The neurobiological effects of naturally-derived polyphenols and phospholipids in cellular & animal models of stress

The molecular and cellular basis of stress neurobiology remain an important research question in clinical science. Indeed, stress-related mental disorders, including depression and anxiety, are currently a major public health concern. Thus, improving our knowledge about the pathophysiology of these neuropsychiatric disorders may enable the development of novel strategies for their treatment and prevention. On the other hand, the inefficacy of currently available therapies for various stress-related disorders, and the numerous side effects that accompany these treatments, have strengthened the search for less invasive strategies with fewer negative side effects. In this regard, the emerging and compelling evidence for nutrition as a potential therapeutic avenue for the treatment of mental disorders suggests that changes in diet are a viable strategy for improving mental health and treating stress-related psychiatric disorders. Moreover, there is considerable evidence suggesting that certain natural compounds available in diet have a therapeutic potential to improve mental health and disease. For instance, naturally occurring phytochemicals, namely polyphenols, are molecular compounds found in different plant sources, such as vegetables and fruits. Also, phospholipids are a class of lipid that comprise a major component of all cell membranes, specially concentrated in lean meat and dairy products. Both polyphenols and phospholipids have demonstrated interesting beneficial effects for human health. However, their therapeutic potential to act prophylactically against the detrimental effects of neuropsychiatric disorders have just begun to be taken seriously. Therefore, in this thesis we have tested the hypothesis that polyphenols and/or phospholipids could improve behavioural and neurobiological outcomes in cellular and animal models of stress. Further, we provide evidence that polyphenols and phospholipids exert neuroprotective effects against the cytotoxicity produced by corticosterone, the main rodent stress hormone, in cortical neurons. Specifically, we have elucidated the potential mechanisms underlying polyphenol-mediated neuroprotection in vitro, and demonstrated that phospholipid exposure positively impacts on neurodevelopmental processes, such as proliferation and differentiation of cultured neural progenitor cells. In addition, we confirmed the therapeutic potential of a dietary intervention with polyphenols by detecting its capacity to reverse depressive- and anxiety-like behaviours induced in a rat model of early-life stress. Moreover, we demonstrated potential implications to modulate BDNF-dependent recovery, regulation of the HPA axis and the microbiota-gut-brain axis in polyphenol-mediated behavioural improvement. Taken together, our findings support the therapeutic potential of polyphenols for stress-related mental disorders, and we further provide evidence for the possible mechanisms by which they may exert these effects. On the other hand, our data reveal that the novel neuromodulatory potential of phospholipids in vitro does not correlate with their inefficacy in attenuating chronic stress-induced behavioural impairment in mice. Nevertheless, these findings contribute to an exciting and growing body of research suggesting that nutritional interventions may have an important role to play in the treatment of stress-related psychiatric conditions