Infants actively experience the sights, smells, sounds, tastes, and textures in the world around them. Under the direction of genetic programs, this sensory stimuli refines the synaptic connections that the brain forms between neurons, allowing the cells to communicate.1 For decades, researchers assumed that genetics and sensory-driven activity were the only factors influencing brain wiring.2
“As a molecular neuroscientist, I believed the brain was its own entity and its own sacrosanct organ that floats on top of our body and oversees everything,” recalled Thomas Biederer, an associate professor at Yale School of Medicine and senior scientist at the Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging (USDA HNRCA). “And that idea was shattered. Understanding of the microbiome, that bacteria and compounds that are secreted in the gut have an effect on the brain—this was the first aha moment for me when it became clear that the brain is affected by other compounds.” Biederer and his team recently determined that a micronutrient found in breast milk increases neuronal connectivity and published their findings in the Proceedings of the National Academy of Sciences.3
Biederer became interested in the effect of diet on postnatal brain connectivity because researchers reported that breastfed infants performed better in intelligence tests later in life.4 These results suggested that diet influences infant brain development, but it was unknown which micronutrients and bioactive compounds within breast milk were responsible for this effect. In an earlier study, Biederer’s group determined that an omega-3 fatty acid, docosahexaenoic acid (DHA), that is present in breast milk improves synaptic connectivity and information processing in the maturing cortex.5
We [hope] that our data can be used to improve pediatric nutrition products and help children to reach their potential.
—Thomas Biederer, Yale School of Medicine and Jean Mayer USDA HNRCA
To determine what other bioactive compounds within breast milk are important for brain development, Biederer and his team examined the composition of human milk samples donated by mothers living in Mexico, China, and the United States as a part of the Global Exploration of Human Milk study.6 The researchers looked for micronutrients that changed in abundance over the course of lactation and that were independent of race or diet, as this conservation would suggest that these components are functionally important. They found that the carbocyclic sugar myo-inositol was abundant during early lactation when the infant’s brain is rapidly forming new synaptic connections but decreased in concentration over the course of lactation.
The researchers tested if myo-inositol could affect brain connectivity by exposing primary human glutamatergic and rat neuronal cultures to the bioactive compound and immunostaining the synapses’ presynaptic and postsynaptic sites. They found that myo-inositol increased the size and abundance of postsynaptic sites. Because scientists have correlated synaptic size with transmission strength,7 this indicated that myo-inositol improved neuronal connectivity. Furthermore, the number of areas showing colocalization between presynaptic and postsynaptic markers in rat neuronal cultures rose with increasing myo-inositol concentration, which suggested that this micronutrient promotes synapse formation.
To validate the effect of myo-inositol on neuronal connectivity in vivo, Biederer and his colleagues included this sugar in diets fed to mouse pups. Upon immunostaining the visual cortex, they determined that myo-inositol supplementation enlarged the postsynaptic sites in this brain region but did not alter their abundance.
Although myo-inositol increases connectivity in developing brains, the researchers did not know if this micronutrient would have a similar effect in mature brains, which endogenously produce the compound.8 They prepared organotypic brain slices from mice, which are thin sections of living tissue that scientists grow in vitro. After applying myo-inositol to mature organotypic slice cultures, the researchers revealed that myo-inositol increased brain connectivity, indicating that the micronutrient could also be important for adult brains. However, scientists have associated myo-inositol accumulation or depletion with some brain disorders, which suggests that further work is needed before clinicians can recommend myo-inositol supplementation for adult patients.
“The focus on breast milk, and especially the collaboration with a study that allowed them to look at the components of breast milk across groups and across countries, I think was really inspired and a clever way to figure out the central components that are going to be important for brain development,” said Kimberley McAllister, a neuroscientist at the University of California, Davis, who was not involved in the study. “Trying to figure out what we can do from a dietary perspective to promote brain health, and to even potentially prevent or treat brain disease is incredibly important, and it is an untapped area for scientific discovery.”
Although myo-inositol improves neuronal wiring in developing brains, Biederer emphasized that this bioactive compound supports endogenous processes already occurring in the brain, and he did not want his work to contribute to the stress placed on mothers to breastfeed their infants. “Breast milk is the gold standard,” Biederer said. “But we [hope] that our data can be used to improve pediatric nutrition products and help children to reach their potential.”
- Choi BJ, et al. Building a circuit through correlated spontaneous neuronal activity in the developing vertebrate and invertebrate visual systems. Genes Dev. 2021;35(9-10):677-691.
- Penn AA, Shatz CJ. Brain waves and brain wiring: the role of endogenous and sensory-driven neural activity in development. Pediatr Res. 1999;45(4):447-458.
- Paquette AF, et al. The human milk component myo-inositol promotes neuronal connectivity. PNAS. 2023;120(30):e2221413120.
- Horta BL, et al. Breastfeeding and intelligence: A systematic review and meta-analysis. Acta Paediatr Oslo Nor 1992. 2015;104(467):14-19.
- Carbone BE, et al. Synaptic connectivity and cortical maturation are promoted by the ω-3 fatty acid docosahexaenoic acid. Cereb Cortex. 2020;30(1):226-240.
- Woo JG, et al. Specific infant feeding practices do not consistently explain variation in anthropometry at age 1 year in urban United States, Mexico, and China cohorts. J Nutr. 2013;143(2):166-174.
- Holler S, et al. Structure and function of a neocortical synapse. Nature. 2021;591(7848):111-116.
- Bizzarri M, et al. Pharmacodynamics and pharmacokinetics of inositol(s) in health and disease. Expert Opin Drug Metab Toxicol. 2016;12(10):1181-1196.