Adult neurogenesis

Why Rakic couldn’t find the new neurons

 Old methods like 3H thymidine → hard to perform, you need a lot of material before it shows
up
 3H thymidine is not specific; you see a new cell but what kind?
 if you give too much it becomes toxic→ DNA damage
 injections in monkeys → during developmental phases, maybe they didn’t see it in the
hippocampus because it develops later in life
 species differences.

Locations for adult neurogenesis

Hippocampal dentate gyrus (subgranular zone)

neurogenesis in the subventricular zone (lateral ventricles)

● stem cells in the lateral ventricles
● cell migrate a lot, fast, thanks to specific chemoattractant
● → rostral migratory stream → olfactory bulb
● Cells differentiate while migrating
● 1st tangential migration, when they reach the target → radial migration → reach the target
and get incorporated
○ dogs
○ mice
○ a little in humans
● in humans the cortex is larger → migration follows a different stream, more complex. but
there are cells moving in this area in humans too.
○ but what would be the functional role?
○ Can we smell more than we know?
● In mice, stimulate the smell → a lot more neurogenesis. need more cells to compute new
patterns of complex smells

double stain with BrdU and all the other normal stainings to see which kind of neuron it is
(e.g. GABA NPY ChA1)

to see if cells make connections: inject a tracer/virus and see where it ends up. you can see
if they make contact and also if they work functionally (synaptic release of vesicles). a lot of
dendrites and cells become more complex as they grow older.

to see if they are functionally active: electrophysiological experiment. viral infection to detect new
cells → find the new ones. use electrodes to record the function of that single cell. you can stimulate
from the entorhinal cortex and see if something goes to CA3. Compared to the neighboring cell
(normal cell, not originated from AHN). New cells behave like the others, same electrophysiological
properties → well integrated in the circuit.

what is the function: to test it you can take them out and see what happens. you can do this
with chemotherapy (like in cancer), specific drugs targeting dividing cells. MAM (drug used)
 ● problems with learning and short-term memory
● but first paper has a lot of limitations
○ eye blink test, weird choice
○ measured activity in CA3 but not DG
○ drug resistance after a while
■ not all cells are killed
■ some are left so they keep functioning
○ chemotherapy makes you sick → attacks all dividing cells
■ eye blink was done because the animals were too sick to perform a
normal test like the MWM
○ MAM is toxic for the cerebellum  problems when moving around
● inducible transgenic mice → activation of the apoptotic pathway in stem cells in the DG.
water maze test. good quality study.
● timing is really important; it takes a while for the cells to be integrated and functional
(about 2 months)
new cells all the time → cells with a memory for a very specific time (important for hippocampal
function).
● spatial memory
● spatial pattern separation (tell apart very similar situations, finding your bike every
day at the entrance)
● used especially when the test becomes difficult.

stimulation of neurogenesis:
● EE
● physical activity
○ new cells
○ better pattern separation, learning and memory
● look at all the different housing environments
○ → physical activity is the main stimulus
● learning also helps

drugs and neurogenesis

● antidepressants stimulate neurogenesis
○ tianeptine is an example, commonly used after stress
○ most work in younger animals, not so much in older ones
● ECS electro compulsive therapy
○ invasive
○ used sometimes in severe cases of depression
○ local epileptic insult

a lot of molecular factors, microRNAs and transcription factors have a role in stimulating
neurogenesis

the neurogenic reserve hypothesis:

If you are always housed in the same environment at some point neurogenesis is no longer
needed/used. then you have no reserve for when you actually need it.
If you challenge your brain, you build a reserve that allows you to adapt and work,
responding really well to new situations later in life.

Other techniques that have been used

 MRS magnetic resonance spectroscopy
o In live human brains
o 1.28ppm indicates adult neurogenesis
 Birthdating with C14
o Heavy and rare isotope
o A lot during the nuclear testing times in the 70s