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  • br Acknowledgements We apologize to our distinguished collea

    2021-11-22


    Acknowledgements We apologize to our distinguished colleagues whose work has not been cited owing to space limitations. This work was funded by the Italian Association for Cancer Research (AIRC, Milan, Italy, IG 14732 to A.M.); Italian Ministry of University and Education (Finanziamenti per la Ricerca di Base IDEAS RBID08C9N7 to A.M.; Programma Operativo Nazionale PON01_01958 to A.M.; PRIN 2010FHH32M_002 to A.M.); Italian Ministry of Health (GR-2008-1143546 and GR-2010-2314703 to A.M.); NR-Net Marie Curie ITN to A.M.; University of Bari, Italy (ORBA 08WEZJ, 07X7Q1, 06BXVC, IDEA GRBA0802SJ to A.M.). Marica Cariello is a fellow of the Italian Association of Cancer Research (AIRC). RMG is funded by the Imperial College Junior Research Fellowship 2012.
    Introduction Major depressive disorder is a multi-causal psychiatric disorder and affects up to 17% of the global population (Ohgami et al., 2009, Rickels et al., 2009). Current antidepressants in clinical practice are basically developed based on the monoaminergic hypothesis which means that deficiency of extracellular serotonin (5-HT) and noradrenaline (NA) is the main cause of depression (Bymaster et al., 2003). However, these antidepressants are ineffective for a substantial proportion of patients, while only 30% of patients are completely cured (Schloss and Henn, 2004, Boku et al., 2017). The incomplete understanding of the pathophysiology of depression has limited the development of highly effective drugs against this disorder. Thus, developing novel pharmacological targets beyond 5-HT and NA is presently a promising strategy to treat depression (Boku et al., 2017). Farnesoid X receptor (FXR), also known as a bile (-)-JQ1 sale receptor (BAR), is a nuclear receptor which is widely expressed in liver and intestine (Thomas et al., 2010). Similar to other nuclear receptors, when activated, FXR translocates to nucleus, forms a dimer and binds to hormone response elements on DNA, and then regulates the expression of certain genes (Moris et al., 2017). It is well-known that FXR plays an important role in synthesis, secretion and transport of bile acid (Cave et al., 2016, Yuan and Li, 2016, Moris et al., 2017). However, we have noticed that in 2014, Seok et al. reported that after activation, FXR repressed the function of cAMP-response element binding protein (CREB) by disrupting the association between CREB and CREB regulated transcription coactivator 2 (CRTC2), suggesting the role of FXR on CREB activity (Seok et al., 2014). CREB is an important transcription factor which controls the biosynthesis of many pro-survival proteins, including brain-derived neurotrophic factor (BDNF) (Finkbeiner et al., 1997, Tao et al., 1998). It has been demonstrated that both CREB and BDNF are closely involved in the pathophysiology of depression (Nestler et al., 2002). Previous studies have showed that the levels of BDNF and pCREB in hippocampus and medial prefrontal cortex (mPFC) were modulated by chronic stress and antidepressant treatments, while deficiency of BDNF/CREB made rodents susceptible to depression (Xu et al., 2016, Xu et al., 2017, Li et al., 2017b, Zhu et al., 2017). Besides, FXR was found to have expressions in brain (Huang et al., 2016). Therefore, here we speculated that FXR may play a role in depression by modulating the function of CREB.
    Materials and methods
    Results
    Discussion FXR, activated by bile acid, acts as a multifunctional nuclear receptor and plays vital roles in metabolism of bile acid lipid and glucose, protection of liver, control of intestinal bacterial growth, and the pathogenesis of antherosclerosis (Kim et al., 2016). However, since it has been demonstrated that FXR has expression in neurons, until now there are very few studies exploring the role of FXR in the central nervous system (Huang et al., 2016). Here, we found that chronic stress fully enhanced the expression of FXR in hippocampus, but not mPFC. We also proved that overexpression of hippocampal FXR promoted depression in rats, while knockdown of hippocampal FXR induced antidepressant-like effects in rats. These results are interesting and convincible.