Lecture 4: Neural Stem Cells and Adult Neurogenesis

Question 1

Neural stem cells arise from ___ and are ___

Answer 1

1) Ectoderm
2) Multipotent

Question 2

What is not derived from neural stem cells?

Answer 2

Microgalia

Question 3

Describe neural stem cells

Answer 3

• Can self renew
  -Can give rise to neurons, astrocytes, and oligodendrocytes

Question 4

What is neurulation?

Answer 4

The process in which the neural plate bends and later fuses to form the hollow tube that will eventually differentiate into the brain and the spinal cord of the CNS.

Question 5

Describe neuroepithelial cells

Answer 5

-Are multipotent neural stem cells of early embryonic development.

Question 6

True or False we have unnecessary cells that are killed off during apoptosis and refined during development.

Answer 6

True

Question 7

__ generate first then __ is generated

Answer 7

1) Neurons
2) Microglia

Question 8

Myelination occurs until people are around ____

Answer 8

25

Question 9

True or False: synaptic refinement occurs throughout life.

Answer 9

True

Question 10

What do radial glial cells do during cortical development?

Answer 10

They asymmetrically divide to produce migrating neural progenitors that further divide and mature into cortical neurons.

Question 11

Describe glial cells

Answer 11

• not astrocytes
  -act like neural stem cells
  1) differentiate
  2) self-renew

Question 12

True or False: The Human brain is NOT the largest brain. It is the largest primate brain.

Answer 12

True

Question 13

What is the radial unit hypothesis?

Answer 13

A continuous radial glial scaffold is made up of fibers along which neurons migrate.
It is key for understanding cortical organization for brain development.
Hypothesis: radial fibers guide the migration of neurons from where they’re born (down at the ventricle) to where they reside (top of the cortex).
Thought to guide neurons in the early stages of cortical migration.

Question 14

What was the experiment that helped change/add to the radial unit hypothesis?

Answer 14

Used retroviruses to label cells in progenitor zones in a mouse by injecting a virus in utero into the ventricle.
Result: Saw clones of the radial glial cell (1) and 2-3 other cells arranged along the radial glial fiber.

Question 15

Why did the retrovirus experiment turn out that way?

Answer 15

Initially infected radial glial cells over time divide and produce clones which self-renewed.
1 radial glial cell in each clone.
Daughter cells accumulate and some turn into neurons.

Question 16

What do intermediate progenitor cells do?

Answer 16

They divide symmetrically to produce 2 daughter cells hat continue migrating to the cortex and become a pair of cortical neurons.

Question 17

Explains the process the radial glial cells undergo in development?

Answer 17

-Radial glial cell divides at the surface of the ventricle and produces a daughter cell.
-Nuclues of a radial glial moved back up .
Goes through inter kinetic nuclear migration.
Daughter cells migrating along parental radial fibers.

Question 18

Do neural stem cells persist in adults and if so, can they produce new neurons and glia?

Answer 18

The first evidence of adult neurogenesis came from studying mitosis in adult brains with tritiated thymidine

Question 19

Explain the Titrated thymidine experiment

Answer 19

Joseph Altman used tritiated thymidine to provide evidence of DNA replication = mitosis.
He fed the trotted thymidine which is radioactive to rats (because rats use this when dividing) and then examined slices of the rat brain. He found silver grains that looked like newborn neurons that had grown in adult mice.

Question 20

In what two regions within the adult mammalian brain does neurogenesis occur?

Answer 20

1) The subventrictular zone (SVZ) of the lateral ventricles.
2) The dentate gyrus of the hippocampus (implicated in olfaction) (Important for mice in particular.

Question 21

Is the rate of adult neurogenesis altered by anything?

Answer 21

Aging Decrease
Neurological diseases Decrease
Stress Decrease
Exercise Increase
Enriched environment increase

Question 22

What does an enriched environment do?

Answer 22

It increases adult neurogenesis.
Mice living in enriched housing produce 20% more neurons in the dentate gyrus.

Question 23

What is the Morris Water maze?

