From embryonic neural progenitor cells (NPCs) to adult hippocampal neurogenesis (AHN)

Question 1

What are the 2 locations of adult neural stem cells?

Answer 1

In the hippocampus:

1. Subventricular zone of the lateral ventricles
2. Subgranular zone of the dentate gyrus

Question 2

What are neuroepithelial cells?

Answer 2

> Embryonic neural stem cells (NSCs)
- form the neural tube

> Non-specialised cells

Question 3

What are the capacities of neuroepithelial / embryonic neural stem cells?

Answer 3

> Self-renewal
- ensures sufficient numbers of embryonic stem cells are present to enable the generation of all different brain cells needed

> Differentiation

• divide and generate more-specialised cell types
• make all the different brain cell types: neurons, astrocytes, oligodendrocytes

Question 4

What are the different ways of neurogenesis?

Answer 4

1. Embryonic neural stem cells divides, generating another NSC and a neuron
2. Embryonic neural stem cell divides, generating a progenitor cell (e.g. radial glial cell) and a neuron
3. This radial glial cell has ability to self-renew by dividing to generate another radial glial cell and a neuron
   OR to generate a dedicated progenitor cell (can only generate a single cell type)

Radial glial cells cannot make embryonic NSCs

Question 5

What is asymmetric differentiation?

Answer 5

When a parent cell makes 2 different progeny.

Question 6

What is a dedicated progenitor cell?

Answer 6

A progenitor cell that can only generate a single cell type

-> cannot make radial glial cells or embryonic NSCs

Question 7

What is the cellular specialisation during differentiation?

Answer 7

Neuroepithelial embryonic NSC (least specialised cell)

-> Radial glial cell -> Dedicated progenitor cell -> Neuron

Question 8

What are the lineage relationships from neuroepithelial / embryonic NSCs to neurons and glial cells?

Answer 8

1. Embryonic NSCs
   - self-renew
   - generate progenitor cells (e.g. radial glial cell)
   - generate dedicated progenitor cells which generate neurons
2. Radial glial cells
   - self-renew
   - generate dedicated progenitor cells, which generate oligodendrocytes, astrocytes, or neurons
   - generate adult NSCs, which generate neurons throughout our lifetime

Question 9

Why are there so many ways to generate neurons?

Answer 9

It is considered that there are many types of neurons that need to be made over a very specific time period during development.

Question 10

How was active hippocampal neurogenesis in adult humans demonstrated?

Answer 10

Jonas Frisen’s group at the Karolinska Institute evaluated the generation of hippocampal cells in postmortem human brains by measuring the concentration of nuclear bomb test-derived carbon-14

• 14C concentrations in hippocampal neuron genomic DNA correspond to a time after date of birth of the individual
• > neurogenesis throughout life

Question 11

Where is the neural stem cell niche and what happens in it?

Answer 11

In the granular cell layer of the dentate gyrus of the hippocampus, there is the neural stem cell niche

• where NSCs proliferate, migrate and differentiate
• NSCs mature into neurons, receive input from entorhinal cortex and extend projections into the CA3 (outside the dentate gyrus)

Question 12

What is the maturation period of neural stem cells (in rodents)?

Answer 12

4 to 6 weeks for NSCs to mature into neurons

Question 13

What do quantitative studies show on adult neurogenesis?

Answer 13

> Approximately 700 new neurons in adult humans added in each hippocampus per day
-> by the time we’re 50, we have replaced the entire granular cell-population with adult-born neurons

> Approximately 70% of the bulbar neurons are replaced during a 6-week period in an adult rodent

Question 14

What do transplantation studies show regarding the adult neurogenic microenvironment?

Answer 14

Direct evidence for regulation of neuronal fate - determination of stem cells - by extrinsic signals derived from neurogenic environment

> NSC derived from a non-neurogenic region (e.g. spinal cord) produce neurons only when transplanted into a neurogenic region (dentate gyrus or subventricular zone)

> Adult NSC derived from neurogenic region will differentiate into neurons only in neurogenic environment (DG or SVZ)

Question 15

What constitutes a neurogenic niche?

Answer 15

> Endothelial cells
Blood vessels
Astrocytes

Question 16

What is the evidence on astroglia inducing neurogenesis from adult neural stem cells, and the role of the microenvironment?

