Adult hippocampal neurogenesis: can new neurons regulate my mood and improve my memory?

Question 1

What was discovered by Altman and Das?

What technique did they use?

Answer 1

They described mitotic activity in the post-natal hippocampus for the first time, an indirect indication of post-natal neurogenesis.

The authors did that by injecting rats with a radiolabelled form of the DNA neucleocyte thymidine, called thymidine-H3. This is a way to trick the DNA so that thymidine-H3, as we said, a DNA precursor, will be incorporated by the DNA during cell division and because it is radiolabelled, it is possible to identify these cells by appropriate staining methods.

Question 2

What Jonas Frisen in the prestigious Karolinksa Institute in Sweden discovered in 2013? How?

Answer 2

The authors took advantage of the fact that during the post-war periods, the levels of atmospheric C14 raised dramatically as a function of nuclear bomb testing. C14, they hypothesised, would be absorbed by plants and go up in the food chain until reaching us. In other words, they hypothesised that the brain of people living in those years would absorb C14 as well. As you know, C14 is widely used as a well-established dating method. Therefore, if we were able to date neuronal cells in the post-mortem brain, and if we know the year that person was born, then we would be able to know whether neuronal cells are born after the person’s birth. That is exactly what they found, that neurons were continually generated years after people’s date of birth, providing us strong evidence supporting that adult hippocampal neurogenesis does take place in the adult human brain.

Question 3

Where adult hippocampal neurogenesis occurs? Why?

Answer 3

In the dentate gyrus of the hippocampus due to the specific signalling molecules present in this tiny area of the brain that generates a neurogenic niche.

Question 4

What is adult hippocampal neurogenesis?

What type of neurons are considered?

Answer 4

Generation of excitatory neurons (not any neuron) in the granule cell layer of the dentate gyrus of the hippocampus.

Question 5

Describe the circuit

Answer 5

1. Neurons in the DG who receive information from the entorhinal cortex through the perforant path and will send projections to area CA3 of the hippocampus through mossy fibres.
2. CA3 neurons, in turn, will communicate with neurons in CA1 through the Schaffer collaterals.
3. And after being processed by the tri-synaptic circuit (dentate gyrus – CA3 – CA1) information will be sent via the subiculum to several cortical and subcortical areas of the brain.

Question 6

Describe the process

Answer 6

1. It starts from a population of radial glial cell-like precursor cells known as type I cells.

These cells have astrocytic properties, and express neural stem cell markers, but don’t display a very intense mitotic activity.

2. When they do divide, these cells originate intermediate progenitor cells. With first, a glial phenotype, type IIA and then a neuronal phenotype, type IIB.
3. Next we have the migratory stage, and our cells now are called neuroblasts, type III. That is, they have committed to a neuronal phenotype but are still very immature neurons. These cells will then exit the cell cycle and start a stage of maturation.
4. This means that they will start extending their dendrites into the molecular layer of the dentate gyrus and their axon to area CA3. During this stage, our newly born neurons show increased synaptic plasticity. And it is then believed that this makes these cells special facilitators of hippocampal function. After some weeks of maturation, these neurons acquire characteristics of matured granule cells and become undistinguishable from them.

Question 7

What are the stages of adult hippocampal neurogenesis (4)?

How these processes are regulated?

Answer 7

1. Proliferation
2. Differentiation
3. Migration
4. Integration

Molecules can direct or inhibit each of the neurogenic stages

Question 8

What marker is DCX?

Answer 8

Doublecortin is a marker of immature neurons.

This suggests that adult hippocampal neurogenesis is important to regulate anxious behaviour.

Question 9

What is stress?

Answer 9

Subjective state of sensing potentially adverse changes in the environment that will lead to a response that enables the animal to adapt to the changing environment.

Question 10

Stress cascade response (3)

Answer 10

Question 11

What are the two categories of stressors?

Answer 11

Because of the different physiological pathways, stressors are triggering there are slightly different:

Physical

Psychosocial

Question 12

Whats is cortisol?

How it mediates stress response?

Answer 12

Cortisol is a steroid hormone produced by the adrenal cortex in response to stress.

It is important to know that the amygdala sends projections to areas such as the brainstem, which regulates for instance our cardiac or respiratory activities, as well as fear responses like freezing and the hypothalamus.

Question 13

Hypothalamus actions under the stress (2)

Answer 13

Question 14

What is the relationship between neurogenesis and stress?

Answer 14

Chronic stress leads to higher concentrations of cortisol. And cortisol is associated with higher rates of cell death in the dentate gyrus.

This decreased level of neurogenesis will then be detrimental to the downregulation of the HPA axis. So more cortisol will be released and the organism will be in a physiological state of possible predisposition to depression.

Question 15

How Snyder and colleagues inhibit neurogenesis (2 techniques)?

