Hippocampal neurogenesis Flashcards
What are the two main pathways of neurogenesis in rodents?
A. Neural stem cells migrate from the subventricular zone to the olfactory bulb
B Neural stem cells in migrate through the granule cell layer of the dentate gyrus, where they give rise to new dentate gyral neurons, receiving projections from the EC and projecting to CA3.
What is the main pathways of neurogenesis in human?
Carbon dating studies have shown that there is not neurogenesis in the olfactory bulb. however there is neurogenesis in the dentate gyrus, where neural stem cells in the subgranualar zone give rise to neural progenitor cells, which then migrate to the granular cell layer.
There has also been evidence of neural stem cells moving from the subventricular zone to the striatum.
What is the role of the neurogenic microenvironment indetermining stem cell differentiation?
Dubbed as the niche, the environment is pivotal. For example, common multipotent neural stem cells in the spinal cord only differentiate into oligodendrocytes or astrocytes. However, if they are transplanted to the dentate gryus, they can also give rise to neurons. Similarly, common multipotent neural stem cells transplanted from hippocampus to the spinal cord no longer give rise to neurons - only oligodendrocytes and astrocytes.
What are the neurodevelopment lineages of different CNS cells?
neurons, oligodendrocytes and astrocytes are all derived from common multipotent neural stem cells.
Microglia on the other hand enter from outside the CNS before the BBB is formed. They are derived from common myeloid progenitor cells.
What makes up the hippocampal niche?
There are many blood vessels and thus endothelial cells. There are also many astrocytes.
What is the role of astrocytes in hippocampal neurogenesis?
Astrocytes play a key role in the extrinsic singalling required for differentiation of adult neural stem cells. Their influence depends on a number of factors, including depends on a number of factors, including gene expression of the astrocytes. They mediate this both through cell-cell contact, and through soluble factors.
A very simple experiment demonstrated that the type of astrocyte present with neural stem cells alters the amount of neurogenesis. Adult neural stem cells grown in a petri dish will not develop into neurons if they are grown only on a laminin subtrate with no astrocyte present. They will also not differentiate in the presence of spinal cord (adult or neonatal) astrocytes. They grow in the presence of hippocampal astrocytes, and most effectively with neonatal hippocampal astrocytes.
What are the hypothesised functions of adult hippocampal neurogenesis?
• Increase spatial memory capacity,
• Reduce interference between memories (pattern separation)
• Are involved in forgetting/Clearance of established context-
memories
• Encode temporal context to memories [Theory]
How may hippocampal neurogenesis support pattern separation?
Pattern separation is required to distinguish between two very similar memories. It has been shown that rats with decreased neurogenesis can distinguish between two far arms of a maze, but not between two close arms (more similar).
It is hypothesised that the learning of new information of similar memories is directed to the new neurons. If there are not new neurons, then there is a greater overlap and intereference in encoding, and pattern separation cannot be performed.
It has been shown that old dentate gyral cells support pattern completion, and new dentate gyral cells are required for pattern completion.
How is hippocampal neurogenesis involved in clearance and forgetting?
Established memories may interfere with the encoding of new similar memories.
Hippocampal neurogenesis has been shown to decrease the stability of existing memories when the new memories are similar (but not when the new memories are highly dissimilar).
Neurogenesis may therefore be supportive in creating entirely new memories, but not for replacing memories.
How may hippocampal neurogenesis provide temporal separation?
Episodic memories that involve quite different content such as alien abduction and yellow car - but happen close together - can become temporally associated because although the mature neurons that encode the memory will not overlap, they will have some overlap in the young population of neurons (Y1). However, a temporally distant event will be encoded by another new population of neurons (Y2) and will have no overlap with Y1, therefore it will not become associated with memories of yellow cars and alien abductions.
Factors that may increase hippocampal neurogenesis
Sex
Exercise
Learning
Development and incorporation of new neurons does not simply occur at peristant low levels - it is highly susceptible to influence from behavioural influences.
Factors that may decrease hippocampal neurogenesis
Ageing
Chronic sleep deprivation
Stress
What are the effects of exercise on hippocampal neurogenesis?
It has been shown in mice that it increases the level of hippocamapal neurogenesis in the dentate gyrus, and that this also increases learning in the water morris maze.
Genetically manipulated mice that normally exhibit low levels of neurogenesis can be restored back to baseline through exercise, and their water morris maze score returned.
Exercise is considered to increase neural cell proliferation.
However, interestingly, it has been shown that running after learning decreases contextual fear memory storge.
The manipulations are carried out by placing a running wheel in the mouse cage.
What is the relationship between astrocytes, ageing and neurogenesis?
While astrocytic density remains constant with age, as shown by GFAP staining in the hippocampus. However, their secretion of proneurogenic growth factors declines and this correlates with the degree of hippocampal neurogenesis.
Astrocytes minimally secrete BDNF, and while this does not decline, the density of BDNF growth factor receptor does decline. The levels of BDNF correlate with memory and hippocampal volume in older poeple.
NPCs are found in close proximity to astrocytes, which supports the theory that astrocytes are important to the neurogenic niche.
What is the relationship between vasculature, ageing and neurogenesis?
NPC are physically proximal to endothelial cells of the vasculature, which are also closely contacted by astrocytic end-feet. There are many extrinsic factors secreted the vasculature to stimulate proliferation, neuronal differentiation, and survival.
Exercise, shown to increase neural stem cell proliferation, increases the surface area covered by blood vessels specifically in the dentate gyrus.
Vascular endothelial growth factor has also been shown to upregulate neurogenesis, as well as endothelial cell proliferation.
Reduced blood flow to brain regions means that less o2 and glucose reaches neurons and glial cells - reduced ATP and therefore reduced synthesis of growth factors etc. In extreme blood flow it can lead to oxidative stress, excitotoxicity and even cell death, as occuring in stroke. MRIs reveal that very small infarcts are increasingly common with age, leading to microregions of neural death.
