Brain organoids reveal in detail the harms of prenatal alcohol exposure

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

The consequences of prenatal alcohol exposure (PAE) are reflected in the various diagnoses that are emerging under the umbrella of Fetal Alcohol Spectrum Disorders. At one end of the spectrum, growth deficits and physical differences define fetal alcohol syndrome (FAS), but in most cases irreversible brain damage leads to behavioral and learning problems, even without physical impact. . Experts estimate that 1.1 to 5% of American school children – up to 1 in 20 – may be affected by EPA, with some percentage suffering from FAS.

Although the clinical effects of fetal alcohol spectrum disorders are well documented, the precise molecular effects on the human fetal cerebral cortex are not fully understood. In a new study, published on November 16, 2022 in Molecular psychiatryresearchers at the University of California, San Diego School of Medicine have used human brain organoids to document more precisely how alcohol exposure alters the development and function of new brain cells.

“The findings underscore the broad threat of alcohol exposure to the fetal brain. The harm inflicted is deep and widespread,” said Alysson R. Muotri, PhD, professor in the Departments of Pediatrics and Cellular and Molecular Medicine. from UC San Diego School of Medicine.

Muotri is co-corresponding author of 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, Muotri and his colleagues created three-dimensional brain organoids that develop similarly to human fetal corticogenesis – the formation of the outer layers of the brain that house many high-level functions, such as reasoning, conscious thought, emotional control and speech.

Alcohol exposure at different stages of fetal brain development has produced different but consistently negative effects, from fundamental dysfunction of cellular processes to faulty construction of brain architecture and inadequate creation of supporting cells (gliogenesis ) and connections between brain cells (synaptogenesis).

The researchers went on to perform electrophysiology recordings to monitor patterns of electrical activity in cortical organoids, documenting and confirming altered cortical organoid function.

The authors said the results improve on previous studies using animal models.

“They overcome 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 geneticist at Rady Children’s Hospital-San Diego. “In fact, they show that organoids are a valuable model to better, more completely and deeply assess the effects of alcohol exposure on human brain development.”

Co-author Kenneth L. Jones, MD, professor of pediatrics at UC San Diego School of Medicine, explained, “This is crucial because we can better see which important growth and signaling pathways are disrupted and perhaps discovering new targets to prevent or prevent therapeutically. the neuropathology of prenatal alcohol exposure. The good news is that some of these alterations have been reversed using specific experimental drugs.

Co-authors include: Jason W. Adams, Priscilla D. Negraes, Justin Truong, Timothy Tran, Ryan Szeto, Carmen Teodorof, and Stephen A. Spector, all at UC San Diego.

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