Does the Adult Human Brain Make New Neurons? Part Three: Beyond the Hippocampus

Abstract

The first two parts of this series followed a dispute conducted almost entirely within one structure. Both camps examined the dentate gyrus of the hippocampus, disagreed about what was in it, and drew conclusions about the adult human brain from that single site.

This part steps outside that frame, following a 2020 review in Frontiers in Cellular Neuroscience that surveys the evidence for neuron formation in regions outside the two classical zones — the hypothalamus, the striatum, the substantia nigra, the cortex, and the amygdala.

A warning about what follows, which we place at the top because it governs everything: most of this evidence comes from rodents. Where human data exist we say so explicitly, and where they do not we say that too. The most interesting findings in this article are the two places where human evidence is strong — one positive, one firmly negative.

1.The Frame Both Sides Accepted

For most of the past fifty years, adult neurogenesis has meant two places: the dentate gyrus of the hippocampus, and the subventricular zone lining the lateral ventricles, whose new cells migrate toward the olfactory bulb. These are the classical niches, and the stages of development within them are described in detail.

That framing is a historical accident as much as a biological fact. Those regions were where the first labelling studies looked, and once a field establishes where to look, subsequent work tends to look there. The review's premise is that new neurons have since been reported in several other regions, and that the question of whether the adult brain generates neurons has been answered too narrowly.

2.The Striatum: The Strongest Human Evidence Outside the Hippocampus

If any region outside the classical niches has a solid claim to adult neurogenesis in humans, it is the striatum, and the reason is that it was examined with the same isotopic method described in Part One.

Ernst and colleagues applied carbon-14 birthdating — using the atmospheric signature left by Cold War nuclear testing — to human striatal tissue, and reported evidence of neurons generated during adulthood. This is a different kind of finding from a marker study. It does not depend on a protein surviving postmortem delay, and it does not require anyone to judge whether a cell looks immature.

There is supporting circumstantial evidence. Transcriptome analysis of human tissue found doublecortin levels in the striatum comparable to those in the hippocampus. Calretinin-expressing neurons of the relevant class have been reported in the striatum of rats, monkeys and humans, though in varying amounts across species.

Notably, the human pattern appears to differ from the rodent one. In rodents, new striatal neurons are generated largely in response to injury such as ischaemia. The human finding suggests a process occurring under ordinary conditions. If that holds, it is a case where extrapolating from the mouse would have given the wrong answer in both directions — predicting no baseline turnover, and predicting an injury response that may not translate.

3.The Cortex: A Negative Result Worth Taking Seriously

The cerebral cortex is where the popular imagination places the interesting parts of the mind, and it is where the human evidence is most clearly negative. This deserves emphasis, because negative results in this field are usually contested and this one has held up.

The laboratory picture looked promising. Arsenijevic and colleagues isolated progenitor cells from adult human frontal and temporal cortex, and showed that treating them with growth factors produced multipotent neurospheres — clusters capable of generating multiple cell types. On that basis, the adult human cortex clearly retains some latent neurogenic potential.

The isotopic evidence points the other way. Bhardwaj and colleagues measured carbon-14 in postmortem cortical tissue from individuals whose exposure history was known, and found that none of the mature neurons examined carried the signature of DNA synthesised during adulthood. The cortical neurons a person has as an adult appear to be the ones they had as a child.

A later analysis using the same approach found that cortical stroke did not appear to induce or increase neurogenesis in humans, closing off the possibility that injury unlocks the potential seen in the dish. The review's conclusion is unambiguous: generation of new neurons in the human cortex is unlikely to continue into adulthood.

We highlight this because it is the clearest example in the whole series of the gap between what cells can do when removed from the body and what they do inside it. A progenitor cell that forms neurospheres in culture is demonstrating a capacity, not a behaviour.

4.The Amygdala: Immature Neurons That Are Waiting

The most intriguing human finding in the review concerns the amygdala, and it comes from the same group whose hippocampal work anchored Part Two — which is worth noting, because it shows a laboratory reporting a positive finding in one structure while arguing for a negative one in another.

In the paralaminar nuclei of the human amygdala, they identified a population of cells co-expressing doublecortin and PSA-NCAM — the same pair of markers at issue in the hippocampal dispute. The interpretation is different, however, and this is what makes the finding unusual. Rather than a stream of newly born cells, this appears to be a population of neurons generated earlier and held in an immature state, with maturation continuing through adolescence and potentially influenced by experience.

That is a conceptually distinct idea from neurogenesis as usually discussed. It proposes a reserve: cells already present, arrested part-way through development, available to be recruited later. Whether that reserve is refilled in adulthood is a separate question the finding does not answer.

5.The Hypothalamus: Mostly Rodent, But Not Only Rodent

The hypothalamus regulates appetite, energy balance, reproduction and social behaviour, and the rodent literature suggests it also generates new neurons in adulthood, with the process responsive to metabolic state and to signalling molecules that alter body weight.

The human evidence is thinner and we will not overstate it. Doublecortin-positive neuroblasts have been detected in the hypothalamus of mice, sheep and humans, though with somewhat different distributions across the three. The functional work — linking these cells to feeding behaviour, to mating, to social function — is rodent work, and the review is explicit that whether it extends to humans remains to be determined.

We include the region for completeness and because the human cell detection is real. Everything downstream of that detection should be read as a hypothesis about humans, not a finding.

6.Reading Across Species Without Fooling Yourself

The pattern across these regions is instructive. In the striatum, human and rodent findings diverge in the specifics. In the cortex, the rodent-derived expectation that latent potential implies actual turnover is contradicted by human isotopic data. In the hypothalamus, the cells are found across species but the functional consequences are established in only one.

This is the same problem that generated the hippocampal dispute, in a different form. Markers, timescales and functional interpretations calibrated in rodents are being applied to a brain that is larger, longer-lived, and — on the evidence of the striatal comparison — does not necessarily do the same things in the same places.

The review is candid that the presence and significance of adult neurogenesis in the human brain, and particularly outside the classical zones, remains an area of debate. That is the correct register, and it is worth contrasting with how these findings tend to be described elsewhere.

7.Why the Map Matters More Than the Verdict

Taken together, the three parts of this series describe a field in a state that is uncomfortable but not unhealthy. A central claim is genuinely contested. The methods that would resolve it are improving but incomplete. The most reliable human evidence — isotopic birthdating — is available for only a few regions, and where it is available it has produced one clear positive result, in the striatum, and one clear negative, in the cortex.

What changes when you widen the frame is the shape of the question. 'Does the adult human brain make new neurons?' has no single answer, because the brain is not one tissue. It appears to be yes in the striatum, no in the cortex, disputed in the hippocampus, and unresolved elsewhere. A verdict that applied to the whole organ was never going to be available.

For anyone reading claims about brain regeneration, that is the practical lesson of this series. Ask which region. Ask which species. Ask which method — and specifically, whether the evidence is a marker that could have degraded, or a birth date that could not.

Editorial Comment

MindHeaven® makes no claim that any product influences the formation of new neurons in the human brain, in any region. The literature reviewed across these three articles does not support such claims for any nutrient, supplement or intervention, and we would regard any product marketed on that basis as making a promise the science has not made. We publish this series to describe the state of the evidence, including the parts of it that are unresolved.