Work

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

Year: 2026

Type: article

Abstract: 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.

Source: Journal of Clinical Investigation

DOI: 10.1172/jci211427

Authors: Quan-Son Eric Le, Luis E. Rosas-Vidal

Language: English

Topic: Memory and Neural Mechanisms

Subfield: Cognitive Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $5,200

Funders: Northwestern University, National Alliance for Research on Schizophrenia and Depression, Feinberg School of Medicine