Chronic stress, anhedonia, and reward-circuit dysfunction in depression: Mechanisms, models, and novel therapeutic approaches

Chronic stress remains one of the most robust precipitants of major depressive disorder, in which anhedonia (the loss of motivation, pleasure, and interest) is a particularly disabling and treatment-resistant dimension. Converging evidence places the mesocorticolimbic reward system and connected hippocampal circuitry at the center of this pathology. Across the ventral tegmental area (VTA), nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and hippocampus, sustained stress and allostatic load disrupt dopaminergic and glutamatergic signaling, functionally decoupling motivation, hedonic capacity, and reward learning.Experimental paradigms such as unpredictable chronic mild stress (UCMS), social defeat, and corticosterone exposure now yield reproducible anhedonic phenotypes amenable to multilevel dissection, while transcriptomic, proteomic, and epigenetic profiling have revealed stress-responsive molecular signatures, implicating HPA-axis dysregulation, glucocorticoid receptor signaling, and neuroinflammatory mechanisms as upstream drivers. Yet the field remains fragmented: molecular, circuit-level, and behavioral findings are often studied in isolation, cross-species translation is incomplete, and sex-dependent trajectories are under-integrated across experimental modalities.This Research Topic aims to synthesize insights across molecular, circuit, and behavioral levels and to bridge preclinical and human research, connecting molecular remodeling of stress-exposed brain circuits with changes in motivational drive and reward processing.We encourage contributions that explicitly test mechanistic hypotheses linking molecular and cellular alterations to circuit and behavioral outputs, including sex-specific outcomes, and studies evaluating mechanism-anchored therapeutic strategies (e.g., pharmacological, phytotherapeutic, behavioral, and nutritional) designed to restore motivation and hedonic function through targeted modulation of reward-circuit dynamics.We welcome interdisciplinary contributions addressing, but not limited to, the following subthemes:• Reward-circuit architecture and dysfunction in depression: mesocorticolimbic dopamine and the VTA–NAc–mPFC–hippocampus axis under chronic stress.• Motivational, consummatory, and anticipatory components of anhedonia: effort-based decision-making, stress-induced motivational deficits, and computational frameworks.• Animal models of stress-induced anhedonia: UCMS, chronic restraint and social defeat, corticosterone exposure, and translational behavioral readouts.• Endocrine and immune drivers of anhedonia: HPA axis dysregulation, glucocorticoid signaling, and stress-driven neuroinflammation (IL-6, TNF-α, inflammatory subtype of depression).• Molecular and cellular signatures of stress-induced anhedonia: transcriptomic, proteomic, and epigenetic remodeling (including alternative splicing); adult hippocampal neurogenesis, glial dynamics, and neurotrophic signaling (BDNF and beyond); leveraging single-cell and spatial approaches.• Sex-dependent molecular and behavioral trajectories of stress-induced anhedonia.• From animal molecular phenotypes to human biomarkers of stress-related anhedonia: peripheral, neuroimaging, and model-derived computational markers.• Novel therapeutic and preventive approaches: rapid-acting antidepressants, kappa-opioid antagonists, anti-inflammatory strategies, herbal and phytotherapeutic compounds, and behavioral and nutritional stress-resilience interventions. Topic editors: Ravid Doron, Grzegorz R Juszczak Source: https://www.frontiersin.org/research-topics/81516/chronic-stress-anhedonia-and-reward-circuit-dysfunction-in-depression-mechanisms-models-and-novel-therapeutic-approaches