Fear attenuation collaborations to optimize translation

Abstract

Here, we describe the efforts we dedicated to the challenge of modifying entrenched emotionally laden memories. In recent years, through a number of collaborations and using a combination of behavioral, molecular, and computational approaches, we: (a) developed novel approaches to fear attenuation that engage mechanisms that differ from those engaged during extinction (Monfils), (b) examined whether our approaches can generalize to other reinforcers (Lee, Gonzales, Chaudhri, Cofresi, and Monfils), (c) derived principled explanations for the differential outcomes of our approaches (Niv, Gershman, Song, and Monfils), (d) developed better assessment metrics to evaluate outcome success (Shumake and Monfils), (e) identified biomarkers that can explain significant variance in our outcomes of interest (Shumake and Monfils), and (f) developed better basic research assays and translated efforts to the clinic (Smits, Telch, Otto, Shumake, and Monfils). We briefly highlight each of these milestones and conclude with final remarks and extracted principles. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Figure 1.

Initial CS presentations during extinction and retrieval-extinction both activate the prefrontal cortex (PFC) and amygdala; however, as the procedures progress, their patterns of neural activation diverge. Extinction continues to engage the PFC while retrieval-extinction does not. While both paradigms continue to activate the amygdala, retrieval-extinction activates the same cells that were originally active during fear acquisition. Upon test, extinction relies upon the PFC to suppress the fear memory in the amygdala, resulting in a return of conditioned response. Retrieval-extinction is thought to update the original fear memory in the amygdala, preventing the return of fear (Clem and Huganir 2010; Monfils et al., 2009; Monfils and Holmes 2018). Created with BioRender.com.

Figure 2.

Adapted from Shumake et al., 2018 showing phenotypic extinction subgroups identified by cluster analysis of 215 subjects. Each panel indicates a subgroup with similar freezing trajectories, ordered from largest group (top) to smallest group (bottom). Black lines depict the median freezing behavior for each subgroup across three phases of training (24 hr after acquisition, end of extinction, and 24 hr after reinstatement). The horizontal dashed line indicates data-driven criteria for fear remission (37.5%). Subgroup 1: Mild initial fear with successful extinction and long-term fear reduction (20% of sample). Subgroup 2: Severe initial fear with moderately successful extinction followed by return of fear (20% of sample). Subgroup 3: Mild initial fear with largely successful extinction followed by return of fear (15% of sample). Subgroup 4: Severe initial fear with largely successful extinction and long-term fear reduction (13% of sample). Subgroup 5: Severe, persistent fear (13% of sample). Subgroup 6: Fear incubation (12% of sample). Subgroup 7: A more extreme version of Subgroup 2 (8% of sample).