Summary: Environmental factors like stress and medication exposure during pregnancy can shape brain development, but the mechanisms remain unclear. Researchers used brain organoids to study the effects of synthetic glucocorticoids, commonly given to prevent complications in premature births.
They found that prolonged exposure led to a shift in neuron types, increasing inhibitory neurons while decreasing excitatory neurons. This imbalance, previously linked to psychiatric disorders in genetic studies, is now shown to result from environmental exposure.
Key Facts:
- Neuron Type Shift: Synthetic glucocorticoid exposure increased inhibitory neurons and decreased excitatory neurons in developing brain organoids.
- Prenatal Sensitivity: The study suggests that the fetal brain is highly susceptible to environmental influences, including medications given during pregnancy.
- Disease Risk Implications: While neuron imbalances have been linked to psychiatric disorders, it is unclear whether these changes increase vulnerability or resilience.
Source: Max Planck Institute
Infections, chemicals, stress – these environmental factors influence the risk of developing psychiatric or neurological disorders, especially if they occur before birth. The biological mechanisms behind this are still not fully understood.
Researchers investigated the impact of glucocorticoids, a type of steroid hormone, on the early stages of brain development. They found a shift in neuron types, showing that the developing brain is more susceptible to external influences than previously thought.
Glucocorticoids are part of the body’s natural stress response, and are essential for normal fetal development.
Therefore, if there is a risk of pre-term delivery, synthetic glucocorticoids are often prescribed during pregnancy to promote lung development. In fact, in 2020, ten percent of all births (or 13 million newborns) were premature, making glucocorticoids a widely used medication around the world.
In a newly published study, Leander Dony and his colleagues at the Max Planck Institute of Psychiatry in Munich, headed by Elisabeth Binder, used brain organoids to test the effects of synthetic glucocorticoids on brain development.
Brain organoids are models of the developing brain that are derived from human stem cells and mature in a petri dish. In this study, organoids were exposed to synthetic glucocorticoids for an extended period of time, simulating excessive exposure during early pregnancy.
The exposed organoids were then compared to unexposed, control organoids that were considered to follow a normal brain development path.
Shift in neuron types observed
The researchers’ main finding was a shift in the distribution of neuron types: In the exposed organoids, there was a higher proportion of inhibitory neurons and a lower proportion of excitatory neurons than in the unexposed organoids.
Excitatory neurons cause the next neurons to fire, passing a signal on, while inhibitory neurons reduce the likelihood that the next neuron will fire, slowing a signal down.
“These results show us that the human brain is very malleable and susceptible to external influences during the early stages of development, even more so than we previously thought”, Dony shares.
While an imbalance in neuron types has been linked to psychiatric and neurological disorders from a genetic perspective, this is the first study to show the same impact from environmental exposure.
More research is needed to understand what the results of this study mean for disease risk:
“We see an increased amount of inhibitory neurons, but our study results do not show us whether this means an increased risk or resilience to certain disorders later in life”, Cruceanu explains.
Brain organoids offer a unique opportunity for scientists to understand the development of the brain in its earliest stages. Knowing which factors influence disease risk later on in life, whether environmental factors, genetic risk factors or a combination thereof, can help to develop treatments and preventive measures in the future.
They worked in collaboration with research groups at the Karolinska Institutet in Stockholm and Helmholtz Munich, headed by Cristiana Cruceanu and Fabian Theis respectively.
About this neurodevelopment research news
Author: Annalena Huber
Source: Max Planck Institute
Contact: Annalena Huber – Max Planck Institute
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Chronic exposure to glucocorticoids amplifies inhibitory neuron cell fate during human neurodevelopment in organoids” by Elisabeth Binder et al. Science Advances
Abstract
Chronic exposure to glucocorticoids amplifies inhibitory neuron cell fate during human neurodevelopment in organoids
Disruptions in the tightly regulated process of human brain development have been linked to increased risk for brain and mental illnesses.
While the genetic contribution to these diseases is well established, important environmental factors have been less studied at molecular and cellular levels.
Here, we used single-cell and cell type–specific techniques to investigate the effect of glucocorticoid (GC) exposure, a mediator of antenatal environmental risk, on gene regulation and lineage specification in unguided human neural organoids.
We characterized the transcriptional response to chronic GC exposure during neural differentiation and studied the underlying gene regulatory networks by integrating single-cell transcriptomics with chromatin accessibility data.
We found lasting cell type–specific changes that included autism risk genes and several transcription factors associated with neurodevelopment.
Chronic GC exposure influenced lineage specification primarily by priming the inhibitory neuron lineage through transcription factors like PBX3.
We provide evidence for convergence of genetic and environmental risk factors through a common mechanism of altering lineage specification.
