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SEM 1 2024 > Neurogenesis > Flashcards

Neurogenesis Flashcards

1
Q

Compare the % of new neurons in different brain regions

A
  • Increased over time in the detate gyrus
  • Increased over time in the granular cell layer and mitral cell layer, but in the olfactory ventricles they eventually dropped
  • Increased initially in the cerebellum, and then eventually dropped
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2
Q

Rats were injected with tritiated thymidine and then the % of new neurons was recorded. What are the 2 areas of the rat brain that were found to have new neurons?

A

the lateral ventricles (subventricular zone) –> these cells migrate via the rostral migratory stream towards the olfactory bulb

the hippocampus (specifically, the dentate gyrus)

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3
Q

How did researchers determine whether neurogenesis occurs in human brains?

A

Human brain tissue was obtained post-mortem from cancer patients who had been treated with the thymidine analog, BrdU, that labels DNA during the S phase

Used antibodies & immunohistochemistry to label the neurons that have the BrdU

Found that neurons can continue to grow even up to 2 years after injection of BrdU

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4
Q

Mice were given a drug called 9TBD which switches on a particular gene. How did this affect neurogenesis?

Restoration of Klf9 expression to physiological levels restored dendritic spines AND reverted levels of neurogenesis to a steady state

A
  • In the dentate gyrus region, dendritic spiens reduced a LOT after injection of 9TBD (it increases Klf9)
  • However, they grew back in the ‘chase’ period, showing it is reversible
  • Overexpression of 9TBD leads to a huge increase in DCX (which is expressed by neuroblasts and migrating immature neurons)
  • Reducing number of dendritic spines in mature neurons allows IMMATURE neurons to develop bc they are now getting more synaptic input

Nestin & MCM2 also increase with more Klf9

Didn’t really affect the olfactory bulb or CA1 region of the dentate gyrus; Klf9 activates neural stem cells without affecting olfactory bulb neurogenesis

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5
Q

2 groups of mice (12 months vs 17 months) were given either a control or 9-TB-Dox (which increases Klf9). What were the key findings?

A

Mice in the Klf9 group were better able to distinguish between their environments & respond to shock - had better memory

Contextual memory precision is enhanced in middle-aged and aged mice with expanded populations of 5-8 week old adult born dentate gyrus cells

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6
Q

In Elizabeth Gould’s study, 12 monkeys were injected with BrdU and immunohistochemistry was used to identify the labelled cells. What were the key findings?

A
  • These cells were lining the lateral ventricles (similar to subventricular zone)
  • After a week of injecting BrdU, they found that some of the labelled cells had begun to migrate towards the cortex
  • By 2 weeks, they saw quite a few cortical neurons
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7
Q

Name 4 regions, asides from the detate gyrus and lateral ventricles, that are thought to be involved in neurogenesis

A

Hypothalamus (migration of new neurons to hypothalamis nuclei)
Prefrontal cortex
Striatum / substantia nigra (involved in Parkinson’s disease –> dopaminergic; neurons degenerate and this causes issues)
Amygdala (control of emotion & reg. of stress)

Researchers also believe the **central canal **(basically a modified ventricle - is where the CSP flows into the spinal cord from the forebrain), the NTS, and the dorsal motor nucleus of the vagus undergo neurogenesis

DAPI, EdU, and NeuN were all found in the NTS

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8
Q

Distinguish between neurogenesis in a hypertensive animal vs a normatensive animal

A
  • WAY more EdU cells in the NTS of hypertensive animals
  • Seems like there is more neurogenesis in hypertensive animals
  • But not a major difference in the central canal (the higher the blood pressure, the more EdU cells there are - we don’t know why)
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9
Q

Two mice were crossed to produce a mouse knwon as the Nestin-CreER/Rosa-YFP reporter mouse. What happens when this mouse is given tomoxaphin?

