L3 Neurogenesis

Question 1

What are the two zones in the brain in which neurogenesis occurs?

Answer 1

1) Subventricular zone of lateral ventricle (cells born here and migrate to striatum)
2) Subgranular zone of hippocampus (dentate gyrus)

Question 2

Sub regions of the hippocampus: (learning, cog, HPA, anxiety)

1) _____ (emotion, fear)
2) ___ (working memory, cognition, mood)

Answer 2

Amygdala

PFC

Question 3

Studying neurogenesis:
Studies look at cells that progress through _____ phase. DNA replicates and new DNA is formed.
Rodents are injected with ____ which is incorporated into DNA in place of thymidine.
Kill the rodent and see where ____ is incorporated in the brain e.g. in the ____ ____ where ____ __ spots can be counted to see where new ______ have grown.

Answer 3

Mitotic 
BRDU
BRDU 
Dentate gyrus 
BRDU +ve
Neurones

Question 4

_____ et al ____ assessed generation of _____ cells in human by measuring conc of nuclear bomb test derived ___ in genomic DNA. Found that around ___ new neurons are added/day - an annual turnover of 1.75% of neurons within renewing fraction with a modest decline during _____.

Answer 4

Spalding et al 2013
Hippocampal 
14C 
700
Ageing

Question 5

Serotonin regulates neurogenesis:
5HT neurones are some of the earliest neurones in brain - located in _______ layer of _____ _____.
Have a role in growth of neurones and directing neurones - in _______ neurogenesis.
- In normal control brains and ones treated with 5HT agonists there is a significant increase in ______.
- _____ et al ____, found that activation or blockade of multiple 5HT receptors alters proliferation of cells

Answer 5

Subgranular layer of dentate gyrus
Hippocampal
Neurogenesis
Banasr et al 2004

Question 6

_____ et al ___, found that activation of ______ with 8-OH-DPAT increased the number of _____ +ve cells vs control. A prolonged activation was needed to stimulate cell proliferation (_ hrs).
8-OH-DPAT reverses decrease in number of _____ +ve labelled cells in rats depleted of serotonin by ____. So can rescue the decrease in no neurones with 8-OH-DPAT.

Answer 6

Banasr et al 2004
5HT1AR 
BRDU 
4hrs
BRDU 
PCPA

Question 7

When the brain is depleted of serotonin nerve cells using ____ a reduction in new neurones occurs. ____ is an agonist at the 5HT1B receptor and reverses the reduction in _______.

Answer 7

PCPA
Sumatriptan
Neurogenesis

Question 8

Administration of ___ (5HT2A/2C agonist) produced ____ _____ in cell proliferation.
Administration of ______ resulted in a ____ in ____ labelled cells

Answer 8

DOI
No change 
Ketanserin
Decrease 
BRDU

Question 9

_____ could contribute to localisation of neurogenesis. Overlapping ______ systems could contribute to the creation of neurogenic niches. __ and __ projections with dense 5HT releasing projections in neurogenic locations of SVZ and ______ zone. Neurogenesis occurs when these _____ systems overlap.

(____, 2005)

Answer 9

Neurotransmitters 
Neurotransmitter 
NA and DA
Subgranular 
Neurotransmitter
Haag, 2005

So cooperation of neurotransmitter systems contribute to the establishment of conditions for neurogenesis in these niches.

Question 10

Neurotrophins stimulate neurogenesis:
Neurotophic growth factors family has _ proteins including _____ that binds ______ receptor kinases (TrKA B & C) Intracellular _____ residues are phosphorylated and activate the receptor - Ras and Raf are involved in differentiation and survival and activity dependent plasticity.

Answer 10

4
BDNF
Tyrosine
Tyrosine

Question 11

Corticosteroids decrease neurogenesis:
glucocorticoids e.g. _____ (humans) and _____ (rats) act via ___ and ____.
Acute treatment with ______ significantly ____ of [3H]____ labelled cells in hilius of ___ _____.

Aderenalectomy __ number of _____ specific _____ immunoreactive [3H]_____ labelled cells in granule layer compared to ____ operation.

