# Role of Quercetin in Depressive-Like Behaviors: Findings from Animal Models
## 1 Introduction  
Depressive-like behaviors are a mental disorder that affects approximately 264 million people around the world. Depression is often characterized by cognitive impairment and anxiety [1, 2]. Furthermore, this condition is known to impair the functions of the hippocampus and the prefrontal cortex [3]. Both brain structures play an important role in decision-making processes, therefore dysfunction at this level can induce a greater predisposition to negative emotions [4]. In these areas are located many glucocorticoid receptors involved in depressive-like behaviors [5]. Noteworthy, the glucocorticoid receptors mediate the regulation of the hypothalamic-pituitary-adrenal (HPA) axis through negative feedback inhibitory mechanisms. The HPA axis promotes the secretion of corticotropin-releasing hormone that is transported in the anterior pituitary and induces the release of adrenocortic hormone, which in turn stimulates the adrenal cortex to secrete glucocorticoids such as cortisol which binds to receptors intracellular for glucocorticoids [6]. Moreover, the HPA axis plays an important role in the response to external stimuli and internal, such as psychological stresses [7]. Indeed, it was observed that chronic stress induces depression [8], highlighting the close relationship between oxidative stress and mood disturbance [9]. This condition is characterized by a complex pathophysiological mechanism, that also involves the reduction of the monoamine system such as neurotransmission of serotonin, dopamine, and noradrenaline [10]. Additionally, immunological alterations and excessive inflammation are further pathological events that play an important role in depression [11, 12]. Most antidepressant drugs aim at correcting the neurotransmitter imbalances involved in the regulation of the mind and emotions [13]. However, there is a high rate of treatment-resistant depressed subjects. Additionally, most anti-depressants own a long latency and numerous side effects. Therefore, the need for new, more efficient and safe antidepressant drugs is growing. Today, phytotherapy, which promotes the application of plants in the treatment of diseases [14], represents a useful source for the development of more effective antidepressants. Several medicinal plants were used in the treatment of various neurological diseases [15; 16]. Phenolic compounds such as flavonoids represent a promising class of natural compounds important in neuropharmacology, thanks to their antioxidant and neuroprotective properties [17]. Fruits and vegetables, important sources in the daily diet, are reservoirs of these bioactive compounds [18]. Flavonoids are a class of polyphenols, widely distributed in the plant kingdom, thus, with a normal diet, humans take an average of 1-2 g/day [19]. Among them, quercetin (3,3\({}^{\prime}\),4\({}^{\prime}\),5,7-pentahydroxyflavone) is the flavonoid most abundant in food and consumed by humans [20]. Several evidences show that fruit and vegetable thanks to their high content of quercetin protect brain tissue from neurodegeneration induced by oxidative stress [21; 22]. Quercetin protects neurons from oxidative stress by inhibiting the formation of hydroperoxide, reducing free radicals and restoring antioxidant enzymes [23; 24]. Additionally, quercetin due to its ability to cross the blood-brain barrier appears in the brain several hours after administration, thus, exerting its neuroprotective effects [25]. It has also been shown to exert anxiolytic effects and improve cognitive deficits [26]. Several findings highlight the protective role of quercetin against depressive-like disorders. Indeed, the freeze-dried onion powder and _Ginkgo biloba_ leaves, rich in quercetin, have an antidepressant action [27; 28]. Moreover, this flavonoid improving behavioral disturbances in mice and rats with anxiety and depressive-like behaviors induced by the corticotropin-releasing factor [29; 30].