Extinction-recruited prefrontal-hypothalamic pathway encodes positive affect to sustain fear extinction in...

Effective psychotherapeutic interventions for post-traumatic stress disorder (PTSD) rely on fear extinction to suppress maladaptive fear responses, yet their long-term efficacy is limited by high relapse rates. Notably, extinction involves not only fear inhibition but also affective engagement. However, whether and how internal affective components contribute to extinction retrieval and long-term persistence remain unclear. Here, we demonstrate that positive affective experiences arising during extinction govern the long-term persistence of extinction and resistance to spontaneous recovery. We identify a subpopulation of medial prefrontal cortex (mPFC) extinction neurons projecting to supramammillary nucleus glutamatergic (SuMGlu) neurons that encodes positive affective experience during extinction and selectively governs long-term extinction persistence. This ensemble is spatially, anatomically, and transcriptionally distinct from mPFC extinction neurons projecting to zona incerta somatostatin-expressing (ZISST) neurons, which primarily support extinction retrieval. Transcriptomic profiling reveals enrichment of sirtuin 1 (Sirt1) within SuM-projecting extinction ensembles, and bidirectional manipulation of SIRT1 alters extinction relapse vulnerability in a PTSD mouse model. These findings provide a cortical-hypothalamic framework incorporating molecular features that governs the long-term persistence of fear extinction and resistance to relapse through positive affective processes.