Answer 11

Cortisol 
corticosterone 
MR and GR
Corticosterone 
Reduced 
Thymidine 
Dentate gyrus 

Increased 
Neurone 
Endolase 
Thymidine 
Sham

Question 12

Antidepressants increase hippocampal neurogenesis:
____ et al _____
- Electrical stimulation increased BRDU labelled cells
- Chronic _____ increased BRDU labeled cells but acute _____ had no effect (need 14-28days to see increase in hippocampal neurogenesis)

SO acutely increased ____ but maybe no initial therapeutic improvement as need to grow and integrate new cells into neuronal network (neurogenesis) HENCE the therapeutic delay with SSRIs.

Answer 12

Malberg et al 2000
Fluoxetine
Fluoxetine
5HT

Question 13

SSRIs require 5HT1A receptor for effects on neurogenesis:
_____ et al _____
Study with KO mice: ___ latency than WT to begin feeding in open field experiment. KO mice selectively insensitive to behavioural effects of ____ and to _____ effects of ____ as less ____ was labelled. However other ADs did work e.g. desimipramine and caused improved behaviour so shows that SSRIs require 5HT1AR.

Answer 13

Santarelli et al 2003
Increased 
Fluoxetine 
Neurogenic 
BRDU

Question 14

Antidepressants increase neurotrophic factor signalling:
SSRIs, MAOIs, TCAs increase ____ ____ in hippocampus as does ECS.
Autophosphorlylation of ____ increased by antidepressant treatment (activates receptors and then differentiation and survival of cells is promoted)

Answer 14

BDNF
MRNA
TRKB

Question 15

So in the ____ gyrus:
Stress increases GC and decreases VEGF which leads to ____ neurogenesis
ADT increases NE and ___ and increases VEGF and BDNF which leads to ____ neurogenesis.

Answer 15

Decreased
5HT
Increased

Question 16

CA3 pyramidal cells
Stress increases GC and decreases BDNF leading to dendrite ____
ADT increases NE and 5HT and BDNF leading to increased ____ and growth of _____.

Answer 16

Atrophy
Survival and growth of dendrites

So stress decreases the ability to make functional connections to nerve cells

Question 17

Role of BDNF:
BDNF level ____ in PM brains/plasma from depressed Pts
Antidepressant treatment _____ BDNF levels to normal range
___ in BDNF gene (Val-___ sub) associated with memory impairments and mood disorders.
Val-___ carriers have a _____ hippocampal volume relative to Val-Val controle.

Answer 17

Reduced
Restores 
SNP 
Met
Met 
Reduced

Question 18

BDNF Val __ mice - ____ et al ____.
Substitue Val for ___ due to ____ in BDNF gene.
Substitution made mice resistant to ____ effects.
Homozygous substitution meant mice spent less time in the centre of open field study compared to WT as more anxious - only responded partially to _____.

Varient BDNF = _____ predisposition to anxiety and depressive disorders and resistant to _____ and reduced BDNF means reduced neurogenesis.

Answer 18

Val 66 mice - Chen et al 2006
Fluoxetine 
Fluoxetine 
Genetic 
Fluoxetine

Question 19

Neurotrophic factors entered the clinic BUT don’t readily cross the ____ or penetrate far. Also tried directly injecting them into ventricles but they don’t spread far. Some of the small molecules developed were also found to be ______.

Answer 19

BBB

Carcinogenic

Question 20

Is impaired neurogenesis CAUSE or CONSEQUENCE of depression?
Impaired neurogenesis could lead to ____ _____ which leads to affective or ___ disorders.

OR

____ ______ could lead to affective or ____ disorders which lead to impaired neurogenesis.

Answer 20

vulnerable phenotype
Cognitive

Vulnerable phenotype
Cognitive

Question 21

____ et al _____
AD effects ____ by x-ray hippocampal ______
Also all monoaminergic ADs increase hippocampal neurogenesis and ECT and glutamatergic ligands and C___ antagonists.

Answer 21

Santerelli et al 2003
abolished
Irradiation
CRF1R

Question 22

Issues with neurogenic theory of depression:

• Neurogenic effects of ADs vary with specific species and ____ backgrounds
• Hippocampal irradiation prevents AD effects in some behavioural paradigms but not others
• Decreased neurogenesis in animal models does not CAUSE depression
• Depressed pts don’t have decreased neural cell proliferation (___ et al ____)
• hippocampal neurogenesis implicated in a range of disorders.

Answer 22

Genetic

Reif et al 2006