A

When the mouse is given tomoxaphin, it inhibits a stop codon which allows YFP to be expressed

This enables the expression of Nestin

All the cells that express Nestin also express YFP

Tomoxaphin labels all new neurons born within those 5 days of tomoxaphin treatment

Result: labelling of YFP in SVZ, RMS, and SGZ (dentate gyrus)

As the neurons aged, they became MORE sensitive to stimulation - day 4 hardly nothing, day 26 they had much larger responses & action potentials firing

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10
Q

FOS is one of the markers used for cell activation. What are some of its properties?

A
  • A transcription factor
  • when you stimulate a particular cell, it will start to express FOS
  • hypotensive OR hypertensive challenge leads to colocalization of FOS & BrdU which means the BrdU active cells are also activated by these stimuli
  • is an established activity marker for neurons
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11
Q

What is the role of AraC in regulating blood pressure?

A
  • AraC incorporates into DNA & inhibits DNA replication by forming cleavage compelexes with topoisomerase
  • If you inhibit this enzyme, the DNA gets coiled so tightly it starts to fragment, so you start to kill off any cells that are undergoing division & DNA replication
  • If you infuse AraC into the brains of rats, you don’t see any double cortin staining - it is a way to knock out these neurons

Pre-AraC = normal blood pressure

Post-AraC = a more rightward curve so it shows that these cells are important in blood pressure handling

When DNA is formed, it is a double helix and highly coiled - topoisomerase relaxes that coiling

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12
Q

What are the 3 key roles of the oxygen cascade?

A
  1. maintains blood pH
  2. matchs metabolism
  3. temperature regulation
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13
Q

Outline the steps in INSPIRATION

A
  1. Phrenic nerve sends signal to diaphragm
  2. Diaphragm contracts (shortens, goes down)
  3. Thorax volume expands
  4. Causes drop in pressure comp. to atm pressure
  5. Air flows INTO lungs
  6. The recurrent laryngeal nerve (a branch of vagus nerve) innervates abductor muscles of upper airways
  7. These muscles contract to open the airways
  8. Increase in radius, decrease in resistance, increase in flow

Subglottal pressure falls, matching the intra-alveolar pressure falling and so on

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14
Q

Outline the steps in POST-INSPIRATION

A
  1. No activity in diaphragm, so it starts relaxing & begins moving up
  2. Volume starts to decrease, pressure increases
  3. Phrenic nerve is NOT active
  4. Recurret laryngeal nerve –> innervates adductor muscles
  5. Decrease in radius, increase in resistance, decrease in flow
  6. Slows the escape of air (allows for longer diffusion of O2 into tissue)

This post-inspiration phase is when most modulation happens

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15
Q

Outline the steps in LATE EXPIRATION

A
  1. Phrenic nerve is still quiet
  2. Recurrent laryngeal nerve has little to no activity - upper airways open up a bit to allow for release of air
  3. Compression of thorax by relaxation of diaphragm & external intercostal muscles
  4. Intra-alveolar pressure returns to atmospheric pressure
  5. Exit of air is much faster now than in post-inspiration phase
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16
Q

What is another muscle that contracts during inspiration?

A

the genioglossus muscle that is innervated by the hypoglossal nerve

17
Q

The ventral surface of the medulla is important in breathing. The scientists wanted to understand which brainstem region is the source of respiratory rhythm. What did they do?

A
  1. They sliced diff parts of the brainstem
  2. When they reached mid-medulla they started losing respiratory rhythm
  3. Found that activation of the hypoglossal nerve caused stimulation of the pre-BotC neuron
  4. If the pre-Botc neuron was inhibited, the hypoglossal nerve would be inhibited too
  5. This led them to conclude that the pre-Botc is enough to generate respiratory rhythm
18
Q

What might happen to breathing if the pre-BotC is destroyed?

A
  • Breathing frequency will decrease
  • Breathing will become erratic
  • Breathing will cease entirely
19
Q

Phrenic nerve activity was compared with the activity of Pre-BotC. What was found?