Answer 23

A commonly used test of hippocampal dependent learning.
Task: mouse placed on platform in a water maze and expected to solve it and either has spatial memory tested as well as speed.
Normal mouse will get better over time as spatial memory improves with the number of trials.
Enriched mouse also will get to the platform quicker (as this increases neurogenesis).
Result: Mice housed in enriched environments learned to solve water maze in 2 days instead of the usual 4 days.

Question 24

How long does it take for newborn neurons to grow to maturity?

Answer 24

6 weeks
(It took 6 weeks for neurons to become functionally activated by the water maze task).

Question 25

Enrichment also enhances production of the neurotrophic factor _____

Answer 25

BDNF (Brain Derived Neurotrophic Factor)
Which supports synapse growth and neurogenesis.

Question 26

What else can increase neurogenesis and learning and memory and increases BDNF?

Answer 26

Exercise
Running and enrichment both independently increase new neurons in the hippocampus.

Question 27

Explain what running vs enrichment promote?

Answer 27

Running: promotes proliferation
Enrichment: promotes survival

Question 28

Increasing neurogenesis in aged mice with a genetic approach improves ___ and ____

Answer 28

learning and memory

Question 29

Explain the experiment where neurogenesis was increased in mice.

Answer 29

They induced mitosis which means more neurons were born and survived.
They manipulated the number of neurons.
They increased cell cycle genes and then turned them off to let the neurons mature.

Question 30

Do genetic factors also effect adult neurogenesis?

Answer 30

Adult neurogenesis rates vary 6 fold across different mouse strains.

Question 31

Does adult neurogenesis also occur in humans?

Answer 31

Maybe: The answer is still disputed

Question 32

Explain the Bromodexoyuridine (BrdU) experiment.

Answer 32

BrdU is a thymidine analog that was used to make cancers more sensitive to radiotherapy. Using immunofluorescent labeling for BrdU and for one of the neuronal markers, NeuN, calbindin or neuron specific enolase (NSE), we demonstrate that new neurons, as defined by these markers, are generated from dividing progenitor cells in the dentate gyrus of adult humans. Results further indicate that the human hippocampus retains its ability to generate neurons throughout life.

Question 33

Explain the nuclear bomb testing and atmospheric experiment

Answer 33

Nuclear bomb testing provided additional evidence of adult neurogenesis.
It peaked between 1961-1962 (340 megatons were detonated in the atmosphere by the US and Soviet Union).
In this experiment, the levels of C14 were analyzed in people born in 1961
Result: the levels of C14 in some hippocampal neurons matched the atmospheric C14 levels that existed several years after their birth. This showed that neurogenesis was occurring throughout life.

Question 34

What is an experiment that did not support the hypothesis of adult neurogenesis?

Answer 34

One experiment found that human hippocampal neurogenesis dropped sharply in children and was nearly undetectable in adults.
Green cells were mitotic cells
and Purplecells were NSC markers.
No green and purple cells detected in 35 year old humans.
On the contrary:
Green = mitotic cells
Red= NSC marker
Some green and red cells detected in 35 year old humans.

Question 35

What about using a newer method like single cell RNA sequencing?

Answer 35

Different method, different conclusion!
Verdict is still out.

Question 36

Describe the experiment that supports that exercise can increase hippocampal volume in humans.

Answer 36

120 individuals disease free between 55 and 80 were either placed on aerobic or a stretching exercise regime.
Hippocampi of aerobic exercisers grew wheras the hippocampus of stretchers shrank (likely age-related).
The more the aerobic improvement (VO2 max) the greater the growth in the hippocampus.
The greater the growth, the more the increase in BDNF found in blood.

Question 37

____ aerobic activity correlates with ____ hippocampal volume and ____ BDNF levels

Answer 37

1) Aerobic
2) increased
3) increased

Question 38

How can the use of exercise be mediated in contributing to larger hippocampal volume?

Answer 38

Via increased neurogenesis, increased synaptic density, increased number of glia, or even increased vascularization.