# Role of Quercetin in Depressive-Like Behaviors: Findings from Animal Models
## 5 [PERSON] in Animal Models of Depressive-Like Behaviors
### Quercetin Effects in Animal Models Exposed to Acute Stress  
Inflammation is an important pathogen mechanism involved in the development of depression [130]. Indeed, depressed subjects show elevated levels of pro-inflammatory markers, such as C-reactive protein, IL-6, and a reduced level of BDNF [131; 132]. Also, in depressed subjects, a decrease of BDNF/ tropomyosin receptor kinase B (TrkB) signaling pathway and impaired neuronal plasticity play an important role in the pathogenesis of depressive disorders [133]. In this context, [PERSON] et al. evaluated the effects of quercetin (95% of purity), on lipopolysaccharide-induced depressive-like behavior and its mechanism of action. LPS is used to induce inflammatory stimuli; however, LPS-treated rats have been shown to exhibit depressive-like behavior. Researchers demonstrated that both quercetin (40 mg/kg) and ibuprofen (240 mg/kg) administered via gavage for 14 days improved body-weight gain in rats and ameliorated the impaired LPS-induced neuropsychiatric behaviors including anxiety, depression, and memory impairment. This data highlights the close relationship between inflammation and depression. Moreover, treatment with LPS reduced the protein expression of BDNF, p-TrkB/TrkB, triggering receptors expressed on myeloid cells (TREM) 1, Copine 6, and synapsin-1, both in the hippocampus and prefrontal cortex; conversely, the expression of TREM2 was increased. However, quercetin treatment reversed the expression levels of these proteins, similarly to groups treated with ibuprofen and fluoxetine (5 mg/kg). So quercetin could exert these anti-depressive effects reduced neuroinflammation response and enhancing neuroplasticity [43]. Also, in a model of depressive-like behaviors induced by cancer, quercetin combined to exercise training mediated the anti-depressive effects, reducing inflammatory cytokines, which in turn, in the prefrontal cortex, enhanced BDNF/TrkB/\(\beta\)-catenin axis, a major signaling pathway with anti-depressive action. Indeed, after the last injection of 1,2-dimethylhydrazine (DMH) to induce cancer, mice received quercetin (50 mg/kg) and exercise training for 84 days. The combination of quercetin and exercise ameliorated the DMH-induced depressive-like behaviors. Indeed, compare to mono-treatment groups, this combination treatment reduced the immobility time and enhanced ambulation and rearing counts. The combination treatment also reduced the IL-1\(\beta\) and TNF-\(\alpha\) serum and tissue levels, which instead increased following DMH injections [44]. In this regard, [PERSON] et al. investigated the role of the BDNF-TrkB signaling pathway in hippocampal tissues of estrogen receptor \(\alpha\) deficiency-female mice, that induced behaviors similar to depression. Oral administration of quercetin (100 mg/kg) for 70 days improved the depressive responses in mice. Furthermore, estrogen receptor \(\alpha\) deficiency induced a decrease in the number of hippocampal neurons compared to the control group; which conversely, increased following treatment with quercetin. This flavonoid also reduced apoptosis by increasing anti-apoptotic proteins, such as Bcl-2 and reducing pro-apoptotic proteins, such as activated Bax and cleaved caspase-3. Immunoblotting analysis in hippocampal tissue demonstrated that the deficit of the estrogen receptor \(\alpha\) significantly decreased BDNF levels and the phosphorylation of its downstream targets such as TrkB, protein kinase B (Akt), and extracellular regulatory protein kinase 1/2 (ERK1/2). Conversely, quercetin significantly increased the expression levels of these proteins, highlighting that the antidepressant effect of quercetin could be mediated by modulation of BDNF-Akt/ERK1/2 signaling [45], as also observed in the study described above [44]. Quercetin is also able to reduce plasma cortisol levels, improving memory deficits and alleviating stress-induced disorders [30, 134].