21 Feb 2014

In most regions of the brain, you don’t get a second chance: The neurons you’re born with are the only ones you’ll ever have. Now, researchers have discovered that fresh starts abound in the striatum, a part of the brain that integrates motor and cognitive functions. Measuring tiny traces of carbon-14 that integrated into people’s DNA to date the age of neurons, investigators led by Jonas Frisén at the Karolinska Institute in Stockholm report that the striatum receives regular shipments of neural precursors throughout life. Interestingly, striatal tissue from people with Huntington’s disease lacks these newcomers. Reported in the February 20 Cell, the findings reveal a new pattern of adult brain neurogenesis and, if replicated, open up the potential for new treatment strategies aimed at neurodegenerative disease and stroke.

“The study is elegantly done, and they have really reached the limit of what is achievable in humans,” said Mark Mehler at Albert Einstein College of Medicine in New York City. Mehler was not involved in the study. “The work brings in a whole new parameter—that there are constantly renewing neurons in the striatum.” 

Continuous birth of new neurons has long been known to occur in two regions of the mammalian brain: the dentate gyrus of the hippocampus, and the subventricular zone (SVZ) of the lateral ventricle. In both these places, a well of self-renewing neural stem cells gives rise to rapidly proliferating neuronal precursors, or neuroblasts. Frisén’s lab recently showed that at about 700 neurons per day, neurogenesis in the hippocampus occurs at a higher rate than previously thought. Those new neurons might aid in cognition and the formation of memories (see Jun 2013 news story). However, the fate of neurons generated from the SVZ in people has always puzzled neuroscientists. In most mammals, new neurons migrate from the SVZ to the olfactory bulb, but in humans, the olfactory neuron population is set at birth (see Bergmann et al., 2012).

If not to the olfactory bulb, where do neuroblasts from the human SVZ go? To find out, first author Aurélie Ernst and colleagues checked in the striatum—the SVZ’s next-door neighbor. The researchers stained postmortem brain samples for the neuroblast markers doublecortin (DCX) and polysialylated neural cell adhesion molecule PSA-NCAM. They detected small numbers of marker-positive cells in the hippocampus, as expected, but also in the striatum (see image below). None were detected in the cerebellum, a region thought to harbor no new neurons. Most of the DCX-positive cells in the striatum were devoid of lipofuscin, a pigment that accumulates with age, suggesting that the neurons were no more than a few months old. While the researchers couldn’t rule out that the cells came from elsewhere, the most likely source is the nearby SVZ, Frisén said.

To confirm the age of these young-looking neurons, the researchers employed a method they had developed in previous studies: dating cells based on the concentration of carbon-14 in their DNA. Spewed into the atmosphere by nuclear bomb tests starting in 1955, the isotope integrates into the DNA of dividing cells. Since atmospheric levels of C14 have since steadily declined, the researchers can date cells by comparing their DNA C14 levels to the atmospheric record. Ratios of C14 to other carbon isotopes that correspond to those in the atmosphere after a person’s birth indicate that DNA synthesis and cell turnover has occurred. 

The researchers used accelerator mass spectrometry to measure C14 in neuronal nuclei collected from 30 people ranging from 3 to 79 years of age. In both the lateral ventricle and the striatum, C14 concentrations corresponded to the amount of isotope in the atmosphere after, not at, birth, indicating that the cells were younger than the tissue donors themselves. The researchers found no evidence of cell turnover in the cerebellum or occipital cortex.

“The new findings are good news for SVZ researchers,” wrote Gerd Kempermann, Center for Regenerative Therapies, Dresden, Germany, in a Cell preview to be published February 27. “While the olfactory path for adult-born neurons seems to be limited, going hand-in-hand with the diminished role for olfaction in humans, SVZ precursor cells may be doing something altogether different, and perhaps even more exciting,” he wrote. 

But which cells turn over in the striatum? Two possibilities existed. Interneurons, which make up 25 percent of striatal neurons, forge connections with other neurons in close proximity. Medium spiny neurons, which make up the rest, connect to other regions of the brain. To find out which regenerated, the researchers isolated nuclei from striatal cells, then used flow cytometry to sort them based on nuclear expression of the neuron marker NeuN and the medium spiny neuron maker DARPP32. The investigators chose to sort nuclei rather than whole cells because the approach relies less on the isolation of intact cells, which is difficult from postmortem tissue. C14 measurements showed that interneurons, but not medium spiny neurons, had been replenished since birth. Harmonizing with their C14 findings, a mathematical model used by the researchers suggested that 25 percent of striatal neurons participated in cycling, and that within that population, about 2.7 percent of neurons switched out per year. The turnover rate decreased only modestly with age. 

The findings could be particularly exciting for researchers studying Huntington's, which primarily affects the striatum. The researchers looked for differences in cell turnover in the postmortem brains of 11 HD patients. They found no signs of turnover in the striatum of people with intermediate and advanced stages of HD. However, a low level of renewal was apparent in the striatum of two patients who had been in the early stages of the disease when they died. It was unclear if new neurons were absent from patients with later-stage disease because those neurons were no longer being made, or if those new neurons degenerated. It is possible that both are true in HD, said Frisén. 

HD is marked by degeneration of medium spiny neurons, not necessarily interneurons. However, interneurons provide the microcircuitry that dictates the output of medium spiny neurons, and the field is gaining an appreciation for the importance of this support role, Mehler said. “Subtle degrees of modulation can have dramatic effects on function, such that the small percentage of interneurons that turn over every year could have a big impact on disease.” 

