From odorant perception to stress resilience: Transcriptomic insights into olfactory receptor-driven neuromodulation and antidepressant-like effects of linalyl acetate.

Olfactory stimulation has emerged as a non-invasive strategy to modulate brain function; however, the molecular mechanisms linking odorant-receptor interactions to central neurobiological outcomes remain poorly defined. In this study, we investigated the antidepressant-like effects of linalyl acetate (LA) and elucidated its olfactory-driven signaling mechanisms using integrated computational, transcriptomic, and in vivo approaches. In silico analyses identified OR2B3 as a candidate olfactory receptor for LA, supported by structural similarity assessment and docking simulations. In human nasal epithelial cells, LA treatment induced coordinated transcriptional programs enriched for olfactory receptors, chemosensory cilia, GPCR signaling, and synapse-related pathways, indicating activation of receptor-guided sensory signaling networks. These findings were further supported by RT-PCR validation, which confirmed significant upregulation of OR2B3 and OR6A2, as well as modulation of cilium-associated signaling components, including ADCY3. In vivo, repeated LA inhalation significantly reduced immobility time in the tail suspension test, demonstrating antidepressant-like behavioral effects. These behavioral outcomes were accompanied by decreased serum corticosterone and pro-inflammatory cytokines, together with increased brain-derived neurotrophic factor levels in serum, cerebral cortex, and hippocampus. Neurochemical analyses further revealed enhanced monoaminergic (dopamine, noradrenaline, serotonin) and cholinergic signaling. Transcriptomic profiling of the olfactory bulb and hippocampus revealed dose-dependent enrichment of metabolic, synaptic, neurotrophin, and intracellular signaling pathways, highlighting coordinated metabolic-synaptic coupling and neuroplasticity-associated programs. Collectively, these findings demonstrate that LA engages olfactory receptors to activate cilia-centered chemosensory signaling that propagates into central metabolic, synaptic, and neurotrophic networks, ultimately modulating stress-related neurobiology. This study establishes a molecular framework for odorant-mediated neuromodulation and supports the therapeutic potential of olfactory-based interventions for mood regulation.