week 6 - adult hippocampal neurogenesis Flashcards
(25 cards)
what is adult neurogeneisis
the process in which neurons are generated from neural stem ells in the adult
where do we have neural stem cells?
throughout the brain and the spinal chord
What can neural stem cells produce
neuron
oligodendrocyte
astrocyte
eevidence for adult neurogeneis:
altman and das (1965)
used autoradiography and histological evidence to suggest adult neurogenesis exists
where does adult neurogenesis occur (rodents)?
in the hippocampus. In the subventricular zone of the lateral ventricals and in the subgranular zone of the dentate gyrus
what is the pathway of adult hippocampal neurogeneiss(rodents)
LATERAL VENTRICLE
- The neural stem cells reside in the Subventricular zone of the Lateral ventricle
- As the neurons mature they migrate along the RMP path into the olfactory bulb where they form interneurons
DENTAE GYRUS (hippocmapus)
- Neural stem cells reside in the subventricular zone of the dentae gyrus
- the cells proliferate in the dentate gyrus.
- Then they migrate through the granual cell layer of the dentae gyrus
- They ifferentiate, formign synapses with fibres from the entorinhal cortex, recieve=ing input from the entorinal cortex and project along the mossy fibre pathway to CA3.
- In the rodent brain it takes 4-8 weeks to mature and make connections
What experiments shows hippocampal neurogenesis in adult humans
spalding et al 2013
- used carbon dating with C14 from nuclear bomb to see if they if there was c14 in neurons which will show if the neurons are new.
- This worked because in the 60s there was a nuclear bomb trial which meant that c14 in the atmosphere increased
- Their study c14 according to atmospheric levels, only in neurons in the dentae gyrus of the human hippocampus, in humans born before the 1960s
-which is where the rodent models showed adult neurogenesis too.
Zhao et al. (2022, Nature) analysed the molecular profiles of immature neurons across the lifespan.
Found immature neuron markers (e.g. DCX, PROX1) present from childhood into adulthood in the dentae gyrus, however the level of neurogenesis does decrease as you get older
Suggests a sustained population of immature neurons in the dentate gyrus, supporting ongoing plasticity.
where is there evidence of adult neurogenesis in humans?
in the dentate gyrus in the hippocampus
We might have it in the SVZ and migrates to the striatum, however not sure
It definitly doesnt migrate from the SVZ to the olfactory bulb in humans
How many neurons in the rodent olfactory bulb are replaced during 6 weeks?
70% of neurons
what do quantitative studies say about neurogenesis
We create 700 new neurons per day in the hippocampus in the adult. By the time we turn 50 we will have replaced the entire granule cells
What experiments show that the neurogenic niche is important in neurogenesis
Take a neural stem cell from a spinal cord.
Grow the neural stemcell in a dish. If you transplate it into the dentate gyrus you get neurons
If you transplant it into a non-neurogenic region you dont get neurons.
This shows that the neurogenic niche is very important here
Whats important in the neurogenic niche?
Proximity to endothelial cells
Proximity to astrocytes
Blood vessels
Neural Progenitor cells
What experiments can tell us about the neurogenic microenvironment
song et al 2002 cultured neural stem cells in a petri dish and compared the amount of astrocytes from the hippocampus, or amount of astrocytes from the spinal chord with whether stem cells become neurons
and found that it is the astrocyttes in the hippocampus that are sending the signal for stem cells to become neurons. The younger the astrocytes the better.
Read this paper.
What did Song et al. (2002) discover about astroglia and neurogenesis from adult neural stem cells?
Key Methods:
Cultured adult NSCs with astrocytes from different sources:
Adult hippocampus
Adult spinal cord
Neonatal astrocytes
Primary skin fibroblasts (control)
Assessed neuronal differentiation using MAP2ab and GFP labelling (MAP2ab⁺/GFP⁺ = newly formed neurons).
Main Findings:
Adult hippocampal astrocytes significantly promoted neurogenesis from adult NSCs.
Spinal cord and skin-derived astrocytes supported much lower levels of neuronal differentiation.
The neurogenic effect was region-specific — suggesting that the local astrocytic environment in the hippocampus is critical for adult neurogenesis.
Graph (panel c) shows the highest % of neurons in cultures with hippocampal astrocytes (red bar), compared to spinal cord or skin.
✅ Conclusion:
Astrocytes from the adult hippocampus create a pro-neurogenic environment that supports the differentiation of adult neural stem cells into neurons. This underscores the importance of the local microenvironment in regulating adult neurogenesis.
What are the molecular control of adult neurogenesis?
Lie et al, 2004
- back in 2004 they only knew that there was some repression in the niche of not making astrocytes so much
Mu, lee and gage 2010
- Found hundreds of factors that are key players in modulating neurogenesis
Choose one factor thats listed in the 2010 paper that i recognise from another coourse and read a couple of papers about how they modulate neurogenesis
what is one example of a factor that contributes to molecular control of neurogenesis
There are hundreds of factors that modulate adult neurogenesis in the hippocampus. These include growth factors, transcription factors and mRNA
FOR EXAMPLE:
wnt signalling regulates adult hippocampal neurogenesis (lie et al 2005)
They found that Wnt is found in the granule cells, where neurogenesis happens. This made them think that maybe wnt is important for neurogenesis.
