Scientists have discovered that the human brain is formed from two distinct populations of cells. This finding suggests that during evolution, two nervous systems with very different functions came together to create the human brain we have today. This discovery has allowed researchers to grow hindbrain neurons (the posterior part of the brain that helps regulate vital functions such as breathing and heart rate) in the laboratory; an achievement that opens new avenues for studying diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and other disorders involving the brainstem.
According to ScienceDaily, scientists long regarded the brain as a single organ with a common developmental origin, but a new study led by Stanford School of Medicine challenges this basic assumption and shows that what we call the “brain” may have been built from two distinct systems that evolved separately over hundreds of millions of years.
Under a view that prevailed for decades, all brain regions grow from an initial population of progenitor cells. In that model, the forebrain, midbrain and hindbrain all trace back to a common starting point in development, but the new findings present a different picture.
Researchers found that the human brain apparently combines two nervous systems that evolved in the distant past: one produces structures responsible for vital functions such as breathing and heart rate regulation, and the other creates regions associated with abilities like language, mathematics, abstract thought and reflection on our own existence.
The findings of this study, published in Nature Neuroscience, may help explain why growing some brain cells in the lab has been so difficult. They may also open new opportunities to study brainstem-involving diseases, including spinal muscular atrophy and amyotrophic lateral sclerosis - also known as Lou Gehrig’s disease.
Kyle Luo, an associate professor of developmental biology, said: “For the first time we have shown that the anterior part of the brain arises from a progenitor population completely different from the posterior part. Our discovery means we can now grow hindbrain neurons in the lab and study their function.”
Two developmental origins for the brain
The adult brain is divided into three main parts: forebrain, midbrain and hindbrain. The forebrain contributes to abilities most associated with complex thought, including language, self-awareness and abstract reasoning. In contrast, the hindbrain is located at the back of the skull and helps control automatic processes essential for survival such as breathing, sleep, heart rate regulation and hunger. Hindbrain neurons also control the facial, tongue and throat muscles important for speaking and swallowing.
Despite the vital role of the hindbrain, scientists have long struggled to produce human neurons of this region in the laboratory. That limitation has made studying serious brainstem-involving diseases, including SMA and ALS, much harder.
SMA is one of the leading genetic causes of death in children under one year of age. ALS is often diagnosed between ages 40 and 70 and affects both the forebrain and hindbrain. In both diseases, specific groups of hindbrain neurons gradually lose function. Patients may eventually lose the ability to swallow; a condition that increases the risk of pneumonia if food or liquids enter the lungs. In later stages, they may also lose the ability to breathe.
Pathways separate from the earliest stages of development
The main clue came when researchers examined one of the earliest stages of embryonic development. During gastrulation, the basic body plan begins to form. They found that the hindbrain does not emerge later as a branch of the developmental pathway that gives rise to the forebrain and midbrain. Instead, it follows its own distinct developmental trajectory from the very beginning and forms concurrently with the other parts.
To study this process, researchers examined developing mouse embryos and identified two distinct populations of brain progenitor cells. According to them, one cell population expresses a gene called Otx2 and becomes the forebrain and midbrain. The second population expresses a gene called Gbx2 and forms the hindbrain. The researchers found that these two populations remain separate and do not overlap even in the earliest stages they examined.
The difference became clearer when the team examined chromatin, the material that packages DNA inside cells and helps regulate access to genes. The anterior neural ectoderm, which later makes the forebrain and midbrain, and the posterior neural ectoderm that forms the hindbrain had fundamentally different chromatin landscapes, and these differences effectively placed cells on two separate developmental tracks from the very start.
This finding may explain why previous attempts to create hindbrain neurons were so difficult: researchers were likely trying to redirect progenitor cells toward a path those cells were not capable of taking.
Growing human hindbrain neurons in the laboratory
After discovering that the hindbrain follows an independent developmental path, researchers used that knowledge to solve one of the major laboratory challenges. The team for the first time succeeded in converting human pluripotent stem cells - cells that can become many types of body cells - into functional hindbrain motor neurons.
The produced cells behaved like real hindbrain neurons: they generated electrical signals known as action potentials and produced proteins associated with specific hindbrain regions that control facial muscles and muscles involved in swallowing.
This research could be highly important for scientists studying SMA, ALS and other brainstem-damaging diseases. One of their main obstacles was access to human tissue. For standard research you cannot take brainstem samples from living patients, and therefore directly studying damaged neurons was very difficult. The ability to grow hindbrain neurons in the lab could allow researchers to examine with much greater precision what goes wrong in these diseases.
The hindbrain also plays an important role in another area of medicine: weight control, because it contains neural circuits that regulate hunger - circuits targeted by weight-loss drugs such as semaglutide.