Answer 16

> Adult NSC derived from hippocampus co-cultured with adult hippocampal astrocytes can differentiate into neurons

> Adult NSC co-cultured with astrocytes from a non-neurogenic region (e.g. spinal cord) rarely differentiate into neurons

> NSCs produced most neurons with neonatal hippocampal astrocytes, followed by adult hippocampal astrocytes
- neonatal spinal cord astrocytes lead to lower number of neurons produced compared to control condition - without any astrocytes

Question 17

What is the role of Wnt signalling in the molecular control of adult hippocampal neurogenesis?

Answer 17

> Adult NSC treated with Wnt factors differentiate into neurons
- fourfold increase of neuroblasts (young neurons) produced when NSCs are cultured in presence of Wnt

> Injection with dominant negative Wnt lentivirus blocked Wnt signalling which reduced adult hippocampal neurogenesis
- 8-fold decrease of newborn neurons when Wnt signalling is blocked

Question 18

What is the functional relevance of adult neurogenesis regarding learning and memory?

Answer 18

Bi-directional link between neurogenesis and learning

> Level of neurogenesis in dentate gyrus is positively correlated with hippocampal dependent learning tasks
- blocking neurogenesis blocks hippocampal dependent learning abilities

> Hippocampal dependent learning can modulate neurogenesis

Question 19

What do computational theories propose about the effect of neurogenesis on hippocampal dependent learning?
What is ‘pattern separation’?

Answer 19

New neurons:

• increase memory capacity
• reduce interference between memories = ‘pattern separation’
• or add information about time to memories
• or induce forgetting during infancy

Question 20

What is the functional relevance of adult neurogenesis regarding mood and depression?

Answer 20

Adult neurogenesis is implicated in mood regulation and depression:

• neurogenesis is reduced in animal models of depression
• many treatments for depression promote adult hippocampal neurogenesis
• neurogenesis alone cannot mediate the effect of antidepressants BUT blocking neurogenesis inhibits the efficacy of antidepressants

Question 21

What are the modulating factors of adult hippocampal neurogenesis?

Answer 21

> Ageing
> Exercise
> Learning
> Stress
> Diet
> Enriched environment (toys in the cages of rodents)
> Sleep deprivation

Question 22

What is the evidence behind the influence of ageing on adult hippocampal neurogenesis?

Answer 22

Authors used parabiosis approach:

• fusing the circulatory system of an old and young mice
• they let the mice attached for 3 months and then looked at their adult hippocampal neurogenesis
• they labelled neuroblasts with doublecortin (Dcx)

> Young isochronic: nice level of neuroblasts
Young heterochronic (young-old): decreased level of neuroblasts
Old isochronic: dramatic reduced level of neuroblasts
Old heterochronic: higher level compared to old isochronic

> Injection of plasma

• young mice injected with young plasma has a normal level of neuroblasts
• young mice injected with old plasma has a decreased level of neuroblasts (neurogenesis)
• correlated with their learning and memory abilities

Question 23

What is the evidence on the influence of exercise on adult neurogenesis?

Answer 23

In rodents: runners vs. controls

- 30% increase of NSCs proliferating -> neurogenesis

Question 24

What is the evidence of the modulation of adult hippocampal neurogenesis by diet?

Answer 24

> Animal model studies:

• Limiting Kcal intake to 30% or intermittent fasting increased neurogenesis
• Omega-3 fatty acid contained in oily fish (e.g. salmon) will increase neurogenesis
• Diets rich in saturated fats will decrease neurogenesis
• Alcohol is detrimental to neurogenesis BUT Resveratrol contained in red wine has a positive effect

> Group of Japanese scientists found that soft food will decrease neurogenesis

Question 25

What do human studies show on the influence of food on adult hippocampal neurogenesis, memory and mood?

Answer 25

Human studies have shown to impact memory and mood:

• food modulates behaviour in same direction as with neurogenesis (e.g. decreased calorie intake, intake of flavonoids, Omega-3 fatty acid)
• > increased neurogenesis, cognition and mood improvement

-> Diets rich in saturated fats will decrease learning and memory abilities, and exacerbate symptoms of depression

Question 26

What are neurotrophic factors?

Answer 26

Endogenous proteins regulating survival, growth, morphological plasticity and synthesis, for differentiated functions of neurons.

Question 27

What are neuroblasts?

Answer 27

Undifferentiated precursors of the central nervous system (CNS).