Neural Basis of Motivation and Learning (NEUR0014)
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Adult Neurogenesis and the Dentate Gyrus
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Neural Basis of Motivation and Learning (NEUR0014)
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University College London (UCL)
Adult Neurogenesis and the Dentate Gyrus (Lecture 6 of 16 in NEUR0014: Neural Basis of Motivation and Learning)
Thorough review of adult neurogenesis in the dentate gyrus in both mammals and humans, and how this relates to memory storage and recall.
Neural Basis of Motivation and Learning (NEUR0014)
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Voorbeeld van de inhoud
Lecture 6: Adult Neurogenesis and the Dentate
Gyrus
Adult Neurogenesis, learning and memory and Dentate Gyrus Commented [IM129]: BDNF and NGF likely control DG
neurogenesis (major growth factors)
Continuation of: the role of the hippocampus in learning and memory, specifically the DG field
Adult neurogenesis in mammals
• Dentate gyrus (SGZ) continues to generate neurons even in adult life; very unusual in
mammalian brain
History and background
Neuroscience dogma up until the 1960s;
‘In the adult centres the nerve paths are something fixed, ended and immutable. Everything
may die, nothing may be regenerated’ - Santiago Ramon y Cajal
• Adult CNS is fixed
o Only generate neurons during pre-natal embryogenesis
o Cells can die (i.e. developmental pruning) Commented [IM130]: Developmental phenomenon: cells with
expansive dendritic trees; dendritic trees can make synapses and die
o Adult neuronal regeneration is not possible, thus CNS injuries can be devastating off
The first evidence this might not be true in all circumstances;
(Altman, 1963) - Autoradiographic investigation of cell proliferation in the brains of rats
and cats
• Found dense labelling (Thymine-(radioactive)Tritium), indicative of DNA synthesis, in the
dentate gyrus of the hippocampus
• This was very controversial: Doesn’t necessarily indicate neurogenesis; Thymidine uptake
could also indicate DNA repair
o Also, at the time, this method couldn’t differentiate between neuronal and non-
neuronal cells in the brain (e.g. glia, which do proliferate during adulthood) Commented [IM131]: Non-neuronal cells are born and
proliferate in adulthood – so this would be particularly controversial
Conclusion: This was not accepted as clear evidence of neurogenesis in adult mammals, at the time
Commented [IM132]: Altman’s career suffered as a result
Some of the big steps forward in the ‘rediscovery’ of Altman’s work (20 years later), include new
techniques for labelling DNA:
Visualisation of newly generated neurons
• Incorporation of nucleotide analogs (e.g. BrdU (bromo-deoxyuridine), [3H]-thymidine)
• Another analogue for DNA base pair, that’s incorporated into DNA when cell is synthesising
(or repairing) DNA while the animal is dosed with this BrdU drug, thus one can effectively
time-stamp when a piece of DNA has been synthesised
o Advantages: permanent tracing, tracing of whole population of dividing cells, good Commented [IM133]: You label all of the dividing cells in the
animal, thus can get a measure on the amount of neurogenesis in
birth dating the whole animal brain from one injection
§ BrdU is more amenable than radioactive-labelling to modern imaging Commented [IM134]: BRDU is metabolised and extreted by the
techniques, and can be combined with other types of imaging, thus much animal within hours, thus get really accurate ~1day timestamp of
when DNA is synthesised
easier to get a definite answer on cell type (e.g. BrdU cell co-labelled with
NeuN marker to signify neuronal cell type)
, § Can use this technique to get definite answer that neurons are being
labelled
o Disadvantages: only visualises cell nucleus, cannot exclude incorporation due to
DNA repair (rather than cell division)
Conclusions: Advancements in DNA labelling techniques allowed quantitative discrimination
between neuronal and non-neuronal cells; however, this still could not tell you if you’re labelling a
neuron because it’s a newly created neuron, during the time BrdU circulated the system, or if
labelled nucleotide has been incorporated due to DNA repair
Nowadays, we have another powerful technique to visualise newly generated neurons:
• Genetic marking of (newborn neurons) by retroviruses (variants of murine leukaemia virus
which only integrate after cell mitosis)
o Retroviruses only label cells undergoing mitosis
o Advantages: specifically infects dividing cells, permanent tracing, good birth dating,
whole cell visualisation (definite marking of neurons)
o Disadvantages: only few cells marked (can’t tell how many cells born in entire
population), invasive method
This technique can definitively tell us: there are new cells being born in neurons of the adult brain,
removing the DNA repair controversy.
Conclusion: Evidence (-GFP) that virus has infected a cell à know neuron was undergoing mitosis Commented [IM135]: Injection into brain à kill animal and
take brain slices
(i.e. cell division), thus there was a neuron being born, at the time the virus was around. Technique
solved a lot of potential problems with previous findings: labelled whole cell, definitely neurons, Use GFP to trace
know timeframe when neuron was born. However, only a few cells are labelled (patchy), thus
different to perceive neurogenesis at population level.
Accumulating evidence for adult neurogenesis (1980s-90s)
During 80-90s it became more indisputable that Joseph Altman was correct, that there was
neurogenesis in some specific areas of the adult mammalian brain.
Some of the strongest supporting evidence:
• (Nottebohm, 1985) - Neuronal Replacement in Adulthood (Birds)
o Not mammals, but other vertebrate group, illustrating neurogenesis, its function and
importance
o Adult neurogenesis pervasive in some adult bird species and clearly linked to
learning and memory
• (Kuhn et al. 1996) – confirmed that there was neurogenesis in the dentate gyrus of adult
rats
• (Kornack & Rakic, 1999) - Continuation of neurogenesis in the hippocampus of the adult Commented [IM136]: Pasco Rakic was one of the strongest
arguers against Altman’s theory of neurogenesis in the adult
macaque monkey mammalian brain
Clear confirmation that adult neurogenesis (and gliogenesis) occurs in hippocampal dentate gyrus
non-human primates
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