Know Your Brain: Neurogenesis — A Germ Of A Thought

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neurogenesis
A new neuron. Photo: Jason Snyder via CC BY 2.0

Fewer ideas in neuroscience have been as fundamentally wrong and widespread as the notion that the human brain doesn’t generate new cells — that we have a peak number of neurons once we reach adulthood and can’t grow new ones — with only a short window of time to build up all the smarts we will ever have in life. It’s a relatively new idea, even in the fairly young field that is neuroscience — with researchers only scratching the surface about three decades ago.

To understand how we form brain cells — particularly neurons — in the first place, and continue to grow them throughout our lives, we must investigate the process known as “neurogenesis.” Even before we are born, the process is very much taking place, as a region called the neural tube begins to form the central nervous system and releases “neural stem cells” (NSC) that begin to accumulate within the embryo. Once a significant number of these NSCs have piled up, they take on an elongated, radial shape, taking the form of large glial or “glue” cells.

The glial cells divide once again, splitting off into neuronal precursors, which will divide themselves between one and three more times into neurons. Rather than form attachments as soon as they develop, a great deal of molecular movement throughout the brain must disperse each newly formed neuron to its current space, connecting with proteins and then diffusing through the nervous system using the Notch signaling pathway. Neurons born within the ventricular zone, for example, must then make their way to the cortical plate.

As we grow, the birth of neurons is confined to two regions of the brain. There’s the subventricular zone, found within the brain’s hippocampus. Here, the NSCs produce granule cells — extremely small cellular bodies that play a role in memory formation and learning. Second, is the subventricular zone, where NSCs migrate toward the olfactory bulb and produce interneurons that connect the brain regions used for our sense of smell. While olfactory bulb neurons continue to appear in mammals after birth, this is rarely the case in humans. Our sense of smell has often played a close role with memory formation — being just one bit of sensory data we use when producing memories — and learning and memory are at least two known functions that adult neurogenesis plays a role in.

Neurogenesis And The Spectrum

Although spectrum disorders that we frequently associate with autism have been linked to hundreds of genes expressed throughout the body, researchers at the University of California, San Francisco isolated 10 different genes associated with autism that also play a role in neurogenesis, after they sought to find out where the genes cause their effects by interacting.

“Finding shared risk and resilience factors sustains our hope that the field can use the study of individual genes to find treatment targets that work more broadly,” said the study’s lead investigator Dr. Matthew State, a professor of psychiatry and behavioral sciences at the University of California, San Francisco.

Using new CRISPR gene-editing technology, State and his team of researchers looked at genes in a species of aquatic clawed frog known as Xenopus tropicalis, the same species used as a genetic model in most biomedical research. While mice and rats tend to make for the most common test subjects in autism research, Xenopus has a specific advantage: When the first fertilized cell of the embryo splits in half, each daughter cell and its subsequent progeny keeps to its own space.

If State’s team were to edit a gene on the left side of one daughter cell, for example, it would then develop into a tadpole with that same mutation occurring in the entire left half of its body — but only on that side. The researchers are also able to monitor brain development as it occurs in the tadpoles that happen in utero to humans and other mammals. As the convergence began in the developing tadpoles, the team saw indications that all 10 of these genes play a part in the initial development of neurons. Getting a more detailed picture of this process could be the way to find better autism treatments, although there are still some roadblocks ahead, and mechanisms to understand further.

“What we really need right now is a molecular mechanism,” says Willsey. “In order to get therapeutics, we need to know what these genes are doing, what’s in common to them and what are some pathways we could manipulate.”

The Developing Brain

In just one day, a single pair of Xenopus frogs is capable of producing thousands of embryos, which in about a week, grow into freely swimming tadpoles.

Within each of the embryo used for the study, researchers selected and edited one of 10 genes strongly correlated with autism: ADNP, ANK2, ARID1B, CHD2, CHD8, DYRK1A, NRXN1, POGZ, SCN2A, or SYNGAP1. Each of them is expressed inside the frogs’ cerebrum at different stages similar to what prenatal brain development looks like in people, another important discovery by the team.

Tadpoles who hatched with any of these mutations either exhibited an unusually large or characteristically smaller cerebrum than their counterparts. All of the mutations also contained a larger proportion of the neural progenitor cells than the controls did as well.

“That’s what was so surprising to us,” said Willsey. “Even for genes that are thought to be primarily at the synapse, we still saw changes in brain size and neural progenitor maturation.”

In the brain of a human infant, these 10 genes, and an additional 92 others that play a role in autism, act as blueprints that signal proteins within the cortex to set off the process of neural differentiation.

The researchers set their sights on the expression of DYRK1A and slowed it down in the brains of their tadpoles with a chemical inhibitor. They then tried cancer drugs that suppress cell growth and found that 17 compounds altered the progenitor cell ratio, particularly altering the body’s use of estrogen. This caused the tadpoles’ cerebrums to reduce to the same size as cerebrums that strongly expressed the genes associated with autism.

Restoring estrogen to the deprived cells brought their development signals back to normal, suggesting it plays a crucial role in the creation of neurons. While estrogen itself isn’t a viable option for treatment, pinpointing the exact role it plays could lead researchers to a potential cure. The impact of estrogen could potentially be one reason why higher rates of autism are observed in men than women, according to Willsey, although an obvious outlier is that spectrum disorders may simply be underdiagnosed in women. Estrogen has also been known to decrease hyperactivity in zebrafish who had mutations in a different autism-linked gene, CNTNAP2.

Where Do We Go From Here?

The team’s method could be useful for both screening drugs and studying genes whose functions are less well known, says Dr. Sarah Elsea, professor of molecular and human genetics at Baylor College of Medicine in Houston, Texas, who did not partake in the research.

“The process they laid out is quite nice,” she says. “It’s a template to do additional work.”

It could also help researchers identify drugs to alleviate specific difficulties seen in autistic people with different underlying genetics, such as circadian rhythm disruptions that lead to sleep problems, Elsea says.

“One of the greatest possible outcomes that we have from something like this is that there might be one medication that works in individuals who have autism associated with those 10 genes,” Elsea says. “Maybe there is something that could be identified that would help make their days just a little bit better.”

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We believe that neuroscience is the next great scientific frontier, and that advances in understanding the nature of the brain, consciousness, behavior, and health will transform human life in this century.

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