Module 6 · Brain Stem Cells

Neural Stem Cells

For most of the twentieth century, the adult mammalian brain was thought to produce no new neurons. Joseph Altman’s 1962 tritiated-thymidine observations of adult rat dentate gyrus were dismissed as artefact for two decades. By the 1990s the consensus had shifted: adult mammals do generate new neurons, in at least two discrete niches — the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. Whether this extends to adult humans remains one of the most contested questions in current neuroscience.

1. Embryonic Neural Stem Cells: The Radial Glia Story

During embryonic development, the cortex is built from radial glia — elongated cells spanning the full thickness of the cortical wall, whose cell bodies reside in the ventricular zone. Radial glia were once considered scaffolds; Kriegstein & Alvarez-Buylla (2005) demonstrated that they are the principal neural stem cells of the developing cortex, dividing at the ventricular surface and generating all cortical neurones through a series of intermediate progenitors.

The outer radial glia (oRG) — a subset found in expanded form in primates, especially humans — may be the cellular substrate of cortical expansion that distinguishes humans from other mammals (Hansen 2010, Pollen 2019). Their proliferative behaviour is qualitatively different and remains a leading hypothesis for how evolution scaled up the human brain.

2. Adult Neurogenic Niches in Rodents

Two canonical sites of adult neurogenesis in mice and rats:

Subventricular zone (SVZ)

Lining the lateral ventricles. Alvarez-Buylla’s hierarchy: Type B (quiescent astrocytic NSCs) → Type C (transit-amplifying) → Type A (neuroblasts). Type A cells migrate through the rostral migratory stream (RMS) to the olfactory bulb, differentiating into granule and periglomerular interneurones. In rodents, this produces ~30 000 new olfactory neurons per day. It is largely absent in adult humans (Sorrells 2018).

Subgranular zone (SGZ)

In the hippocampal dentate gyrus. Radial-glia-like cells (Type 1) produce transient amplifying cells (Type 2) then neuroblasts (Type 3) then immature granule cells that integrate into the dentate granule layer and project to CA3. Adult-born granule neurones mature over ~6–8 weeks, forming pattern-separation-relevant circuits. Implicated in hippocampal-dependent learning, spatial memory, and depression.

A third site — the hypothalamic tanycyte niche — has recently been added to the canon; tanycyte-derived neurogenesis may regulate energy balance (Kokoeva 2005, Yoo 2021).

3. Signalling in Neural Niches

Dominant signalling axes:

WNT: promotes neural stem-cell proliferation; hippocampal WNT decline with age tracks neurogenesis decline.
Notch: maintains quiescence of Type 1 and Type B cells via Hes1/Hes5 oscillations (lateral inhibition).
BMP: promotes astrocytic fate; high BMP in aged niches may explain astrocyte bias.
Neurotrophic factors: BDNF, IGF-1, VEGF support neurogenesis. Exercise elevates all three; this is a leading explanation for the cognitive benefit of aerobic activity (van Praag 1999).
Inflammation: microglial cytokines (IL-6, TNF) and neurotransmitter cues from local circuits feed back onto NSCs. Chronic inflammation suppresses neurogenesis; this is one pathway by which stress and depression reduce hippocampal plasticity.

Simulation: Adult Neurogenesis Dynamics

Python

script.py46 lines

import numpy as np, matplotlib
matplotlib.use('Agg')
import matplotlib.pyplot as plt

# Age-dependent adult neurogenesis rate in the dentate gyrus
# Data compiled from Spalding 2013 (humans) + rodent longitudinal studies
age = np.linspace(0, 90, 200)
# Human DG neurogenesis (cells/day), from Spalding 14C dating
# Roughly exponential decline: ~700/day in young adult to ~100/day in elderly
rate_humans = 700 * np.exp(-age/50)

# Mouse/rat DG neurogenesis - steeper decline, normalized
rate_rodent = 1.0 * np.exp(-age/30)   # relative

fig, (ax1, ax2) = plt.subplots(1, 2, figsize=(14, 5.5), facecolor='#0a0a1a')
for ax in (ax1, ax2):
    ax.set_facecolor('#111827'); ax.tick_params(colors='#cbd5e1')
    for s in ax.spines.values(): s.set_color('#334155')
    ax.grid(True, color='#334155', alpha=0.3)

ax1.plot(age, rate_humans, color='#fbbf24', lw=2.6)
ax1.set_xlabel('Age (years)', color='#cbd5e1')
ax1.set_ylabel('New DG neurons per day (human)', color='#cbd5e1')
ax1.set_title('Human hippocampal neurogenesis vs age (Spalding 2013)',
              color='#fda4af', fontweight='bold')
ax1.axhspan(0, 50, color='#f87171', alpha=0.1, label='Below detection threshold')
ax1.legend(facecolor='#1e293b', edgecolor='#334155', labelcolor='#cbd5e1')

