# 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 Chronic Stress
In line with the previous study, the antidepressant action of quercetin can be linked to its ability to significantly increase the levels of antioxidants such as SOD, GSH, and CAT and restore the levels of 5-HT in the brain tissue of mice. Additionally, the researchers also showed that quercetin significantly decreased IL-6 and TNF-\(\alpha\) levels in brain tissues, which were increased following model induction. Since an excessive inflammatory response is also often responsible for the increased release of glutamate; quercetin also reduced this excitatory synaptic neurotransmitter. Thus, in addition to antioxidant activity, this flavonoid is also capable of exerting an anti-inflammatory action and reducing excitotoxicity [34]. Likewise, [PERSON] et al., observed that orally quercetin treatment (30 mg/kg), for 21 days, reduced anxiety in animals subjected to unexpected stress, attenuated anhedonia, and improved short- and long-term memory deficits. Quercetin reduced the expression levels of total thiol, TBARS, and NO; conversely, it increased the levels of the antioxidant enzyme CAT. Noteworthy, quercetin treatment also reduced hippocampal gene expression levels for TNF-\(\alpha\), IL-6, IL-1\(\beta\), and Cyclooxygenase-2 (COX-2). The cresyl violet staining showed that the hippocampal neurons of the stressed animals showed marked signs of neuronal damage. Conversely, stressed mice treated with quercetin owned neuron morphology similar to the control group. Thus, quercetin may be improving anxiety, depression, and cognitive dysfunction stress-induced, preventing neuronal damage and attenuating oxidative and pro-inflammatory responses [35]. In a similar way to quercetin, quercetin-3-\(\alpha\)-l-arabinofuranoside (Avicularin), a glycoside of quercetin exerted an anti-depressant effect on a mouse model of depression induced by chronic unpredictable mild stress. Administration of Avicularin (1.25, 2.5, or 5.0 mg/kg) via gavage for 21 days significantly decreased the immobility time of mice, in a dose-dependent manner. It exerted similar effects obtained in the fluoxetine (20 mg/kg) group. Avicularin significantly reduced the TNF-\(\alpha\), IL-6, IL-1\(\beta\), inducible NO synthase, and COX-2 that instead were higher in the hippocampi of stressed mice. Moreover, Avicularin exerted anti-inflammatory effects inhibiting the activation of MEK/ERK/nuclear factor-kB (NF-kB) signaling pathway; conversely, it was activated significantly in mice exposed to stress. Similar to fluoxetine, this glycoside of quercetin reduced Bax and Caspase-3 levels, in a dose-dependent manner, thus reducing neuroinflammation and apoptosis in hippocampus [36]. [PERSON] et al. investigated the molecular mechanisms underlying the neuroprotective and antidepressant effects of quercetin in a murine model of unpredictable mild chronic stress. The chronic unpredictable mild stress was induced exposing mice to nine different stressors (physical restraint; horizontal oscillation, noise; clip tail; fasting; crowding; water deprivation; 45\({}^{\circ}\) inclined cage; and overnight illumination) for 21 days. Treatment with quercetin (15 and 30 mg/kg), administered via gavage for 21 days, improved depressive-like behaviors. Indeed, the treatment restored stress-induced weight loss, improved locomotor activity in the open field test, and reduced immobility time in the FST. Furthermore, quercetin improved anhedonia, which is important in depressive-type behaviors. Besides, quercetin could induce maturation and survival of neural progenitor cells as demonstrated through immunohistochemical examination of the hippocampus. Indeed, it was observed an increase of the number of doublecortin (DCX)-positive and BrdU/NeuN-double-positive cells, in a dose-dependent manner. Furthermore, this flavonoid raised the protein levels of Forkhead box transcription factor G1 (FoxG1), p-CREB, and BDNF in the hippocampus, which had been downregulated following stress.