Effects of resveratrol in a chronic stress model of layer chicks: insights from transcriptomics, metabolomics, and network pharmacology

Chronic stress induces neuroinflammation, hypothalamic dysfunction, and behavioral abnormalities, contributing to depressive-like states. The function of resveratrol (RES), a natural polyphenolic compound with neuroprotective and antidepressant properties, remains underexplored in avian models. This study evaluated the effects of RES on chronic unpredictable mild stress (CUMS), induced depressive-like behaviors in layer chicks and elucidated underlying mechanisms through integrated multi-omics approaches. Behavioral assessments, including open field test (OFT), tonic immobility (TI), and attention bias test (ABT), confirmed that CUMS significantly suppressed body weight and induced depressive-like behaviors characterized by prolonged immobility and reduced exploratory activity (P < 0.05). RES administration dose-dependently mitigated these behavioral impairments. Histological analyses showed that RES alleviated neuronal damage, inhibited microglial activation, decreased the levels of pro-inflammatory cytokines IL-1β and TNF-α, and increased anti-inflammatory IL-10 levels (P < 0.05). Targeted metabolomics revealed that RES restored hypothalamic neurotransmitter balance by elevating serotonin (5-HT), acetylcholine (ACh), and tryptophan (Trp) levels, while reducing norepinephrine (NE) and glutamate (Glu) concentrations (P < 0.05). Network pharmacology identified 85 putative antidepressant targets of RES, and integration with 700 hypothalamic differentially expressed genes (DEGs) highlighted significant enrichment in NF-κB, MAPK, and PI3K-Akt-mTOR signaling pathways. Western blotting confirmed RES inhibited TLR4/p38 MAPK/NF-κB activation and enhanced phosphorylation of PI3K/Akt/mTOR components (P < 0.05). These findings demonstrate that RES attenuates CUMS induced depressive-like behaviors in layer chicks primarily by modulating neuroinflammation and neurotransmitter metabolism via the MAPK and PI3K-Akt-mTOR pathways, offering mechanistic insights and supporting RES as a nutritional intervention to improve stress resilience in poultry.