Screening of Antidepressant Active Components from Thymus quinquecostatus and the Underlying Mechanisms Based on Neural Stem Cell and Glial Cell Plasticity

This study aimed to screen the active components of Thymus quinquecostatus with antidepressant effects and to explore the underlying mechanisms based on hippocampal neuroplasticity. A chronic restraint stress (CRS) mouse model of depression was established. The intervention effects of five active components—thyme volatile oil, thymol, carvacrol, p-cymene, and β-caryophyllene (BCP)—were systematically evaluated using behavioral, endocrine, histomorphological, and molecular approaches (50 mg/kg, intraperitoneal injection, once daily for 14 days). All active components significantly reduced serum corticosterone levels (decreased by 27.1%–64.7%, P < 0.001) and increased the sucrose preference rate (increased by 39.5%–55%, P < 0.05). Thymol, carvacrol, and p-cymene significantly shortened immobility time in the tail suspension test (decreased by 8.4%–20.9%), whereas thymol, BCP, and volatile oil effectively reduced feeding latency in the novelty-suppressed feeding test (decreased by 63.4%–67.8%). p-Cymene, BCP, and volatile oil significantly increased the number of BrdU+ proliferating cells and DCX+ immature neurons in the hippocampal dentate gyrus (P < 0.05–0.001). All five components increased the number of microglial terminal endpoints by 41%–70%, indicating a shift toward a resting/anti-inflammatory phenotype, and some components also restored astrocyte morphology and density (P < 0.05). All five components significantly activated AKT (p-AKT/AKT increases of more than 91%), whereas only volatile oil, carvacrol, and p-cymene significantly activated CREB (p-CREB/CREB increases of 34%–50%); suggesting that AKT/CREB signaling participates in the regulation of neuronal survival and plasticity. The active components of thyme ameliorated depression-like behaviors in mice through multi-target synergistic effects, including inhibiting HPA axis overactivation, promoting neurogenesis, inducing glial anti-inflammatory phenotype transformation, and activating AKT/CREB survival signaling. Among them, p-cymene, BCP, carvacrol, and volatile oil displayed promising therapeutic potential, providing an experimental basis for the development of natural multi-target antidepressants based on neural stem cell–glial cell network regulation.