Pattern differentiation and tuning shift in human sensory cortex underlie long-term threat memory

Abstract

The amygdala-prefrontal-cortex circuit has long occupied the center of the threat system,1 but new evidence has rapidly amassed to implicate threat processing outside this canonical circuit.2-4 Through nonhuman research, the sensory cortex has emerged as a critical substrate for long-term threat memory,5-9 underpinned by sensory cortical pattern separation/completion10,11 and tuning shift.12,13 In humans, research has begun to associate the human sensory cortex with long-term threat memory,14,15 but the lack of mechanistic insights obscures a direct linkage. Toward that end, we assessed human olfactory threat conditioning and long-term (9days) threat memory, combining affective appraisal, olfactory psychophysics, and functional magnetic resonance imaging (fMRI) over a linear odor-morphing continuum (five levels of binary mixtures of the conditioned stimuli/CS+ and CS- odors). Affective ratings and olfactory perceptual discrimination confirmed (explicit) affective and perceptual learning and memory via conditioning. fMRI representational similarity analysis (RSA) and voxel-based tuning analysis further revealed associative plasticity in the human olfactory (piriform) cortex, including immediate and lasting pattern differentiation between CS and neighboring non-CS and a late onset, lasting tuning shift toward the CS. The two plastic processes were especially salient and lasting in anxious individuals, among whom they were further correlated. These findings thus support an evolutionarily conserved sensory cortical system of long-term threat representation, which can underpin threat perception and memory. Importantly, hyperfunctioning of this sensory mnemonic system of threat in anxiety further implicates a hitherto underappreciated sensory mechanism of anxiety.