Peptide signaling in the paraventricular thalamus is essential for disrupted adult reward behaviors consequent to early-life adversity.

Abstract

Early-life adversity (ELA) is strongly linked to emotional disorders characterized by dysregulated reward behaviors. However, the mechanisms by which transient neonatal experiences generate enduring, sex-specific alterations in brain function remain unresolved. Paraventricular thalamus (PVT) neurons are selectively activated during ELA and contribute to disrupted adult reward behaviors. Here, we explore the molecular mechanisms behind these enduring, sex-specific disruptions. Combining activity-dependent genetic labeling with translating ribosome affinity purification, we find distinct gene translation programs in ELA and control mice of both sexes. Notably, the receptor for the neuropeptide corticotropin-releasing hormone receptor type 1 (Crhr1), is differentially expressed across rearing and sex in response to reward. CRISPR-Cas9-mediated Crhr1 deletion exclusively in early-life-activated PVT neurons normalizes reward behaviors in both male and female adult ELA mice. Thus, CRHR1 signaling in adult PVT neurons activated by ELA is a required and potentially targetable mechanism underlying sex-specific, ELA-induced disruptions of reward behaviors.