Answer 15

1. Irradiation has been classically known as a method for inducing cell death and that is the principle for example of radiotherapy to treat tumours.

2. Generation of a transgenic mouse line. Creation of a mouse line genetically engineered to express a thymidine kinase (TK) from the herpes virus under the control of the glial fibrillary acidic protein (GFAP) promoter:
   • GFAP positive cells could express the virus TK
   • TK protein makes dividing cells sensitive to valganciclovir, whilst sparing post-mitotic cells.

This means that every time the animal was treated with the drug, then the dividing GFAP positive cells, like those giving rise to the neurogenic process, will be targeted, but not post-mitotic astrocytes.

Question 16

What are cytokines (3 types)?
Whats is their function?

Answer 16

Certain regulatory proteins and glycoproteins are released by microglial cells and peripheral cells, such as white blood cells. Offer immune protection. Can be detrimental to neurogenic niche and cause neuronal death.

Question 17

What is the cognitive load theory by John Sweller?

Answer 17

The theory is about our working memory having limited capacity to handle numerous pieces of information simultaneously. According to the theory, this is not a problem in normal conditions, when only a small amount of information needs to be processed. However, our authors will say, in the case of an episode of inflammation, there would be intruding interceptive sensations of sickness mediated by pro-inflammatory cytokines, and these would likely augment the load and working memory. Besides, these intruding receptive sensations of sickness would limit the ability of the hippocampus to extract information about the temporal contingencies between nociceptive and environmental stimuli. Especially when the environmental stimuli are not remarkably salient, which is the case of diffused contextual cues, as opposed to specific auditory cues.

Question 18

What LPS stand for? How does it affect organism when injected?

Answer 18

It is the major component of the outer membrane of Gram-negative bacteria. Lipopolysaccharide is localized in the outer layer of the membrane and is, in non capsulated strains, exposed on the cell surface. known to trigger inflammatory responses.

Hippocampus-dependent learning: disrupted in rats injected with lipopolysaccharide (LPS)

LPS-treated rats:

• cell proliferation is reduced (decreased number of BrdU)
• depressive-like behaviour increased in all three lab tests

Question 19

What is the microbiota gut-brain axis?

Answer 19

It is a term used to refer to the pathway of communication between the gut and the brain and which is modulated by gut microbiota.

Microbiota are the range of microorganisms that may be commensal, symbiotic, or pathogenic found in and on all multicellular organisms, including plants.

Question 20

What are metabolic processes performed by microbiota (3)?

Answer 20

• breaking down complex sugars
• regulation of gut motility (contraction of the muscles) and homeostasis of the gastrointestinal barrier
• can contribute to disease if disrupted

Question 21

What can happen if microbiota is disrupted (5)?

Answer 21

Question 22

How cancer treatment affects neurogenesis?

Answer 22

Chemotherapy targets dividing cells leading to the adverse effect of decreased adult hippocampal neurogenesis. This has been assessed by researchers here in the IoPPN using the chemotherapy drug TMZ. TMZ treated mice had a decreased number of immature neurons in the ventral but not dorsal hippocampus. TMZ treated mice exhibited depressive-like behaviour in some but not all of the measures of depression used.

Question 23

What is Cartesian dualism?

Answer 23

The mind would be a separate entity from the body

Question 24

What is the relationship between adult hippocampal neurogenesis stress and depression?

Answer 24

So a possible way to understand it is that chronic stress leads to higher concentrations of cortisol. And cortisol is associated with higher rates of cell death in the dentate gyrus. This decreased level of neurogenesis will then be detrimental for the down regulation of the HPA axis. So more cortisol will be released and the organism will be in a physiological state of possible predisposition to depression.

Question 25

What is a promoter?

Answer 25

A promoter is a region in the DNA where the transcription process begins.

A promoter is a sequence of DNA needed to turn a gene on or off. The process of transcription is initiated at the promoter. Usually found near the beginning of a gene, the promoter has a binding site for the enzyme used to make a messenger RNA (mRNA) molecule.

Question 26

How neurogenesis mediates stress response?

Answer 26

Showing that adult hippocampal neurogenesis is important to buffer the stress response, and supporting the idea that without neurogenesis, animals are more prone to exhibiting anxiety and depressive-like behaviour. Supporting these results, we have in B that only 53% of stressed neurogenic-deficient mice had fed, compared with 92% of stressed wild type mice by the end of the ten minutes test.

Question 27

Different pathways by which the peripheral immune system will affect the brain.

Answer 27

Question 28

How do different cytokines affect neurogenesis?

Answer 28

Question 29

What are the ways to investigate the effects through which gut and brain communicate (5)?

Answer 29

Question 30

What is transcription?

Answer 30

Transcription is the process by which the information in a strand of DNA is copied into a new molecule of messenger RNA (mRNA). DNA safely and stably stores genetic material in the nuclei of cells as a reference, or template