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.
Matthew T. Birnie, Lara Taniguchi, Lia M. Harvey et al.· bioRxiv· 0 citations
Predictability, the degree to which environmental inputs are structured, patterned, and reliably signaled over time, has emerged as a central dimension of early experience with unique implications for brain development, stress physiology, and mental health. This review synthesizes convergent evidence from human and animal studies to argue that predictability is intrinsic to optimal brain development. Thus, unpredictable signals from the proximate environment—parents, family, and neighborhood—are a type of early-life adversity that is distinct from, for example, threat or deprivation. We first delineate what predictability means in developmental science, distinguishing it from valence and intensity. We then summarize multilevel mechanisms, from epigenomic regulation to circuit-level adaptions, by which predictable versus unpredictable signals shape developmental trajectories. We consider predictable structure against the backdrop of established types of early-life adversity, examining how resource scarcity, caregiver stress, and chaotic routines create unpredictable patterns that link to childhood and adult psychopathology. Building on conceptual and methodological work in human study cohorts and large populations as well as experimental animals, we discuss how to measure unpredictability (e.g., signal entropy, ecological assessments, questionnaires) and highlight sensitive windows when predictability is crucial for brain maturation. Finally, we propose paths for translational research and prevention of unpredictability-related sequelae on cognitive and mental health.
Mason Hardy, T. Baram· Annual Review of Development...· 0 citations