# 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
Therefore, the FoxG1/CREB/BDNF signaling pathway could be used by quercetin to promote adult hippocampal neurogenesis [37]. Also, [PERSON] et al. demonstrated that dietary polyphenols such as quercetin improved dysregulation of HPA in the maternal separation model. Maternal separation is a valid model to investigate the negative effects of early life stress on brain function and structure, related to depressive-like behaviors and anxiety. To induce this stress model, pups were separated from mothers for 3 h, every day for 12 days. After 8 weeks from exposure to early-life stress and 56 days of quercetin dietary (20 mg/kg), the levels of plasma BDNF increased. Also, dietary ameliorated dysregulation of the HPA axis, lowering the baseline levels of plasma corticosterone compared to the maternal separation model group. In this way, the quercetin diet ameliorated depressive-like behaviors [38]. Consistent with the aforementioned studies, also [PERSON] et al. showed that quercetin ameliorated depressive-like behavior in rats subjected to unpredictable chronic mild stress for 5 weeks. Indeed, intraperitoneally injections with quercetin (30 mg/kg) or resveratrol (20 mg/kg) for 35 days simultaneously to stress exposure, decreased immobility time and increased sucrose consumption. Not unsurprising that the anti-depressive effects of this flavonoid are due to its antioxidant and anti-inflammatory properties. Indeed, quercetin treatment, as also resveratrol, reduced MDA level and increase antioxidant enzymes such as SOD, CAT, and GSH, which are dysregulated in stress conditions. Both flavonoids reduced the NF-kB, IL-6, TNF-\(\alpha\), and IL-1\(\beta\) expression levels. Moreover, the researchers showed that the decreased serum corticosterone levels, restoring the HPA axis could be another mechanism of action used by these flavonoids to exert antidepressive effects [39]. However, also an acute quercetin (50 mg/kg) treatment (3 days) along with predatory stress induction ameliorated depressive-like behaviors. In order to stress induce, three mice were placed in the small cage, and the cat, used as a predator/stressor, was placed in the large cage. Mice were exposed to stress for 15 min for 3 consecutive days. Acute treatment reduced immobility time and improved spatial working memory and voluntary exploration of mice [40]. [PERSON] et al. examined the effects of quercetin-enriched diets, started before, after, or at the same time as exposure to stressors. A quercetin-enriched diet (2 g/kg) for 14 days before exposure to stress prevented depressive-like behaviors. The mice were also treated with a dose of quercetin (0.5 g/kg) comparable to that contained in a diet rich in fruits and vegetables. Also, this quercetin dose, before stress exposure, improved depressive-like behaviors. Additionally, the quercetin diet started before stress increased neuronal activity in the medial prefrontal cortex and hippocampus. Indeed, compared to mice fed a normal diet, the quercetin-enriched diet increased the frequencies of spontaneous excitatory and inhibitory postsynaptic currents both in the medial prefrontal cortex and in the hippocampus. Furthermore, the quercetin-enriched diets prior to stress exposure inhibited the expression of genes related to microglia and astrocyte activation in both the medial prefrontal cortex and hippocampus. Conversely, quercetin-enriched diets administered concurrently and after exposure to stress did not trigger the same antidepressant effects triggered by a long-term diet. Therefore, the data results demonstrate that a long-term diet rich in quercetin or a diet rich in fruits and vegetables could induce antidepressant effects and prevent the damage induced by chronic stress. Furthermore, inhibition of astrocytes and microglia could be a mechanism used by quercetin to regulate neuronal activity and improve depressive-like behaviors [41]. Recently, [PERSON] et al. studied the antidepressant effects and potential mechanism of quercetin in chronic unpredictable mild stress rats, measuring the changes of serum elements.