A

It was found that Pre-BotC activity preces phrenic nerve by just a bit
* Pre-inspiratory neurons or EARLY inspiratory
* Little to no expiratory neurons

20
Q

Scientists used juxtacellular labelling. They placed extracellular electrodes in the Pre-BotC region and drove a dye into the cell that they had recorded from. After the experiment, they sliced up the brain and stained for neurones that contained biocitin (which is what they had driven into the cell they were recording from). What did they find?

This technique would allow tehm to correlate between the CHEMICAL properties of that neuron and the NEURAL ACTIVITY (the recording)

A

They found the NK1R receptor

21
Q

What are the features of Pre-BotC?

A
  • excitatory
  • no unique markers
  • glutamatergic
  • has a glycinergic subset
  • rhythmogenic (not a pattern generator)
  • NK1R receptor expression on membrane
  • Somatostatin (SST) expression in cell bodies
  • Dbx-1 (transcription factor) expression

SST is a (usually) inhibitory neuropeptide
Dbx-1 can be used (from a developmental POV) to trace where these neurons have come from

22
Q

Features of NK1R

A

Neurokinin 1 Receptor
* Endogenous ligand for this receptor = Substance P
* G-protein coupled receptor
* NK1R and its ligand will both be internalized by the post-synaptic cell and stored in vesicles following stimulation by ligand (substance P)

23
Q

One method used to demonstrate that pre-BotC is important in respiratory rhythm involved the use of the ribosomal inactivating protein, Saporin. Explain how this works.

A

Saporin inhibits protein synthesis and leads to cell death; however, to have an effect, it must be internalized by the cell.

  1. SAP & Substance P will be bonded together
  2. Substance P binds to NK1R receptor
  3. Receptor is enndocytosed, bringing SAP & Substance P inside
  4. These vesicles will get broken down by lysosomes
  5. SAP will be released
  6. SAP will bind to ribosomes and inactivate them, leading to cell death
  7. Takes a few days for cell death because proteins in the cell don’t run for a while

NK1R expressing cells in the Pre-BotC are needed for normal breathing rhythm generation

24
Q

Silencing of the pre-BotC by insect peptide allostatin after transfection with AAV resulted in somastatinergic neruons. . .

A

cessation of breathing

Viral delivery of SST promoter driving expression of EGFP and allostostatin receptor

25
Q

Pre-BotC neurons have “intrinsic bursting properties”. What does this mean?

A

They can still depolarize even without synaptic input
But these properties are dependent on persistent sodium currents

Ril = riluzole which blocks Na+

26
Q

How does blocking Ca2+ vs Na+ entry affect the intrinsic bursting properties of pre-BotC

A
  • Blocking Ca2+ ativated non-selective cationic currents using FFA led to smaller intrinsic bursts
  • Blocking both Ca2+ and Na+ led to a complete loss of activity
27
Q

The addition of. . . .after FFA & Ril caused a small return or bursts

A

Substance P

& larger stiimulation of hypoglossal nerve

28
Q

Scientists wanted to know how many small bursts it would take to create a big burst in pre-BotC. Explain the experiment they carried out.

A
  • Lasers able to selectively activate neurons within the Pre-BotC
  • Sample set in a bath solution
  • Caged glutamate - when laser light shines onto the solution it then “uncages it” –> remove cage = glutamate (excitatory)
  • Allowed researchers to selectively activate different clels by incaging diff glutamate around them
  • Activated 6 cells - no changes
  • Activated 9 cells - you get a burst of hypoglossal
  • So, you need a certain number of cells to be stimulated in order to create a network of enough output to drive the hypoglossal
29
Q

Why was the pre-BotC much smaller in people with multiple system atrophy?

A

Because they have problems with breathing

Respiratory rhythm is an emergent property – i.e. emerges after a # of things happen

30
Q

A subset of pre-Botzinger neurones are found to express opioid receptors.
* opioid receptors associated with Ga(inhibitory)
* you are recording from pre-BotC pre-inspiratory neurones in the slice
* You add an opioid receptor agonist

A

Membrane potential would decrease
Respiratory rhythme would reduce / cease

SEM 1 2024 (8 decks)

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