The Invisible Roots of the Mind: Mental Disorders That Begin Before Birth

Scientists have discovered that many genes linked to diseases such as autism, schizophrenia, and Alzheimer's begin to function in the first weeks of fetal brain formation. These early changes in brain stem cells can affect how the brain develops and increase the risk of mental disorders later in life. The discovery helps better understand the origins of these diseases and paves the way for earlier diagnoses and more personalized treatments.

Our brains begin to form in the first weeks of life in the womb, from neural stem cells, special cells that will give rise to all types of neurons and supporting structures.

A groundbreaking new study has shown that many genes linked to diseases such as autism, depression, schizophrenia, Alzheimer's, and Parkinson's are already active in this very early phase of brain formation, well before birth and any symptoms appear. This means that the origin of many of these disorders may be linked to genetic alterations that affect fetal development.

These neural stem cells are guided by specific chemical and genetic signals that tell them what to become, where in the brain to be, and when to act. If these instructions are disrupted, either through inherited or acquired genetic mutations or environmental influences, the brain can develop differently than expected.

This can result in malformations in the cerebral cortex (the outermost and most complex region of the brain) and increase the risk of neurodevelopmental disorders and mental illness later in life.

To better understand how all this works, researchers used data from human and mouse brains, as well as laboratory models made with human stem cells grown in dishes.

The scientists compiled lists of genes linked to various brain diseases, such as microcephaly, epilepsy, hydrocephalus, autism, schizophrenia, ADHD, depression, Alzheimer's and Parkinson's, among others.

They analyzed nearly 3,000 genes previously linked to various brain diseases and simulated how activating or inhibiting these genes affected brain cell behavior at different stages of development. This allowed them to map "critical windows," periods of time during which certain cells are most vulnerable to genetic alterations.

These diseases generally involve problems in the development of the cerebral cortex, the part of the brain responsible for functions such as thought, memory, and behavior.

To understand when and where these genes act in the developing brain, researchers analyzed their activity in very young human brain cells, in the first trimester of pregnancy, and in laboratory models that mimic this development.

They found that risk genes are activated at specific times and in different types of neural stem cells. For example, genes linked to microcephaly and hydrocephalus act in the early stages of brain formation, when cells are still multiplying and defining their functions.

Genes related to autism and epilepsy appear to act in slightly later stages, when cells begin to develop into neurons. The study also showed that some diseases share risk genes with others, indicating that different disorders may arise from similar problems occurring at different times in brain development.

Furthermore, when comparing data from humans with mouse data, scientists observed similar patterns of activation of these genes, which reinforces the results. Finally, they analyzed two genes closely linked to autism, FMRP and CHD8, and realized that, although they are strongly linked to autism, they are also involved in other diseases depending on the phase of the brain in which they act.

In short, the researchers identified "critical windows" in brain development where certain genetic mutations can have more severe impacts, suggesting that many brain diseases can begin in fetal life, long before any symptoms appear.

The study also identified patterns of gene activity shared by several different diseases. For example, genes that affect the early formation of certain areas of the brain may be linked to both autism and schizophrenia, even though these diseases have very different symptoms.

Furthermore, the team of scientists simulated the impact of dysregulating these regulatory genes (called transcription factors) and observed how this alters the fate of cells, whether they become neurons or glia, and whether they occupy the right place in the brain.

A particularly interesting point was the use of stem cells derived from autistic patients. In these cells, the researchers observed alterations in the genes responsible for coordinating the general plan of brain formation—that is, the "map" of where each type of cell should be located.

This reinforces the idea that autism, like other neurological diseases, may have its roots planted long before the first symptoms appear, during the early construction of the brain.

The figure shows how certain genes are controlled (regulated) by other proteins called transcription factors (TFs) during the development or change of a specific cell type (hNSCs, which are human neural stem cells). They analyze this under different conditions and time points to better understand diseases. a) Proportion of target genes for each disease regulon. What is a "regulon"? It's a group of genes that are regulated (turned on or off) by the same transcription factor (TF). They show, for each core transcription factor, how many genes it controls in neural stem cells (hNSCs) at various stages and under certain conditions (with or without FGF2). Each TF is highlighted by when its activity (expression) level is highest, and this highlighting has a statistical value indicating whether this observation is reliable. They also show the total number of genes belonging to these regulatory groups. b) Correlation of expression between core TFs and their target genes. They check whether the activity of the TF and the genes it controls rise and fall together (positive correlation) or in opposite directions (negative correlation). They show how many genes have this significant relationship, both positive and negative, for each disease analyzed. If a high number of genes with this correlation is identified, they highlight this as statistically significant (with symbols such as * or *). They also use colors to indicate at what stage of development the TF's expression was highest. c) Predicted regulatory network. They show a network-like diagram, where each "node" is a gene, and the connections indicate that one TF controls another TF or gene. Genes are colored according to the disease to which they are related. If a TF appears in more than one group, the thicker line indicates the disease in which it is most important. The size of the node indicates how many connections that gene has with other genes. The background of the colors indicates when (at what stage) that TF is most active, as in part (a).

Furthermore, computer simulations revealed how different alterations in these genes, depending on the timing and the cell affected, can lead to different symptoms or even different diseases. Scientists also identified regulatory genes (such as those in the KLF family) that function as true "master controllers" of brain development.

By integrating large databases and using advanced computational tools, the study proposes a new way to understand the origin of mental and neurological diseases from fetal life onward and points the way to more personalized treatments in the future.

These discoveries have great potential for the future. Knowing exactly when and where genes linked to diseases act could enable the development of more precise therapies that directly target the biological causes of these conditions. This paves the way for earlier diagnoses, personalized treatments, and even prevention approaches.

The study represents an important advance in understanding how the brain forms and how subtle errors in this process can have profound impacts on mental and neurological health throughout life.

READ MORE:

Early developmental origins of cortical disorders modeled in human neural stem cells

Xoel Mato-Blanco, Suel-Kee Kim, Alexandre Jourdon, Shaojie Ma, Sang-Hun Choi, Alice M. Giani, Miguel I. Paredes, Andrew T. N. Tebbenkamp, Fuchen Liu, Alvaro Duque, Flora M. Vaccarino, Nenad Sestan, Carlo Colantuoni, Pasko Rakic, Gabriel Santpere, and Nicola Micali 

Nature Communications, volume 16, Article number: 6347 (2025) 

https://doi.org/10.1038/s41467-025-61316-w

Abstract: 

The implications of the early phases of human telencephalic development, involving neural stem cells (NSCs), in the etiology of cortical disorders remain elusive. Here, we explore the expression dynamics of cortical and neuropsychiatric disorder-associated genes in datasets generated from human NSCs across telencephalic fate transitions in vitro and in vivo. We identify risk genes expressed in brain organizers and sequential gene regulatory networks throughout corticogenesis, revealing disease-specific critical phases when NSCs may be more vulnerable to gene dysfunction and converging signaling across multiple diseases. Further, we simulate the impact of risk transcription factor (TF) depletions on neural cell trajectories traversing human corticogenesis and observe a spatiotemporal-dependent effect for each perturbation. Finally, single-cell transcriptomics of autism-affected patient-derived NSCs in vitro reveals recurrent expression alteration of TFs orchestrating brain patterning and NSC lineage commitment. This work opens perspectives to explore human brain dysfunction at early phases of development.