhibitor in flavor-aversion learning

In Experiment 1, rats received 16 nonreinforced trials of exposure to a flavor (A) that was subsequently used as the conditioned stimulus in flavor-aversion conditioning. In the critical condition, Flavor A was presented in compound with a different novel flavor on each of the eight daily trials. This treatment produced latent inhibition, in that this preexposure retarded conditioning just as did 16 trials with A alone. Rats in the control conditions, given no preexposure or exposure just to the sequence of novel flavors, learned readily. Experiment 2 examined the effects of these forms of preexposure on performance on a summation test, in which Flavor A was presented in compound with a separately conditioned flavor (X). The preexposure procedure in which A was presented along with novel flavors rendered A effective in inhibiting the response conditioned to X on that test. The conclusion, that this form of training can establish the target stimulus as a conditioned inhibitor, is predicted by the account of latent inhibition put forward by Hall and Rodríguez (2010) which proposes that the latent inhibition effect is a consequence both of a reduction in the associability of the stimulus and of a process of inhibitory associative learning that opposes the initial expectation that a novel event will be followed by some consequence.

The effect of conditioned inhibitors and preexposed cues on the outcome-specific Pavlovian-to-instrumental transfer effect in humans

Using a human Pavlovian-to-instrumental transfer (PIT) task, Alarcón and Bonardi showed that the selective elevation of instrumental responding produced by excitatory transfer cues was reduced when these cues were presented with a conditioned inhibitor (CI), relative to a control cue that was simply preexposed. However, previous research has shown that preexposed cues might also acquire inhibitor-like properties. This study aimed to contrast the inhibitory properties of CIs and preexposed cues, using novel stimuli as controls, in summation and PIT tests. Participants were trained to perform two actions, each reinforced with a distinct outcome (O1 or O2). Two images were trained as CIs, each signalling the absence of one of the outcomes, by presenting them with a cue that was otherwise followed by that outcome (e.g., A→O1, AI→no O1). In contrast, the preexposed cues were simply presented in the absence of the outcomes. In the summation test, participants rated the likelihood of the outcomes in the presence of two independently trained excitatory cues, each presented with a CI, a preexposed cue, or a novel stimulus. Similarly, in the PIT test, participants performed both actions in the presence and absence of these compounds. In the summation test, the CIs and the preexposed cues reduced participants’ expectations of the outcomes more than the novel stimuli. However, in the PIT test, only the CIs reduced the selective elevation of responding produced by the transfer cues. These results might reflect distinct properties of stimuli trained as CIs and those simply preexposed.