INTRODUCTION
The “Brain Development and Disease” class of the Master’s Degree in Cognitive Science at the University of Trento focuses on brain development’s molecular and cellular mechanisms. Gene networks controlling embryonic brain development, neural plasticity during critical periods, and the pathogenesis of neurodevelopmental disorders are the key subjects addressed in this class. The class aims to give the students a comprehensive overview of brain development, addressing the neurobiological underpinnings of neural development and the possible pathological consequences of their derangement. For their final exam, students are asked to write a research article in which they must describe the expression profile of one gene of their interest, whose altered expression and function has been related to a brain disorder. We acknowledge that studying the expression of one gene at a time has its limitations, since brain disorders are likely of multifactorial origin and their pathogenic mechanisms involve differential dysregulation of several genes. However, for didactic reasons, we think that the study of the expression of one single gene related to a brain disorder is largely enough for students to generate an adequate amount of data for their exam. To achieve this goal, students have to collect gene expression data from the mouse, primate and human Allen Brain Atlases and discuss the data with respect to the disorder of interest. The teacher first provides the students with a tutorial helping them to familiarize with gene expression data collection and analysis. Then, students can practice data collection during class hours and online, plus one-to-one sessions with a tutor flanking the teacher. We previously published a brief report of one of these class activities (Rubino & Bozzi, 2021). Here we describe, in a more extensive way, a new study resulting from our students’ work.
Early life stress (ELS) plays a causal role in many psychiatric disorders, including major depressive disorder (MDD; Cheng et al., 2022). ELS is relevant to one of the most robust hypotheses of MDD mechanism: impairment of the hypothalamus-pituitary-adrenal (HPA) axis. Patients have increased levels of both cortisol and corticotropin-releasing hormone (CRH) as a result of disruption of the glucocorticoid receptor (GR) signaling (Ising et al., 2007). GR signaling disruption then results in impaired feedback inhibition along the HPA axis (de Kloet et al., 2005). In particular, ELS induces lifelong disturbances to HPA function, thereby increasing vulnerability to MDD later in life (Cheng et al., 2022). Importantly, improved HPA system regulation (as measured by stress hormone response to a dexamethasone/CRH test) is associated with enhanced response to treatment (Ising et al., 2007). However, these findings have not yielded clinically successful medications (Malhi and Mann, 2018).
Neuroinflammation is another critical player in MDD pathogenesis. Not only does immune system activation induce symptoms that overlap with those of MDD, but patients with neuroinflammatory diseases also have a high prevalence of MDD (Setiawan et al., 2015). Elevated proinflammatory cytokines are reliably found in patients with MDD; and, remarkably, therapeutically administered cytokines trigger depression approximately half the time (Raison et al., 2006). Although this systemic immune activation has been highly studied as a component of MDD, very little is agreed upon regarding the role or mechanism of action for cytokines in the brain (Beurel et al., 2020).
Despite monumental research efforts spanning decades, MDD pathophysiology is not clear (Malhi and Mann, 2018). Consequently, comprehension of its pharmacological treatment is also insufficient. Low antidepressant acceptability is mainly due to weeks of delay before the full effect, and the adverse side effects that can occur during and after that waiting period (David and Gourion, 2016). Moreover, up to 15% of MDD patients struggle with little to no response to pharmacological interventions (Berlim and Turecki, 2007), with clinical guidance limited to trial and error. The scientific community is at a loss to explain why some patients must suffer through failed treatment attempts while others do not (Grogans et al., 2022). There are no clinically relevant methods for predicting which antidepressant may work best for a given individual (Zeier et al., 2018).
The human FKBP5 gene codes for FK506-binding protein 5, a prolyl isomerase that binds immunosuppressive drugs such as FK506, rapamycin, and cyclosporin A. FKBP5 is located on chromosome 6 and its protein product functions as a cochaperone of heat-shock 90-kD protein-1 (OMIM, Online Mendelian Inheritance in Man, http://omim.org/, OMIM #602623; Gene ID 2289, https://www.ncbi.nlm.nih.gov/gene/2289). FKBP5 codes for an immunophilin, which performs immunoregulation and basic cellular functions. FKBP5 is also related to glucocorticoid signaling (Vermeer et al., 2003) and consequently the stress regulation system. Moreover, FKBP5 alternations in mice have been shown to affect stress responses through HPA axis activity, inflammation, and depressive- and anxiety-like behaviors (Häusl et al., 2021; Gan et al., 2022). This gene may help explain how the HPA axis and immune system mediate antidepressant efficacy. In the course of a student’s assignment, we identified the FKBP5 gene as a key player uniting these two major hypotheses of MDD pathogenesis and treatment response.