IN VITRO
They extracted neural stem cells and grew them in a petri dish
They found that when you add Wnt, you get more new neurons from the stem cells compared to when you don’t add wnt
IN VIVO
They designed a wnt dominant negative plasmid that meant when you inject it, you block wnt signalling
They found that when you block wnt signalling you get 8x less new neurons in vivo
They then overexpressent wnt, and found that when you overexpress wnt in the dentae gyrus you get double the amount of neurons
interestingly, astrocytes express wnt.
What is the functional relevance of adult hippocampal neurogenesis?
- adult hippocampus is reduced in some animal models of depression. Many treatments for depression promote neurogenesis and strudies show that treatment efficacy is dependent on this.
Samuels and hen 2011,
bbc radio 4 discussion
Anacker and hen 2007
Spatial memory:
- New neurons increase spatial memory capacity - the more neurogenesis the better performance in mwm (the level of neurogenesis is positively correlated with spatial learning).
-If you block neurogenesis then that eliminates performance in mwm. Trangenic mice that could make new neurons in the dentae gyrus had impaired performance in the morris water maze following learning, and poorer object recognition in the object recognition task (thuret et al 2009)
PATTERN SEPERATION
- improve pattern seperation (read paper from clelland et al 2009. Having new neurons can permit the second event to utilize new neurons instead of the same old neurons to encode the event in different contexts)
- If you have neurogenesis, you direct learning of new patterns to new neurons. This allows the seperation of different patterns
- Lack of neurogenesis leads to interference/ higher statistical overlap between representations
FORGETTING/ INFANTILE AMNESIA
-Involved in forgetting/clearence of established context memories (infantal amnesia. we don’t remember when we were an infant because at early childhood we have burst of neurogenese which distrubs this. read Frankland et al, 2014.
MEMANTINE STUDY
Increasing neurogenesis weakened existing memories in mice but allows the encoding of new conflictin information. Decreasign neurogenesis stablizied existing memories but impeded the encoding of new conflicting information)
TEMPORAL ENCODING
- Add information about time to new memories. (aimone et al, 2013 - —computational modelling to suggest that the temporal proximity of two events is sufficient to lead to a relationship in their long term episodic memories. in contrast, another event later would not be associated due to time elapsed. Thsi may be because the overlapping young neurons would have a temporal association. But when time has passed, different young neurons creates temporal seperation)
- This is because its the same young neuron that encodes two events. After time passes, there is new young neurons, so events far apart in time are encoded by different neurons
- However this is just a hypothesis because we haven’t tested this experimentally
How does adult hippocampal neurogenesis influence memory clearance and flexibility?
Increased neurogenesis can weaken existing memories, allowing better encoding of new, conflicting information.
Decreased neurogenesis stabilises existing memories but impairs encoding of new, overlapping information.
Shown experimentally using memantine (MEM), an NMDA receptor antagonist that increases neurogenesis.
MEM treatment increased immature neurons (DCX⁺ cells) and reduced memory retention (freezing behaviour), suggesting facilitated forgetting.
Supports the idea that neurogenesis promotes memory clearance to reduce interference and enable new learning.
Describe the object recognition task
A behavioural test used in rodents to assess recognition memory.
Involves two phases:
Sample phase: Rodent explores two identical objects.
Test phase: One object is replaced with a novel object after a delay.
Rodents naturally explore novel objects more if they remember the familiar one.
Measures how much % of time the rodents spend exploring each object.
what is the relevance of adult hippocampal neurogenesis in neurodegenerative disease
You have mood and cognitive impairment in both alzheimers disease and parkinsons disease
Mouse model and post-mortem tissue experiments have found that neurogenesis is altered in these diseases.
There is evidence that evidence in adult hippocampal neurogenesis is altered at the early stage of alzheimers disease
mu and gage 2011
maruszak 2013
berger et al 2020
However, conflicting information - some show increase in neurogensis in AD, some show decrease
There needs to be a systematic comparison, controlled for:
- Age
- Gender
- Genetic background
- Neuropathology Stage
- Methods of ANH detection
Why might modulating neurogeneis be useful in AD
- During the late stage of the disease, patients are losing up to 100x more neurons per day than they could be creating
- So its more important in preventing/slowing the progression of the disease
- Perhaps modulating neurogenesis can prevent memory/mood decline
how can we modulate adult hippocampal neurogenesis?
- learning increases neurogenesis
- chronic stress decreases neurogensis
- chronic sleep deprivation decreases neurogenesis
- sex increases neurogenesis
- ageing decrease neurogenesis (villeda et al 2011, fused circulatory system of mice, young old , old old, and young youong. - crazy study , read it)
- excercise increases neurogenesis (praag et al 1990. Thuret et al 2009 - in mice that don’t have neruogenesis, running can rescue it and lead them to get neurogenesis)
- diet (diet has strong impact on neurogeneis - read a review (marx et al 2021)
How does running influence adult hippocampal neurogenesis and memory?
Voluntary running significantly increases the number of immature neurons in the adult hippocampus.
It can rescued impaired neurogenesis, in mice with no neurogenesis
Running also restores performance on the MWM suggesting a link between physical activity, neurogenesis, and cognitive function.
what is the main paper to read that overviews all of this?
adult neurogenesis in the hippocampus: from stem cells to behvaiour
goncalves et al 2016)
