Prefrontal inputs to the basolateral amygdala differentially regulate context-dependent fear renewal

초록

Fear is an adaptive emotion critical for survival, promoting safety through appropriate defensive responses. However, dysregulation of context-dependent fear modulation is a key contributor to anxiety and related disorders. While extinction therapy is effective treatment, its efficacy is limited by its intrinsic context-specificity; extinguished fear often re-emerges when the conditioned stimuli is encountered outside the extinction context, a phenomenon known as fear renewal. Although the mechanisms underlying fear acquisition and extinction have been extensively studied, the precise circuit- and cell type-specific bases of fear renewal poorly understood. In this study, we hypothesized that distinct neuronal populations within the basolateral amygdala (BLA), particularly those receiving projections from the prefrontal cortex regions, differentially modulate fear renewal. Using optogenetics, we found that inhibition of the prelimbic (PL)-to-BLA circuit suppressed fear renewal, whereas inhibition of the infralimbic (IL)-to-BLA circuit promoted renewal responses. Furthermore, fiber photometry revealed increased calcium activity in the PL-BLA circuit specifically during fear acquisition and renewal phases, highlighting its critical involvement in fear memory expression. . To examine whether BLA-projecting PFC neurons possess distinct molecular profiles, we employed trans-synaptic labeling using AAV serotype 1 to identify BLA neurons receiving prefrontal input, followed by single-cell RNA sequencing of the labeled cells. This approach revealed circuit-specific transcriptional signatures, offering new insight into the molecular mechanisms underlying projection-defined fear circuits. Together, these findings highlight functionally and molecularly distinct PFC-BLA pathways that mediate fear renewal, advancing our understanding of context-dependent fear modulation.