Snapshot: What is Neurogenesis?

Neurons are the cells that serve as building blocks of the nervous system. The brain contains an enormous variety of neurons, and they all need to get a start somewhere. The process by which neurons are formed is called neurogenesis.

An artist’s drawing of neurons in the brain. Photo used under license by Andrii Vodolazhskyi/Shutterstock.com.

When does neurogenesis happen?

Nearly all neurogenesis occurs before the age of 2 when the brain is in the early stages of being formed and refined. While most cells in the body are replaced as they wear out or get injured, neurons in the brain do not. By young adulthood, the brain has largely stopped making new neurons. Other than serving as an excellent reason to wear a helmet and otherwise protect your head from injury, this lack of new neuron formation doesn’t have a noticeable effect on how we go about our daily lives. After all, neurons are an incredibly adaptable cell type that readily change in response to a person’s environment and experiences.

In the past few decades, we have learned that there is an exception to the “all neurons are born early in life” rule. Some research has shown that new neurons can, in fact, be formed during adulthood in specific brain areas. For example, the hippocampus, a brain structure important for its role in forming and maintaining memories, continues to create neurons over the course of one’s life.

The purpose of these newly generated neurons is still debated. However, numerous studies have shown that neuron formation in the hippocampus is reduced in instances of psychiatric and neurodegenerative disorders. This includes certain types of ataxia like SCA1. This is thought to contribute to changes in cognitive function and mood, though the exact mechanisms are still being determined.

Why is neurogenesis interesting for the spinocerebellar ataxias (SCAs), aren’t these neurodegenerative disorders?

Since the discovery of neurodegenerative disorders, most research has focused on symptoms and how to delay symptom onset. This view sees neurodegenerative disorders, like the SCAs, as outcomes of mid to late-life when the toxic effects of mutant proteins become suddenly rampant. However, these disorders are caused by proteins that are present from the very earliest stages of brain formation.

In 2018, researchers studying SCA1 found that neurogenesis is increased in the cerebellum of young mice. This changed how the cerebellum communicates with the rest of the brain. This suggests that cerebellar function can be affected by more than neuronal loss. It could be of wider interest in the SCAs given the cerebellar dysfunction that is common between them. No research on cerebellar neurogenesis has been performed in other SCAs by this point. However, there are some indications that neurogenesis may also be altered in SCA2.

Additionally, Huntington’s Disease, a polyglutamine repeat disorder in the same disease family as several SCAs, has been shown to have increased neurogenesis in the cortex in both young mice and prenatal babies. The combination of these recent studies has made early neuron formation an area of key interest in the study of neurodegenerative disorders.

Current theories in the field contend that while the brain can compensate for changes in neuron numbers in early life, altered neurogenesis could be creating unique brain circuitry in individuals with known disorder-causing protein mutations. These changes could make them more vulnerable to neuronal dysfunction and neurodegeneration later in life.

Evidence for changed neurogenesis in SCAs, both early and late in life, adds a new layer of consideration to what we broadly think of as a mid- to late-life neurodegenerative disease. Additional research in coming years will hopefully provide more insight into how these additional facets of neural health may inform the development of new therapies.

If you would like to learn more about neurogenesis, take a look at these resources by the Queensland Brain Insitute and News-Medical.

Snapshot written by Carrie Sheeler and edited by Dr. Chloe Soutar.

Additional References

Cvetanovic M, Hu YS, Opal P. Mutant Ataxin-1 Inhibits Neural Progenitor Cell Proliferation in SCA1. Cerebellum. 2017 Apr;16(2):340-347. doi: 10.1007/s12311-016-0794-9. PMID: 27306906; PMCID: PMC5510931.

Shukla JP, Deshpande G, Shashidhara LS. Ataxin 2-binding protein 1 is a context-specific positive regulator of Notch signaling during neurogenesis in Drosophila melanogaster. Development. 2017 Mar 1;144(5):905-915. doi: 10.1242/dev.140657. Epub 2017 Feb 7. PMID: 28174239; PMCID: PMC5374347.