Although repopulating the olfactory bulb appears to be the primary purpose of the SVZ in other mammals, studies in rodents and monkeys have shown that following a stroke, new neurons from the SVZ can switch to seeding the striatum. “Up until this paper, we thought that it would’ve taken some insult like that for those neurons to be rerouted in humans,” Mark Ransome at the University of Melbourne, Australia, who was not involved in the study, told Alzforum. “This paper shows that it is the normal process of the SVZ to populate striatal neurons.” Whether this will make it easier for researchers to harness the pathway and boost neurogenesis in the context of striatal assault remains to be shown, Ransome said. 

Frisén agrees, but hopes that boosting striatal neurogenesis may one day help sufferers of stroke, Parkinson’s disease, and Huntington’s disease.  He said, “Just knowing that there is this intrinsic machinery in the human brain makes it tantalizing to try to crank up this process in situations where striatal neurons are lost.”—Jessica Shugart

Comments

1. • Joana Gil-Mohapel
     Island Medical Program, University of British Columbia AND Division of Medical Sciences, University of Victoria
   • Posted: 04 Mar 2014
   • Paper: Neurogenesis in the striatum of the adult human brain.

   It was well known that the human brain retains a certain degree of plasticity throughout postnatal and adult life. Adult hippocampal neurogenesis has been known to occur in the human brain since the pioneer study by Eriksson and colleagues (Eriksson et al., 1998), and neuroscientists speculate that the occurrence of neurogenesis in that brain region may be important in the role that the hippocampus plays in learning and memory. The study by Ernst et al. adds to this by showing the occurrence of postnatal neurogenesis in a different brain region, the striatum, thus illustrating that the human brain is indeed much more plastic than we had originally thought. That new neurons generated in the subventricular zone migrate not to the olfactory bulb (as they do in rodents), but rather to the adjacent striatum, where they differentiate into a particular neuronal population (interneurons) is surprising. This is a very exciting finding as it opens new avenues for the development of potential restorative therapeutic approaches that can utilize the endogenous neurogenic capacity of the brain to replace damaged or degenerating neurons within this brain region.

   I was very convinced by the detailed analysis the authors performed in this study using the Carbon-14 dating technique. Further to that, they were able to corroborate their Carbon-14 results with complementary immunohistochemical techniques. In particular, they found: (i) a population of striatal interneurons that co-expresses immature neuronal markers; and (ii) the presence of IdU-labeled cells (i.e., recently born cells) that co-express neuronal markers in the striatum. Together, these findings corroborate the Carbon-14 dating results and strongly point toward the generation of new neurons in the human adult striatum.

   As the authors of this paper admit, it is difficult to speculate on the role of these new interneurons at this time. This is in part due to the fact that the role of striatal calretinin-expressing interneurons is essentially unknown because this population of interneurons has not been studied in detail. This study by Ernst et al. will certainly increase interest in this particular type of striatal neuron and I predict that we will know more about their function in the near future. Nevertheless, the fact that new interneurons are being generated in the adult human striatum raises the possibility of using this intrinsic neurogenic capacity to develop neuronal replacement strategies for the treatment of diseases where striatal neuronal populations are depleted.

   At this moment it is not clear whether the lack of generation of new interneurons in the striatum in Huntington's disease (HD) may contribute in some way to the pathogenesis of HD or whether it is a simple by-product of the degenerative process that occurs in this brain region during the course of the disease. Although this population of interneurons is not particularly affected in HD, which primarily targets medium spiny projection neurons, it certainly depends on the synaptic connections and neurochemical signals that it receives from the latter. Thus, it is reasonable to speculate that once medium spiny projection neurons are gone as a result of the HD degenerative process, the remaining neuronal populations are also affected. Within this scenario, even if immature interneurons migrate from the subventricular zone into the striatum in the HD brain, the lack of proper input from adjacent medium spiny projection neurons may hinder their final maturation and integration in the existing circuitry. Ultimately, this will contribute to the overall striatal dysfunction observed in HD.

   Going forward, it will be important to clarify the function of these postnatal-born striatal interneurons. Questions to address in future studies include: (1) do these new interneurons become functionally integrated into the existing striatal circuitry (i.e., do they establish functional synapses with other striatal neurons)? And (2) are they functionally distinct from striatal interneurons that were born during development? These are complex questions to address in humans and it may be necessary to use cellular- and/or animal-based models to tackle these issues. Additionally, it will be important to further explore the role that interneurons play in the neuropathology of HD. Again, using animal models (such as some of the available HD transgenic mouse lines) might help with providing some insight into this issue.

   References:

   Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med. 1998 Nov;4(11):1313-7. PubMed.

   View all comments by Joana Gil-Mohapel

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References

News Citations

1. Newborn Neurons Abundant in Adult Human Hippocampus 7 Jun 2013

Paper Citations

1. Bergmann O, Liebl J, Bernard S, Alkass K, Yeung MS, Steier P, Kutschera W, Johnson L, Landén M, Druid H, Spalding KL, Frisén J. The age of olfactory bulb neurons in humans. Neuron. 2012 May 24;74(4):634-9. PubMed.

Further Reading

Papers

1. Ransome MI, Renoir T, Hannan AJ. Hippocampal neurogenesis, cognitive deficits and affective disorder in Huntington's disease. Neural Plast. 2012;2012:874387. Epub 2012 Jun 27 PubMed.
2. Kempermann G. Off the beaten track: new neurons in the adult human striatum. Cell. 2014 Feb 27;156(5):870-1. PubMed.

News

1. Dating the Birth of Human Cells—Carbon 14 Runs Rings around Competition 15 Jul 2005