Vicarious defeat stress (VDS) is not a simple substitute for chronic social defeat stress (CSDS): a comparative study on behavioral and molecular mechanisms in both stress-induced anxiety- and depression-like behaviors.

Social stress is a fundamental environmental factor driving the pathophysiology of neuropsychiatric disorders. Chronic social defeat stress (CSDS) and vicarious defeat stress (VDS) are two widely used social stress paradigms, with VDS initially proposed as an alternative to CSDS. The present study integrated behavioral phenotypes, hippocampal proteomics, synaptic morphology, energy metabolism, neurotransmitter and tryptophan-kynurenine (TRP-KYN) metabolism, and inflammatory indicators to directly compare responses in adult male mice subjected to CSDS and VDS. Both CSDS and VDS mice showed significant social avoidance, reduced open-arm exploration in the elevated plus maze, prolonged feeding latency in the novelty-suppressed feeding test, and increased immobility in the tail suspension test. Meanwhile, reduced center-zone activity in the open field test, fewer transitions and shorter light-compartment time in the light/dark box test, and lower sucrose preference were observed only in CSDS mice. These findings indicate that CSDS produced more extensive and severe behavioral abnormalities. Hippocampal label-free quantitative proteomics identified 38 and 32 differentially expressed proteins in CSDS and VDS mice, respectively, with 11 shared between the two paradigms. Both paradigms caused ATP depletion, increased pro-inflammatory factors, elevated α-synuclein (α-Syn), and decreased postsynaptic density protein 95 (PSD95), with CSDS showing more severe changes. CSDS also upregulated inducible nitric oxide synthase (iNOS) while suppressing transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), whereas VDS increased IL-10 without significantly affecting iNOS or TGF-β. In TRP-KYN metabolism, CSDS increased 3-hydroxykynurenine (3-HK) and quinolinic acid (QA) while decreasing kynurenic acid (KA), whereas VDS did not significantly affect these downstream metabolites. Regarding neurotransmitters, CSDS reduced dopamine (DA), serotonin (5-HT), norepinephrine (NE) and glutamate (Glu), while VDS decreased NE and DA and γ-aminobutyric acid (GABA). Additionally, lactate was significantly increased in VDS mice, whereas CSDS mice showed a non-significant numerical decrease in hippocampal lactate. Collectively, VDS is a distinct stressor rather than a simple substitute for CSDS and has a milder overall impact than CSDS. This study provides guidance for selecting stress models that better align with specific biological questions in preclinical research on anxiety and depression disorders.