L3 Neurogenesis Flashcards
What are the two zones in the brain in which neurogenesis occurs?
1) Subventricular zone of lateral ventricle (cells born here and migrate to striatum)
2) Subgranular zone of hippocampus (dentate gyrus)
Sub regions of the hippocampus: (learning, cog, HPA, anxiety)
1) _____ (emotion, fear)
2) ___ (working memory, cognition, mood)
Amygdala
PFC
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.
Mitotic BRDU BRDU Dentate gyrus BRDU +ve Neurones
_____ 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 _____.
Spalding et al 2013 Hippocampal 14C 700 Ageing
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
Subgranular layer of dentate gyrus
Hippocampal
Neurogenesis
Banasr et al 2004
_____ 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.
Banasr et al 2004 5HT1AR BRDU 4hrs BRDU PCPA
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 _______.
PCPA
Sumatriptan
Neurogenesis
Administration of ___ (5HT2A/2C agonist) produced ____ _____ in cell proliferation.
Administration of ______ resulted in a ____ in ____ labelled cells
DOI No change Ketanserin Decrease BRDU
_____ 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)
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.
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.
4
BDNF
Tyrosine
Tyrosine
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.
Cortisol corticosterone MR and GR Corticosterone Reduced Thymidine Dentate gyrus
Increased Neurone Endolase Thymidine Sham
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.
Malberg et al 2000
Fluoxetine
Fluoxetine
5HT
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.
Santarelli et al 2003 Increased Fluoxetine Neurogenic BRDU
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)
BDNF
MRNA
TRKB
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.
Decreased
5HT
Increased
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 _____.
Atrophy
Survival and growth of dendrites
So stress decreases the ability to make functional connections to nerve cells
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.
Reduced Restores SNP Met Met Reduced
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.
Val 66 mice - Chen et al 2006 Fluoxetine Fluoxetine Genetic Fluoxetine
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 ______.
BBB
Carcinogenic
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.
vulnerable phenotype
Cognitive
Vulnerable phenotype
Cognitive
____ et al _____
AD effects ____ by x-ray hippocampal ______
Also all monoaminergic ADs increase hippocampal neurogenesis and ECT and glutamatergic ligands and C___ antagonists.
Santerelli et al 2003
abolished
Irradiation
CRF1R
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.
Genetic
Reif et al 2006
