A prefrontal–bed nucleus pathway controls aversive memory specificity independently of glucocorticoids

Abstract Adaptive memory requires balancing generalization to avoid similar threats with discrimination to recognize safety. The prevailing view is that stress-induced increases in glucocorticoids underlie the enhancement of memory consolidation, strengthening memories and promoting their generalization—referred to here as the standard model. However, circuits that drive memory consolidation often also regulate glucocorticoid release, confounding whether their effects on memory are circuit-driven or hormonally mediated. Here we identify a prefrontal pathway that controls memory specificity independently of glucocorticoids. Using optogenetic manipulations in male rats, we found that post-training inhibition of the rostral prelimbic cortex (rPL) to anteroventral bed nuclei of the stria terminalis (avBST) pathway promoted contextual generalization in an inhibitory avoidance discrimination task without affecting memory strength. Although this manipulation further elevated corticosterone, it produced generalization even in adrenalectomized rats, demonstrating glucocorticoid independence. Conversely, post-training pathway excitation enhanced contextual discrimination. Recordings of calcium signals revealed context-specific engagement of both avBST and avBST-projecting rPL neurons during memory retrieval, with greater responses in the neutral than the aversive context. These findings reveal glucocorticoid-independent circuit control of memory specificity, setting boundary conditions on the standard model and demonstrating mechanistic heterogeneity that may inform stress-related disorders where memory generalization is a core feature.