Prefrontal inputs to the basolateral amygdala mediate the fear renewal

초록

Fear is an emotion directly associated with safety avoiding danger through appropriate fear responses. There are some fear-related disorders caused by abnormal context-dependent modulation. Extinction therapy is suggested as an effective behavioral treatment for fear-related disorders. However, it has limitations due to the intrinsic property that extinction is highly context-specific. While repetitive exposure can weaken fear, extinguished fear relapses when encountering a conditioned stimulus outside the context of extinction, a phenomenon termed fear renewal. However, precise circuit- and cell type-specific mechanisms in BLA underlying the renewal paradigm are not relatively understood than acquisition and extinction of fear. In this study, we hypothesized that the ‘fear’- neuron population in the amygdala, receiving prefrontal inputs, might have distinct functional roles during the fear renewal. Using an optogenetic method, we reveal that the inactivation of PL-BLA circuits prevents fear renewal, whereas the inactivation of IL-BLA projection promotes fear renewal response. Moreover, we tried to discover candidate representative molecules based on presynaptic regions projecting to the BLA through single-cell RNA sequencing. Single-cell RNA sequencing, unlike existing RNA-seq, can distinguish between changes in circuit-specific cell sub-population and circuit-specific gene expression changes. In this way, key regulatory genes can be identified by obtaining genotypic and phenotypic heterogeneity information at the specific BLA circuit. Our study suggests a functional circuit and its projection-specific molecular and physiological underpinning of the fear renewal in the BLA.