The Effects of Environmental Adversities on Human Neocortical Neurogenesis Modeled in Brain Organoids

Abstract

Over the past decades, a growing body of evidence has demonstrated the impact of prenatal environmental adversity on the development of the human embryonic and fetal brain. Prenatal environmental adversity includes infectious agents, medication, and substances of use as well as inherently maternal factors, such as diabetes and stress. These adversities may cause long-lasting effects if occurring in sensitive time windows and, therefore, have high clinical relevance. However, our knowledge of their influence on specific cellular and molecular processes of in utero brain development remains scarce. This gap of knowledge can be partially explained by the restricted experimental access to the human embryonic and fetal brain and limited recapitulation of human-specific neurodevelopmental events in model organisms. In the past years, novel 3D human stem cell-based in vitro modeling systems, so-called brain organoids, have proven their applicability for modeling early events of human brain development in health and disease. Since their emergence, brain organoids have been successfully employed to study molecular mechanisms of Zika and Herpes simplex virus-associated microcephaly, as well as more subtle events happening upon maternal alcohol and nicotine consumption. These studies converge on pathological mechanisms targeting neural stem cells. In this review, we discuss how brain organoids have recently revealed commonalities and differences in the effects of environmental adversities on human neurogenesis. We highlight both the breakthroughs in understanding the molecular consequences of environmental exposures achieved using organoids as well as the on-going challenges in the field related to variability in protocols and a lack of benchmarking, which make cross-study comparisons difficult.

Roots of the Malformations of Cortical Development in the Cell Biology of Neural Progenitor Cells

“…MCDs can have both monogenic and polygenic causes, whereas genetic mutations can have both convergent and divergent relations with the final phenotypes ( Klingler et al, 2021 ). In addition to genomic mutations, there are various environmental factors that have been implicated in MCDs: alcohol, stress, nicotine, cocaine, hypoxia, and various viral infections, notably ZIKA and SARS-Cov-2 ( Luhmann, 2016 ; Sarieva and Mayer, 2021 ). To tackle the mechanisms through which all of these contribute to the onset of MCDs, it is important to understand the affected features at the cell biological level.…”

Roadbumps at the Crossroads of Integrating Behavioral and In Vitro Approaches for Neurotoxicity Assessment

“…Because the field is in a state of flux, papers reviewing complex systems often highlight their potential with a cursory mention of limitations ( Qian et al, 2019 ; Le Cann et al, 2021 ; Xu and Wen, 2021 ). With the increasing body of data and the number of laboratories incorporating such models and new technologies into their research, the field will have a better knowledge of the models, their benefits and limitations that may affect their translation to clinical problems ( Qian et al, 2019 ; Velasco et al, 2019 ; Chiaradia and Lancaster, 2020 ; Marx, 2020 ; Sarieva and Mayer, 2021 ). As an example, organoids fail to recapitulate the characteristic human cortical development of progenitor maturation trajectories and the emergence of diverse cell subtypes and areal specification of newborn neurons as well as spatially segregation of molecular signatures ( Chen et al, 2019 ; Bhaduri et al, 2020 ).…”

Prenatal nicotine alters development of the laterodorsal tegmentum: Possible role for attention-deficit/hyperactivity disorder and drug dependence

“…When taken together with the fact that there is currently no human data available regarding structural development within the LDT associated with PNE, experimentally examining the issue of PNE-associated changes in the LDT is warranted if we wish to understand fully the mechanisms underlying the higher risk of these maladaptive, cognitive-based behaviors in PNE individuals. While three-dimensional human-derived brain organoid models have recently been used to examine effects on neural development of environmental factors, including nicotine, they do not allow for examination of behavioral associations[ 112 ] (for review, see[ 113 ]). Accordingly, for studies examining synaptic changes that could underlie behavioral outcomes, we require animal models of PNE in which both cellular and behavioral studies can be conducted.…”