Brain organoids reveal in detail damage


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Image: Lab-grown brain organoids help researchers explore the early stages of human brain development.
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Credit: UC San Diego Health Sciences

Alcohol consumption during pregnancy poses a significant risk to the healthy development of the fetus. There is no known safe amount of alcohol during pregnancy.

The consequences of prenatal alcohol exposure are reflected in the different diagnoses presented under the umbrella of fetal alcohol spectrum disorders. At one end of the spectrum, developmental deficits and physical differences define Fetal Alcohol Syndrome (FAS), but in most cases, irreversible brain damage leads to behavior and learning challenges even without physical influence. Experts estimate that 1.1 to 5 percent of school children in the United States—up to 1 in 20—may be affected by PAE, with some percentage suffering from FAS.

Although the clinical implications of fetal alcohol spectrum disorders are well documented, the exact molecular effects on the human fetal neocortex are not fully understood. In a new study published November 16, 2022 in the Molecular PsychiatryResearchers at the University of California, San Diego School of Medicine used human brain organoids to document more specifically how alcohol exposure impairs the growth and functioning of new brain cells.

The findings underscore the widespread threat of alcohol exposure to the fetal brain. “The damage done to them is deep and widespread,” said Allison R. Motry, MD, professor in the departments of pediatrics and cellular and molecular medicine at the University of California San Diego School of Medicine.

Muotri is a co-author on the study with Cleber A. Trujillo, a former project scientist in Muotri’s lab and now associate director of stem cell biology at Massachusetts-based Vesalius Therapeutics.

Using human induced pluripotent stem cells, Mutari and his colleagues created three-dimensional brain organelles that develop similar to the formation of the human embryonic cortex—the formation of the outer layers of the brain that house many higher-order functions, such as reasoning, conscious reasoning, emotional control and speech.

Exposure to alcohol at different points in fetal brain development led to different but always negative effects, from fundamental imbalances in cellular processes, to faulty construction in brain structure and insufficient creation of support cells (cytogenesis) and connections between brain cells (neurogenesis).

The researchers followed up by performing electrophysiology recordings to monitor patterns of electrical activity in cortical organelles, and to document and confirm impairment of cortical organelle function.

The authors said the results are an improvement over previous studies using animal models.

“They beat the suboptimal recapitulation of non-human models,” said co-author Miguel del Campo, MD, PhD, associate professor at UC San Diego School of Medicine and medical genetics at Rady Children’s Hospital in San Diego. “Indeed, these organoids show a valuable model for a better, more comprehensive and in-depth assessment of the effects of alcohol exposure on human brain development.”

“This is critical because we can better see the developmental pathways and prominent signals that are disrupted and potentially discover new targets for therapeutic impairment or prevention of neuropathology from alcohol exposure,” explained co-author Kenneth L. Jones, professor of pediatrics at UC San Diego School of Medicine. before birth. The good news is that some of these alterations have been reversed with specific experimental drugs.”

Co-authors are: Jason W. Adams, Priscilla de Negrais, Justin Trung, Timothy Tran, Ryan Sito, Carmen Teodoroff and Stephen A. Spector, all at the University of San Diego.

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