Cortico-Striatal Activity Characterizes Human Safety Learning via Pavlovian Conditioned Inhibition

Abstract

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.

Translational approaches to the neurobiological study of conditional discrimination and inhibition: Implications for psychiatric disease.

“…While the VMPFC may be involved in the inhibition of prepotent responding—to salient or fearful stimuli—it may also be generally involved in the detection of salience. Recently, the precise neurocircuitry involved in conditioned inhibition was compared to regions engaged during the processing of a CS− cue, not in the context of inhibition (Laing et al, 2022). Results from this study show that conditioned inhibition trials engaged both threat-responsive regions (insula) as well as learning-related cortical regions (dorsolateral prefrontal cortex) in addition to canonical reward-related regions (striatum).…”

Hippocampal Involvement in Safety Signal Learning Varies With Anxiety Among Healthy Adults

“…Research that examines basic mechanisms underlying fear reduction, including investigations of normative anxiety in healthy humans, has the potential to inform optimization of current interventions for individuals with anxiety disorders. Past research in healthy humans ( 3 , 4 , 5 , 13 , 14 ), humans with posttraumatic stress disorder [( 15 ); for a review, see ( 16 )], and nonhuman animals ( 2 , 6 ) has suggested that SSL may serve as a novel mechanism for augmenting fear reduction. However, there is a crucial gap in the literature because the mechanisms that support SSL have not been examined in relation to normative anxiety.…”

“…Second, examining relationships between SSL and trait anxiety in a healthy sample is critical to advance the potential clinical utility of this work. While evidence across species has shown disrupted SSL in adult rodents ( 22 ) and human adults with posttraumatic stress disorder [( 13 ); for a review, see ( 14 )] and trauma exposure ( 13 ), the mechanisms that support SSL have not been examined in relation to normative anxiety. Lastly, studies on the neural bases of SSL have primarily relied on examinations of specific regions in isolation, such as lesions or fiber photometry in a specific brain region in nonhuman animals or region of interest (ROI) analyses in humans [for a review, see ( 2 )].…”

“…Lastly, studies on the neural bases of SSL have primarily relied on examinations of specific regions in isolation, such as lesions or fiber photometry in a specific brain region in nonhuman animals or region of interest (ROI) analyses in humans [for a review, see ( 2 )]. While important findings have emerged from this body of work, such as the potential involvement of the ventral hippocampal–prelimbic cortex pathway ( 6 ), a more exploratory approach investigating the neural correlates of SSL across the whole brain has the potential to yield a richer understanding of other regions or circuits in the brain that may contribute to SSL ( 1 , 14 ).…”

Pattern separation of fear extinction memory

“…To our knowledge, this represents the first direct evidence for pattern separation operations in extinction memory, replicating and extending evidence for pattern completion following conditioned fear ( Starita et al 2019 ). Identifying fear and safety with pattern completion and separation could facilitate further advances in extinction research, with broad implications for the characterization of safety learning ( Laing and Harrison 2021 ; Laing et al 2022b ). Our findings cohere with learning theory explanations for extinction relapse ( Bouton 1994 ), wherein fear renewal is caused by generalizability and intransigence of fear (stimulus–threat) value, which outcompetes rigid “stimulus–no threat” (safety) memory.…”