Xia G, Santostefano K, Hamazaki T, Liu J, Subramony SH, Terada N, Ashizawa T. Generation of human-induced pluripotent stem cells to model spinocerebellar ataxia type 2 in vitro. J Mol Neurosci. 2013 Oct;51(2):237-48. doi: 10.1007/s12031-012-9930-2. Epub 2012 Dec 9. PMID: 23224816; PMCID: PMC3608734.

Barnat M, Capizzi M, Aparicio E, Boluda S, Wennagel D, Kacher R, Kassem R, Lenoir S, Agasse F, Braz BY, Liu JP, Ighil J, Tessier A, Zeitlin SO, Duyckaerts C, Dommergues M, Durr A, Humbert S. Huntington’s disease alters human neurodevelopment. Science. 2020 Aug 14;369(6505):787-793. doi: 10.1126/science.aax3338. Epub 2020 Jul 16. PMID: 32675289; PMCID: PMC7859879.

Snapshot: What is the Hippocampus?

How do you remember your name? Thank your hippocampus, a part of the brain that lies buried in the cerebrum and plays an important role in memory. The hippocampus looks like a seahorse when removed from the brain and hence the name (derived from Hippokampus, the Greek word for seahorse). Our brain consists of two hippocampi, one in each brain hemisphere.

One of the most striking feature of the hippocampus was observed by the Nobel laureate, Santiago Ramón y Cajal, in the 19th century. Cajal recorded his microscopic observation of the hippocampus in the form of beautiful hand drawings:

A very detailed sketch of the hippocampus on paper. The drawing looks very old.
The hippocampus, ink on paper – original drawing by Cajal. See more of Cajal’s drawings in this blog post by Margaret Peot.

He documented that neurons were arranged in unique layers in the hippocampus, a ground-breaking observation that proved to be useful several years later in studying how these neurons communicate with each other and form a circuit (think of it like a logic gate) for collecting and storing memories.

What is the function of the hippocampus?

In the 1950s, a patient named Henry G. Molaison, referred to as patient H.M., suffered from a severe form of epilepsy and went through a surgical procedure where a portion of his brain was removed in an effort to treat epilepsy. His surgery was of moderate success. He managed mild epilepsy for the next 58 years, however, he tragically lost the ability to form new memories as most of his hippocampi were removed during surgery.

H.M. served as the longest case study in history to understand the formation of memory in humans. The hippocampus is important for formation of new memories that we experience, known as explicit memory. This mostly involves remembering facts or events and over a period of time they get stored away permanently as long-term memory by a process called memory consolidation.

From H.M.’s case study it was clear that he was unable to form new memories as he lost the ability to consolidate them for future use. However, some of his long-term memory before the surgery such as events from his childhood or facts about his parents remained intact. This was fascinating for scientists as they were able to conclude that the hippocampus is necessary for memory consolidation but not for memory retrieval – a process required for recollecting memories from the place it was stashed away (this storage space could be in other brain regions), as in the case of H.M.’s older memories before his surgery.

The hippocampus also acts like a GPS in our brain and is important for another type of memory called spatial memory. Groups of cells in the hippocampus called “place cells” co-ordinate with another group of cells called the “grid cells” that exist in another brain region, and help us remember directions and navigate the space around us. The scientists who discovered these cells, John O’Keefe, May Britt-Moser and Edvard Moser were awarded the 2014 Nobel Prize in Physiology and Medicine.

How is the hippocampus affected in neurological disorders?

Many neurological disorders have ties to dysfunction/degeneration of the hippocampus.  Most notably is Alzheimer’s disease (AD), with one of the earliest AD disease symptoms being the loss of spatial memory and short-term memory. A previous article summary in our website also explores how an ataxia related gene increases the risk for Alzheimer’s disease.

If you would like to know more about the story of H.M. and how he transformed our understanding of memory, you can learn more by reading “Permanent Present Tense” by Suzanne Corkin.

If you would like to learn more about the hippocampus, take a look at these resources by Medical News Today and Verywell Mind.

Snapshot written by Dr. Chandana Kondapalli and edited by Dr. Hayley McLoughlin.