Theme 3 | Rare diseases

Investigating the neurobiological effects of cortisol on human embryonic stem cell-derived forebrain neurons at different stages of neuronal development.

Katherine Bassil 

Katherine Bassil1, Gunter Kenis1, Laurence de Nijs1, Bart Rutten1

1Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, 6200MD Maastricht, The Netherlands

Dysregulated hypothalamic-pituitary adrenal axis, in particular hypo- and hyper- function, has long been implicated in stress-related disorders like post-traumatic stress disorder (PTSD). However, only a small percentage of individuals are susceptible to PTSD following trauma exposure and it is unclear whether and how exposure to traumatic stress leads to alterations in cortical neurons that contribute to PTSD susceptibility in these patients. Therefore, the aim of this study was to investigate the chronic effects of the glucocorticoid cortisol (CORT), in hESC-derived neural progenitors and neurons, as a putative in vitro model of traumatic stress.

We generated forebrain neurons from hESCs of a healthy individual, and investigated the effects of chronic CORT exposure at three different neuronal developmental stages: neural progenitor cells, immature, and mature neurons. To assess the effects of chronic stress on cellular processes, we measured changes in mRNA expression of neuronal and glucocorticoid markers, such as Ki67 and FKBP5 respectively. In addition, neuronal activity was evaluated in mature neurons using Ca2+-imaging analysis following chronic CORT or acute norepinephrine (NE) exposure.

A decrease in proliferation and an increase in apoptosis in neural progenitor cells (PRO) was observed. In immature forebrain neurons (Diff(y)), increases in DCX, Pax6 and SYP highlight an early commitment specific to this cell stage. Additionally, a decreased expression in c-Fos and BDNF in mature forebrain neurons (Diff(m)) is seen. A decrease in calcium signaling amplitude was observed following both chronic CORT exposure and acute NE in mature forebrain neurons. 

Together these results suggest an early commitment to differentiation in both neural progenitors and immature neurons during early stages of neuronal development. Changes in synaptic plasticity-related genes highlight possible negative effects of chronic CORT on these mechanisms in mature forebrain neurons. A decrease in amplitude might suggest possible changes to synaptic receptors in mature forebrain neurons. Future research looking into chronic CORT effects in PTSD susceptible and resilient individuals is crucial to determine underlying molecular vulnerability mechanisms.

The School for Mental Health and Neuroscience (MHeNs) strives to advance our understanding of brain-behaviour relationships by using an approach integrating various disciplines in neuro- and behavioural science, medicine, and the life sciences more widely. MHeNs performs high-impact mental health and neuroscience research and educates master's students and PhD researchers. MHeNs performs translational research, meaning practical collaboration between researchers in the lab and in the hospital. MHeNs is one of six graduate schools of the Faculty of Health, Medicine and Life Sciences (FHML) aligned to the Maastricht University Medical Centre+ (MUMC+).