In vitro modeling of glucocorticoid mechanisms in stress-related mental disorders: Current challenges and future perspectives

Abstract

In the last decade, in vitro models has been attracting a great deal of attention for the investigation of a number of mechanisms underlying neurological and mental disorders, including stress-related disorders, for which human brain material has rarely been available. Neuronal cultures have been extensively used to investigate the neurobiological effects of stress hormones, in particular glucocorticoids. Despite great advancements in this area, several challenges and limitations of studies attempting to model and investigate stress-related mechanisms in vitro exist. Such experiments often come along with non-standardized definitions stress paradigms in vitro, variations in cell models and cell types investigated, protocols with differing glucocorticoid concentrations and exposure times, and variability in the assessment of glucocorticoid-induced phenotypes, among others. Hence, drawing consensus conclusions from in-vitro stress studies is challenging. Addressing these limitations and aligning methodological aspects will be the first step towards an improved and standardized way of conducting in vitro studies into stress-related disorders, and is indispensable to reach the full potential of in vitro neuronal models. Here, we consider the most important challenges that need to be overcome and provide initial guidelines to achieve improved use of in vitro neuronal models for investigating mechanisms underlying the development of stress-related mental disorders.

In vitro modeling of the neurobiological effects of glucocorticoids: A review

“…These include a lack of standardized protocols for acute and chronic GC exposure, a broad range of GC concentrations investigated, variability between in vitro models, and lack of standardized assessments for GC-induced phenotypes. It is important to consider these aspects when replicating or designing new experiments ( Bassil et al, 2022 ).…”

“…Nevertheless as showcased in Fig. 3 , each model (and specifically differentiation protocols) carry advantages and limitations that speak to unique research questions and should be taken into consideration in the selection of the model ( Bassil et al, 2022 ). Given that the generation of iPSCs from donors retain the genotype and in some instances even traces of the epigenotype, iPSC-based models can be a promising for investigating gene-environment interactions ( Qian et al, 2016 ), especially that SRDs cannot be explained by underlying genetic vulnerability alone.…”

“…Advances in stem cell technology such as 2D and 3D patient-specific generation of neuronal and glial cultures are expected to help gain new knowledge about individual mechanisms contributing to disease that cannot be understood with human or animal studies alone. Therefore, improved standardized GC paradigms in vitro that better reflect in vivo conditions during stress could provide useful insights to apply in advanced and complex culture models ( Bassil et al, 2022 ). A few suggested steps to take could include: (1) selecting the appropriate model based on its characteristics (see Fig.…”

Dissecting the Long-Term Effect of Stress Early in Life on FKBP5: The Role of miR-20b-5p and miR-29c-3p

“…Other than animal models, in the last decades, neuronal cell cultures have been extensively used to investigate the neurobiological effects of GCs, with most of the in vitro studies focused on the downstream effects of GR activation [ 24 ]. The main advantage of these cell cultures is the possibility to mimic human brain physiology while observing individual cell systems in isolation and in a manner that is highly reproducible as well as cost effective [ 25 ].…”