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

Birnie, M. T.; Taniguchi, L.; Harvey, L. M.; Tetzlaff, M.; Mattioni, L.; Floriou-Servou, A.; Thiagarajan, N.; Angeles, g.; Daglian, J.; Chen, Y.; Baram, T. Z.

doi:10.64898/2026.08.26.747402

bioRxiv · 10.64898/2026.08.26.747402

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

Birnie, M. T.·Taniguchi, L.·Harvey, L. M.·Tetzlaff, M.·Mattioni, L.·Floriou-Servou, A.·Thiagarajan, N.·Angeles, g.·Daglian, J.·Chen, Y.·Baram, T. Z.

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Abstract

Whereas 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 receptor1 (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 that CRH signaling via CRHR1 indeed disrupts reward behaviors in control mice, but is disrupted 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.

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Birnie, M. T., Taniguchi, L., Harvey, L. M., Tetzlaff, M., Mattioni, L., Floriou-Servou, A., Thiagarajan, N., Angeles, g., Daglian, J., Chen, Y., Baram, T. Z.. 2026-08-27. Disrupted neuropeptide-signaling drives enduring reward deficits after early-life stress. https://doi.org/10.64898/2026.08.26.747402

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