# Panel 2: Neural stem cell hierarchy in SVZ
hierarchy = ['Type B\n(quiescent NSC)', 'Type C\n(transit amp.)',
             'Type A\n(neuroblast)', 'Mature neuron\n(OB/cortex)']
frequency = [1, 5, 50, 500]
divtime = [30, 12, 18, 0]
colors = ['#c084fc','#fbbf24','#2dd4bf','#60a5fa']

ax2.bar(hierarchy, frequency, color=colors, edgecolor='#fda4af')
ax2.set_yscale('log')
ax2.set_ylabel('Relative frequency (log)', color='#cbd5e1')
ax2.set_title('SVZ neurogenic lineage (mouse)',
              color='#fda4af', fontweight='bold')
plt.setp(ax2.get_xticklabels(), fontsize=9)

plt.tight_layout()
plt.savefig('output.png', dpi=120, bbox_inches='tight', facecolor='#0a0a1a')
print('Spalding 14C dating: human DG adds ~700 neurons/day, declining with age')
print('SVZ B->C->A lineage: quiescent->amplifying->migrating')

Click Run to execute the Python code

Code will be executed with Python 3 on the server

4. The Human Adult Neurogenesis Controversy

Does adult human hippocampus generate new neurones? The literature of the last decade has oscillated. Key papers:

Eriksson 1998: BrdU-labelled neurones in post-mortem human DG after terminal-patient BrdU infusion; first direct evidence for adult human neurogenesis.
Spalding 2013: ¹⁴C dating of human DG neurones using atmospheric ¹⁴C from Cold War-era nuclear tests. Estimated ~700 new neurones per day in adult human DG, declining with age — small fraction of DG neurons, but non-zero and lifelong.
Sorrells 2018 (Nature): Using DCX/PSA-NCAM immunostaining in fixed human DG, found essentially no immature neurones after age 13. Proposed that adult human neurogenesis is effectively absent.
Moreno-Jiménez 2019 (Nat. Med.): With more rigorous tissue fixation (critical for DCX preservation), detected thousands of immature neurones per DG in adult humans, including Alzheimer’s patients (reduced but present).
Franjic 2022 (Neuron): single-nucleus RNA-seq found an immature-neurone-like population in adult human DG, but its identity is debated.

The current balance of evidence favours continuing but modest adult human hippocampal neurogenesis — perhaps an order of magnitude below rodent levels. Tissue-handling is crucial: DCX is extremely sensitive to post-mortem interval and fixation protocol. No adult human SVZ neurogenesis has been convincingly demonstrated.

5. Clinical Translation

Despite the presence of endogenous NSCs, the adult human brain’s regenerative capacity is extremely limited. Substantial tissue loss (stroke, traumatic injury, neurodegeneration) is not rescued. Clinical strategies:

iPSC-derived dopaminergic neurons for Parkinson’s (Kyoto trial started 2018; Japan marketing approval expected). CiRA’s first-in-human study has now reported several years of follow-up with engraftment and symptomatic improvement.
Stem-cell-derived oligodendrocyte progenitor cells for spinal cord injury (Geron/Asterias OPC1) — first iPSC therapy ever tested in a human being, 2010.
Cortical pyramidal neuron transplantsfor stroke (Michell Allen’s lab; early-phase trials ongoing).
Endogenous neurogenesis modulation: exercise, environmental enrichment, antidepressants (fluoxetine increases SGZ neurogenesis), and more recently small molecules that promote adult NSC proliferation.

6. Neurogenesis, Stress & Depression

Reduced adult hippocampal neurogenesis is observed in rodent models of chronic stress and depression; antidepressants (SSRIs, ketamine) restore it. This has led to the neurogenic hypothesis of depression(Santarelli 2003, Boldrini 2009): antidepressants require new DG neurons for behavioural efficacy. In mouse models, blocking neurogenesis abolishes antidepressant behavioural effects. Translation to humans is less clear — lithium, ketamine, psilocybin, and ECT all increase neural plasticity markers, but whether this is truly via adult neurogenesis or via broader synaptic plasticity is unresolved. It is one of the most interesting frontiers of the field.

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