Disrupted neuropeptide-signaling drives enduring reward deficits after early-life stress

While brain systems mediating acute stress are essential for survival, chronic early-life stress (ELA) may lead to poor ability to experience pleasure (anhedonia), a core feature of depression. For decades, the stress neuropeptide corticotropin-releasing hormone (CRH) has been a target for treating depression, however the failure of several clinical trials blocking CRH receptor 1 (CRHR1) has left the therapeutic role of CRH signaling a major unresolved mystery. Here, we uncover the signaling plasticity behind this enigma with the use of in vivo G protein-coupled activation-based (GRAB) imaging and viral-genetic and pharmacological mechanistic manipulations. We find CRH signaling via CRHR1 indeed disrupts reward behaviors in naïve mice, but is dysregulated in ‘anhedonic’ mice with a history of ELA. Instead, activation of CRH receptor 2 (CRHR2) reverses anhedonia-like behaviors in adult ELA mice. These findings redefine our understanding of stress-mediated anhedonia and provide a precise, novel therapeutic target for stress-related mental illness.