Monday, February 28, 2022

The Ongoing Debate about Hippocampal Neurogenesis in Adult Humans is over.

modified from Franjic et al. (2022). Cross-species comparison shows transcriptomic signatures of neurogenesis in the hippocampus of adult mouse, pig, and monkey but not human.

Does the adult brain generate new neurons throughout the lifespan? The prevailing view in most of the 20th century was that no new neurons are born in the mammalian brain once development ceases. A series of studies in the 1960s showed otherwise, but these were ignored until the 1990s. A now-historical paper from 2000 recounted the death of a dogma: adult neurogenesis is here to stay, even in humans. Thousand of studies in animals (mostly rodents) demonstrated that new neurons are born in the dentate gyrus region of the adult hippocampus, and they can play an important role in learning and memory.

More recently, several papers have questioned whether adult humans really do generate new neurons in the hippocampus (Sorrells et al, 2018, 2021; Franjic et al., 2022). One such paper examined the morphology of dentate gyrus cells taken from post-mortem brains and from tissue surgically removed from epilepsy patients, with ages ranging from prenatal to elderly (Sorrells et al, 2018). The presence of progenitor cells and young neurons was determined using immunohistochemistry (selective staining methods, visible in green and yellow below).

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modified from Fig 2a (Sorrells et al, 2018). Human dentate gyrus (DG) proliferation declines sharply during infancy.

modified from Fig 3d (Sorrells et al, 2018). The number of young neurons declines in the human DG from infancy into childhood.

The paper's title succinctly summarized the findings: “Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.” Immature neurons were rare in the 7 yr old and 13 yr old samples, and absent entirely in adults.

Despite these seemingly convincing results, critiques have identified shortcomings in the way that post-mortem human brain samples are typically processed, as well as other technical issues that affect immunostaining of neurogenic markers (Moreno-Jiménez et al., 2021).

Transcriptomics to the Rescue?

The latest study used different methodology: single-nucleus RNA-sequencing (snRNA-seq) of neurogenic markers in adult hippocampal subregions (Franjic et al., 2022). In a technical tour de force, the authors microdissected samples from five hippocampal subregions from the brains of pigs, macaque monkeys, and humans. Single brain cell nuclei were isolated according to an incredible complex protocol, followed by cellular barcoding, cDNA amplification, sequencing of libraries, single nuclei expression quantification, and hierarchical tree construction. The goal was to create a taxonomy of cell types categorized by gene expression.


  click on image for larger view

Fig 1 (Franjic et al., 2022). Cell type diversity in the human hippocampal-entorhinal system revealed by snRNA-seq. (E) Dendrogram depicting the hierarchical taxonomy across all cell subtypes.

As a cognitive neuroscientist, this level of cellular diversity is astounding and humbling. If you ever feel like you're learning a lot about the how the brain works from fMRI, take a look at the dendrogram above.

Iterative clustering identified 69 transcriptomically distinct cell clusters across all donors that were organized into a dendrogramatic taxonomy reflecting their unique gene expression patterns.

snRNA-seq reveals a neurogenic trajectory in the macaque, pig, and mouse DG that is virtually absent in humans

Using more comprehensive and less disputed methods than previous studies, and incorporating cross-species comparisons, Franjic and colleagues did not observe any signs of neurogenesis in the hippocampus of adult humans. A companion preview article concluded that human adult neurogenesis is unlikely (Nano & Bhaduri, 2022).

These results don't negate or diminish the excellent and informative work on neurogenesis in rodents, but they suggest that the human hippocampus relies on other forms of neuroplasticity to learn and remember.



Franjic D, Skarica M, Ma S, Arellano JI, Tebbenkamp AT, Choi J, Xu C, Li Q, Morozov YM, Andrijevic D, Vrselja Z. et al. (2022). Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron 110: 452-469
Moreno-Jiménez EP, Terreros-Roncal J, Flor-García M, Rábano A, Llorens-Martín M. (2021). Evidences for adult hippocampal neurogenesis in humans. Journal of Neuroscience 41(12):2541-53.
Nano PR, Bhaduri A. (2022). Mounting evidence suggests human adult neurogenesis is unlikely. Neuron 110(3):353-5.
Snyder JS. (2018). Questioning human neurogenesis. Nature 555: 315-316
Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, James D, Mayer S, Chang J, Auguste KI, Chang EF. (2018). Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555(7696):377-81.
Sorrells SF, Paredes MF, Zhang Z, Kang G, Pastor-Alonso O, Biagiotti S, Page CE, Sandoval K, Knox A, Connolly A, Huang EJ. (2021). Positive controls in adults and children support that very few, if any, new neurons are born in the adult human hippocampus. Journal of Neuroscience 41(12):2554-65.

Must-see experiment from Snyder Lab (2014)!  

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