Adult neurogenesis

Question 1

Overall structure

Answer 1

1. Intro
2. adult hippocampal volume
3. serotonin effect
4. Neurotrophin effect
5. glucocorticoid
6. antidepressant effect
7. Chen SNP
8. Neuroprotective agents as antidepressants

Question 2

intro

Answer 2

1. variety of evidence implicating adult neurogenesis in the development of mood disorders and therefore suggest it may be a good target for antidepressant development.
2. Adult neurogenesis is the ability of the brain to generate new nerve cells as an adult and it is thought this provides a buffer for hard times.
3. This process only takes place in a few areas of the brain one of these being the sub-granular zone of the hippocampus.
4. The hippocampus plays a key role in integrating information across a number of brain regions involved in mental health,
5. for example it is involved in learning, cognition and regulating the HPA axis, as well as reciprocal connections with the prefrontal cortex and amygdala which are involved in the control and perception of mood and fear responses respectively.
6. Neurogenesis can be regulated by several extrinsic factors including neurotransmitters, neurotrophic factors, corticosteroids and environmental stimuli which are all associated with depression.

Question 3

Adult hippocampal volume pt

Answer 3

1. decrease in hippocampal volume seen in people with depression.
2. This has been observed in many magnetic resonance imaging studies with some conflicting results such as those found by Rusch et al 2001 who did not find this decrease.
3. However, a meta-analysis of 15 hippocampal volume studies carried out by Campbell et al 2004 concluded that the hippocampal volume was significantly lower in patients with depression compared to control patients
4. and variations seen in previous studies were likely due to factors such as duration of illness.
5. Furthermore, Campbell et al have demonstrated that the magnitude of hippocampal volume reduction is correlated with the length of time depression remains untreated.
6. This decrease in volume has been interpreted by some as being representative of a decrease in hippocampal neurogenesis.

Question 4

Hippocampal volume pt 2

Answer 4

1. However, it is hard to specifically attain these structural changes in the hippocampal volume to changes in adult hippocampal neurogenesis
2. and to know whether the reduced hippocampal volume impacts the development of depression or is a result of a stress-related disease process.
3. Reduced hippocampal volumes have been associated with deficits in visual and verbal memory performance as seen in the study by Frodl et al 2006
4. Moreover, Vyas et al. 2002 .
5. These could therefore suggest that the reduced hippocampal volume may be a result of decreased dendritic branching or connectivity and/ or neuronal death and not reduced AHN..

Question 5

Frodl et al

Answer 5

1. who tested various cognitive functions and
2. found a significant correlation with executive functioning and those who major depression and decreased hippocampal volumes.

Question 6

Vyas et al

Answer 6

1. 2002
2. examined the effects of chronic stress on the structure of hippocampal neurons
3. found that it induced dendritic atrophy as well as debranching in pyramidal neurons of the hippocampus

Question 7

Serotoin

Answer 7

1 fact that multiple biochemical changes which are associated with depression also affect AHN.
2. One of these are neurotransmitters such as serotonin.
3. Banasr et al 2004
4. There have been many studies showing the activation of these 5-HT receptors reduce anxiety and depression with buspirone a partial agonist of 5-HT1A used to reduce anxiety and depression.
5. This effect may be potentially to do with their effect on AHN.
6. Moreover, a study carried out by Jhaveri et al 2010
7. A further study showed, when NA levels are depleted, the ability of the nerve cells to proliferate is decreased, although if they have already
8. undergone proliferation, it had no effect on survival. Similar results have been shown for DA and aCh.

Question 8

Banasr et al

Answer 8

1. 2004,
2. tested the affect that various 5-HT receptors have on neuron proliferation by treating rats with specific receptor sub-type agonists.
3. The 5HT1a agonist showed a significant increase in neuron proliferation after 4 hours and reduction in proliferation and stimulatory effects of the agonist on addition of antagonist PCPA.
4. Furthermore, when 5HT2A receptors were treated with an antagonist, the proliferation was decreased although there was no effect when treated with an agonist.

Question 9

Jhaveri et al

Answer 9

1. 2010
2. using a neurosphere assay of hippocampal tissue demonstrated that there was a significant increase in neurosphere numbers on the addition of noradrenaline
3. suggesting that stimulation of β3-adrenergic receptors also directly increases AHN.

Question 10

Neurotrophins part 1

Answer 10

1. Neurotrophins are growth factors which stimulate neurogenesis in development but also in adults,
2. there are 4 different proteins one of these being brain derived neurotrophic factor (BDNF).
3. They work by binding to tropomyosin-related kinase tyrosine kinase receptors TrkA, B and C.
4. BDNF activates TrkB-FL.
5. Once they bind the ligand the Trks dimerise, allowing the tyrosine kinase residues to become phosphorylated which recruits specific intracellular signalling proteins.
6. These signalling pathways are involved in many different aspects in the development of a neuron including proliferation, differentiation, survival, growth and migration.

