Recently, I came across an article proposing the non-existence of new neuron generation in the adult human brain [1]. This surprised me, as I had long come to assume the existence of neurogenesis in adulthood. Not long ago, I even read that the activity of neurons formed in adult mouse brains during sleep is necessary for memory [2]. As a scientist, I also wondered how the non-existence of something could be studied in-depth. A few days later, a critique of this article showed up to defend the potential of neurogenesis [3]. Confused but interested, I decided to dive deeper and came to realize adult human neurogenesis has been an ongoing debate for over twenty years [7].
Neurogenesis refers to the generation of neurons from neural progenitors or neural stem cells [4]. Over centuries, it has been widely believed that neurogenesis occurs only before birth, and the brain is incapable of regenerating after damage during adulthood [5]. However, a small stream of scientists has claimed that adult neurogenesis occurs in songbirds, rodents, and non-human primates [6]. This discovery of neurogenesis and its functions in learning and memory in other species elicited excitement, as it suggests potential neurogenesis in adult humans.
Why does human neurogenesis matter? If adult human neurogenesis is a real phenomenon, two thrilling future directions could be realized: (1) scientists and doctors could make up lost brain tissue by activating the sleeping neural progenitor cells or transplanting neurons; and (2) humans could be trained to “be smarter” by increasing neurogenesis so as to have more neurons for memory and learning [2-4].
A neuron (green and white) in an insect brain (blue). Credit: NICHD/N. Source: https://upload.wikimedia.org/wikipedia/commons/c/ca/Insect_neuron.png
The difficulty of settling this debate, similar to many debates in science and even philosophy, is that it is impossible to definitively prove the non-existence of something - rather, evidence may be used to cast doubt on certain hypotheses or to provide alternative explanations for something. From the other side, to prove the existence of neurogenesis in adults, a common strategy has been to look for biomarkers such as proteins or RNA species that only newly-generated neurons would contain [2].
A newer and more powerful method that expands on this strategy is RNA sequencing [8, 9]. Compared to previous methods that could only probe a few RNA species at a time, RNA sequencing collects and uses thousands of RNA species to identify newly generated neurons.
Researchers who have used RNA sequencing did not find evidence for neurogenesis. Though some scholars have accepted this conclusion, others argue that more research is required to settle the debate and have pointed out pitfalls of the technique.
First, cell types identified via RNA sequencing require previous knowledge of cell type-specific RNA species. In other words, you need to already know what you are looking for. Accurately identifying adult-born neurons is challenging because their biomarkers are not yet completely resolved. For example, a gene named LPAR1 was recently reported as a neural progenitor cell population marker, only to be debunked by Frantic and colleagues who pointed out that LPAR1 identifies other known proliferative cell groups such as oligodendrocytes and granule cells [8].
Doublecortin (green) and Hoechest (blue) staining in the hippocampus of adult mice brain. Doublecortin is a commonly used marker for newborn neurons in rodents, while not yet in humans. Source: https://upload.wikimedia.org/wikipedia/commons/3/3f/GFAP-driven_thymidine_kinase_20x_-_color_combo2_%285928301834%29.jpg
Secondly, the sample handling process, from collecting brain tissue to isolating single brain cells, is usually lengthy and stressful for the cells. As a result, RNA species are likely missing, potentially including those for adult-born neurons.
In addition to these technical restraints, some alternative hypotheses attesting to the undetectability of adult human neurogenesis have been proposed. For example, it is likely that any adult-born neurons would be suppressed and silenced under healthy conditions, and activated only under diseased conditions. Another possibility is that new adult-born neurons die if they cannot integrate into existing brain circuits, thus evading their detection [3, 10].
In rodents, neurogenesis has only been found in the olfactory system, which serves the sense of smell, and in the hippocampus, which plays a huge role in learning and memory [11]. Rodents rely heavily on their sense of smell for navigation and memory, whereas humans have developed more extensive systems, such as visual cues. It would be interesting to probe for neurogenesis in human individuals who rely more heavily on the olfactory system, or neurogenesis in the visual cortex.
Another possibility of course is that neurogenesis is unable to be detected in human adults simply because it does not exist. Evidence suggests that aquatic mammals, dolphins, porpoises, and whales also lack neurogenesis [12]. It is therefore conceivable that mammals with complex behaviors, larger brains, and longer longevity do not utilize neurogenesis as a support for their brain function.
“We hope that neurogenesis is real in the human brain. It is good to have hope,” says a researcher who is studying neurogenesis in rodents. Whether one is hoping for its existence or trying to prove its non-existence, we are in an exciting time with many ongoing neurogenesis studies in humans fueling the next stage of the debate. With all these hypotheses and alternate explanations, the existence or nonexistence of neurogenesis may eventually segue into another fundamental question in science: what makes us humans special compared to other species?
Edited by Josephine Wu
References
“争鸣：成年人脑内不再有新生神经元？” 知识分子，http://zhishifenzi.com/news/multiple/12087.html. Accessed 14 Feb. 2022.
Kumar, Deependra et al. “Sparse Activity of Hippocampal Adult-Born Neurons during REM Sleep Is Necessary for Memory Consolidation.” Neuron vol. 107,3 (2020): 552-565.e10. doi:10.1016/j.neuron.2020.05.008
“争鸣：成人大脑中有没有神经干细胞？让子弹再飞一会儿。”知识分子，http://zhishifenzi.com/news/multiple/12101.html. Accessed 14 Feb. 2022.
Abdissa, Daba, et al. “Review Article on Adult Neurogenesis in Humans.” Translational Research in Anatomy, Elsevier, 22 Apr. 2020, https://www.sciencedirect.com/science/article/pii/S2214854X20300133.
Lima, Silene M A, and Walace Gomes-Leal. “Neurogenesis in the hippocampus of adult humans: controversy "fixed" at last.” Neural regeneration research vol. 14,11 (2019): 1917-1918. doi:10.4103/1673-5374.259616
Kumar, Ashutosh et al. “ADULT NEUROGENESIS IN HUMANS: A Review of Basic Concepts, History, Current Research, and Clinical Implications.” Innovations in clinical neuroscience vol. 16,5-6 (2019): 30-37.
Gage, Fred H. “Neurogenesis in the Adult Brain.” Journal of Neuroscience, Society for Neuroscience, 1 Feb. 2002. https://www.jneurosci.org/content/22/3/612.
Franjic D, Skarica M, Ma S, et al. Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron. 2022 Feb;110(3):452-469.e14. DOI: 10.1016/j.neuron.2021.10.036. PMID: 34798047.
Ayhan, Fatma, et al. “Resolving Cellular and Molecular Diversity along the Hippocampal Anterior-to-Posterior Axis in Humans.” Neuron, Cell Press, 28 May 2021, https://www.sciencedirect.com/science/article/pii/S0896627321003299.
Ciric, Tina et al. “Dentate gyrus neurons that are born at the peak of development, but not before or after, die in adulthood.” Brain and behavior vol. 9,10 (2019): e01435. doi:10.1002/brb3.1435
Speculation on olfactory reliance in rodents?
Patzke, N., Spocter, M.A., Karlsson, K.Æ. et al. In contrast to many other mammals, cetaceans have relatively small hippocampi that appear to lack adult neurogenesis. Brain Struct Funct 220, 361–383 (2015). https://doi.org/10.1007/s00429-013-0660-1
