Good vibes keep worries at bay: a prefrontal-hypothalamic pathway engages positive affect to mitigate fear

Trauma-related neuropsychiatric disorders are commonly treated with exposure-based therapy, an approach based on fear extinction, in which fear memory and expression are suppressed by repeated exposure to the inciting fear stimulus. Fear extinction–focused research often investigates mechanisms of fear inhibition, but positive affect may also contribute to facilitating extinction. In this issue of the JCI, Lin et al. used activity-dependent neuronal labeling in a model of fear extinction to tag extinction-activated medial prefrontal cortex (mPFC) ensembles, identifying functionally distinct projections to the zona incerta (ZI) and supramamillary nucleus (SuM). While mPFC-ZI projections governed extinction retrieval, mPFC-SuM projections encoded positive affect and reinforced fear extinction persistence. Additionally, Lin et al. discovered that SIRT1-expressing mPFC-SuM extinction-recruited projections control extinction relapse vulnerability, showing that SIRT1 overexpression can be leveraged to reduce fear relapse. Overall, this study shows that key cortico-hypothalamic projections manage extinction retrieval and positive affect to promote fear extinction.