Question 11

Neurotrophins pt 2

Answer 11

1. There have been many studies linking decreased BDNF expression and depression
2. Karege et al 2005
3. The effect of antidepressants on BDNF was investigated by Nibuya et al 1995,
4. These studies suggest that increased BDNF and trkB expression may be responsible for the therapeutic action of antidepressants and this may be through their action of mediating neurogenesis.

Question 12

Karege et al

Answer 12

1. 2005 carried out western blot assays on the hippocampal tissue of drug-free suicide victims and found their levels of BDNF were significantly decreased compared to non-suicide control.
2. However, no significant difference was identified for those victims who were taking anti-depressants suggesting they increase BDNF expression.

Question 13

Nibuya et al

Answer 13

1. 1995
2. using in situ hybridization and Northern blot
3. which found that chronic administration of several antidepressant drugs including sertraline and desipramine as well as ECS led to a significant increase in BDNF mRNA and trkB mRNA in the hippocampus.
4. They also stopped the downregulation of BDNF mRNA in response to restraint stress.

Question 14

Glucocorticoids

Answer 14

1. Glucocorticoids are produced by the adrenal gland and released in response to stress.
2. They are shown to decrease neurogenesis while removing them increases neurogenesis.
3. However, there is a lack of evidence that progenitor cells can respond to glucocorticoids and instead it may be that the glucocorticoids are stimulating glutamate release which effects proliferation via different mechanisms.

Question 15

Antidepressants

Answer 15

1. most convincing evidence comes from the action of antidepressants on neurogenesis.
2. Many antidepressant treatments have been shown to not only increase neurogenesis but for some their therapeutic effects seem reliant on it.
3. Malberg 2000
4. A similar affect was seen by Santerelli et al 2003,

Question 16

Malberg et al

Answer 16

2. investigated the effect of antidepressants on hippocampal neurogenesis in the adult rats and showed that after about 2 weeks of treatment with antidepressants there was a significant increase in Brdu-labelled cells.
3. Furthermore, the process of neurogenesis takes several weeks which is reflected in this study where the increase was only observed after chronic treatment and after a time lag which is consistent with the time course of antidepressants.

Question 17

Santerelli et al

Answer 17

1. 2003,
2. who saw that 5HT1A knockout mice are selectively insensitive to the effects of fluoxetine in the novelty supressed feeding task and were unable to carry out neurogenesis in response to the SSRI,
3. suggesting that SSRIs therapeutic action may be reliant on neurogenesis.
4. Furthermore, they found that x-irradiation (which was shown to reduce neurogenesis in mice by around 85% in the SGV) blocked the effects of antidepressants in the novelty supressed feeding tests.

Question 18

SNP

Answer 18

1.Chen et al 2007
2. These forementioned studies heavily suggest that antidepressant treatments rely on an increase in neurogenesis for their therapeutic effects.
3. However, it is not clear if it is impaired adult neurogenesis that is underlying the cause of depression or just that the enhancement of AHN provides a route for the treatment of depression.

Question 19

Chen et al

Answer 19

1. 2007
2. investigated a single nucleotide polymorphism in the BDNF gene where Val is substituted for Met.
3. This SNP has been previously associated with mood disorders with affected individuals having smaller hippocampal volume.
4. They reproduced the SNP in mice with a point mutation and found when placed in stressful settings the BDNFMet/Met mice increased anxiety-related behaviours and these were not normalized by fluoxetine.

Question 20

treatment

Answer 20

1. This evidence has led to the idea of the potential use of neuroprotective agents as antidepressants.
2. Lee et al 2016,
3. The idea of using neurotrophic factors to increase neurogenesis has reached clinical trials for the compound NSI-189.
4. NSI-189 stimulates AHN in humans and the trial saw significant improvement in symptoms after 28 days with promising signs that the improvement of symptoms last beyond the acute administration.

Question 21

lee et al

Answer 21

1. 2016
2. investigated the use of the P7C3 class of compounds specifically P7C3-120 and found it increased the net magnitude of AHN.
3. They knocked out Cav1.2 calcium channels in mice and found that this decreased BDNF levels and neurogenesis as well as reduced the survival of newborn pre-cursor cells.
4. On treatment with P7C3 neurogenesis was normalised and the survival of newborn pre-cursor cells was increased, but no affect on BDNF levels was observed.
5. This suggests that these channels may be involved in a BDNF-independent mechanism of enhancing AHN and could be a potential target for antidepressants.

Question 22

Conclusion

Answer 22

1. Overall, the majority of evidence does suggest that AHN is a good potential target for antidepressant drug development.
2. Although it is not certain whether depression causes the decrease in AHN or if impaired AHN may lead to depression, this may not actually be important when looking for a treatment as it has been proven either way that enhancing AHN may improve the symptoms of depression.