Week 1 Topic 3 - Microanatomy of the nervous system

Question 1

Who discovered that the brain is not a single continuous entity but composed of individual cellular units?

Answer 1

In 1906, Ramóny Cajal and Camillo Golgi were jointly awarded the Nobel Prize in physiology and medicine for their
discovery that the brain is not a single continuous entity but composed of individual cellular units.

Question 2

What are the two major types of cells that the cells of the nervous system differentiate into during development?

Answer 2

We now know that during development, the cells of the nervous system differentiate into two major cell types:

1. neurons – the
   cells responsible for fast communication along large networks – and the
2. supporting glial subtypes.

Question 3

How do neurons communicate?

Answer 3

Neurons communicate by passing electrical signals along their elongated form and they’re converting this into a chemical signal to activate an electrical signal in the next neural network.

Question 4

How fast does information travel between neurons?

Answer 4

Information travels at different speeds
in different neurons, ranging from 1 mile per hour, the speed of a tortoise, to 268 miles an hour, which is faster
than most Formula 1 racing cars.

Question 5

Are neurons homogenous or heterogeneous?

Answer 5

Neurons are not homogeneous, they are heterogeneous. They come in many forms specialised for their particular function within the nervous system.

Question 6

Can neurons both receive signals and send signals to other cell types?

Answer 6

On the left, we have a classical neuron which both receives signals from and sends signals to
other neurons and has a long, extended shape.

However, some neurons can both receive signals and send signals to other cell types.

For example, sensory neurons can be activated by changes in the skin cells, and lower motor
neurons can stimulate muscle movement.

Some neurons, such as interneurons, can actually send and receive signals with multiple other neurons.

Question 7

Describe the dense lobe structure in the cerebellum.

Answer 7

Even within brain regions, neurons can vary widely.

For example, in the cerebellum, the brain region that primarily coordinates movement, there is a dense lobe structure.

The dense layer in these lobes is generated by millions of small granule cell neurons, which feed into one of the largest types of neuron in the brain, the Purkinje cells, with other interspersed basket and Golgi neurons.

Question 8

What are Purkinje cells?

Answer 8

one of the largest types of neuron in the brain

Purkinje cells release a neurotransmitter called GABA (gamma-aminobutyric acid), which exerts inhibitory actions on certain neurons and thereby reduces the transmission of nerve impulses. These inhibitory functions enable Purkinje cells to regulate and coordinate motor movements.

Question 9

What are Golgi neurons?

Answer 9

The Golgi cell acts by altering the mossy fibre - granule cell synapse. The Golgi cells use GABA as their transmitter. The basal level of GABA produces a postsynaptic leak conductance by tonically activating alpha 6-containing GABA-A receptors on the granule cell.

Question 10

What are granule cells?

Answer 10

Granule cells are the only intrinsic excitatory neurons, the other four neuron types (Purkinje, basket, stellate, and Golgi) involved in computation are all inhibitory and target deep cerebellar nuclei, soma of Purkinje cells, and dendrites of Purkinje and granule cells, respectively.

Question 11

What are mossy fibres?

Answer 11

Mossy fibers are the axons of dentate granule cells in the hippocampal region. In the normal hippocampus, these axons of granule cells elongate within the dentate hilus and stratum lucidum, and innervate hilar cells and CA3 pyramidal cells.

Provide a rich excitatory drive to the cerebellar cortex. They originate from several regions in the brain and spinal cord

Question 12

Which glial cells directly interact with neurons?

Answer 12

But neurons do not function in isolation, they are supported by multiple types of glia. Those that directly interact
with neurons – oligodendrocytes, astrocytes, microglia – and ependymal cells, who line the ventricles of the brain
and the central canal of the spinal cord (similar to epithelial/skin cells). We will now go through each of these cell
types one by one.

Question 13

What are ependymal cells?

Answer 13

line the ventricles of the brain

and the central canal of the spinal cord (similar to epithelial/skin cells).

Question 14

What are the 5 functions of astrocytes?

Answer 14

Astrocytes have many known functions, including

1. distribution of nutrients from the blood supply to neurons,
2. maintenance of extracellular ionic balance and
3. tissue repair.
4. They can also regulate synaptic activity by direct
   contact with synapses, in what is known as the ‘tripartite synapse’, and
5. signal between each other independently
   of neurons via gap junctions – small gaps in the cell membrane that leak charged ions.

Question 15

What are the functions of microglia?

Answer 15

Microglia, as inferred by the name, are smaller than astrocytes and function as the resident immune cells of the

brain.
1. In this function, they clear debris, recruit other cells to sites of damage and aid in tissue repair.

2. In addition
   to debris clearance, they can also degrade synapses – which is essential for synaptic pruning during development
   but may make matters worse by preventing recovery when neurons undergo chronic stress during disease.

Question 16

What are the functions of oligodendrocytes?

Answer 16

The next type of glia, oligodendrocytes, play the same role in the brain as Schwann cells in the periphery. 1. They wrap their processes around neuronal axons secreting the lipid myelin, generating a protective myelin sheath.
2. This sheath also increases the speed of neuronal signalling by insulating the passing of electrical charge along the
axon, in a process called saltatory conduction.
3. Recent data also shows that oligodendrocytes also provide
metabolic support to neurons, aided by their proximity.
4. Demyelinating diseases, like multiple sclerosis, cause
degeneration of the myelin sheath, preventing the brain communicating adequately with the body.

Question 17

What is saltatory conduction?

Answer 17

The process which insulates the passing of electrical charge along the
axon - the propagation of action potentials along myelinated axons from one node of Ranvier to the next node, increasing the conduction velocity of action potentials

Question 18

What happens when different cell types - neurons and/or glia don’t function as they should?

Answer 18

We have now seen that many different cell types contribute to the proper functioning of the brain and, therefore,
it is not surprising that dysfunction of any of these cell types can lead to disease.

Neurons and glia cohabit in a
very delicate balance.

Question 19

What is Neuroinflammation?

Answer 19

Neuroinflammation is the activation of glia within a nervous system. This neuroinflammation
may initially be a defence response to threat, to protect neurons. But chronic activation can lead to the over or
aberrant activation of astrocytes and microglia and toxicity to neurons.

Altered function of astrocytes and
oligodendrocytes can also directly disturb synaptic transmission.

Therefore, these changes can result in
vulnerability of neurons both in neurodevelopmental and neurodegenerative diseases.

Question 20

What is Neuronal morphology?

Answer 20

Neuronal morphology, or shape, is

1. refined during development to fit the function of neurons and is,
2. therefore, highly variable.

Question 21

What does the extent of dendritic arborisation reflect?

Answer 21

The extent of dendritic arborisation, or branching, reflects the level of input that a neuron requires
– as dendrites are the main sites of neuronal input. For example, cerebellar Purkinje cells are highly branched,
as they receive many inputs and are the only input of the entire cerebellar cortex.

Question 22

What is the longest axon in the body?

Answer 22

Axonal length can also vary widely, determining the distance of output in the network. The longest axon in the
body is from the lower motor neurons, which is one meter in length, which is quite incredible for a single cell. To
give you an equivalent – if the cell body was the size of a ping pong ball, the axon would be 380 meters long, just
under four football fields in length.

Question 23

What are dendritic spines and what do they do?

Answer 23

Neurons also have microstructures called dendritic spines. These are small protrusions from dendrites which
form the postsynaptic side of a synapse with axon tunnels from other neurons. Dendritic spines come in different
forms, from long and thin to mushroom shaped. Their shape and size will affect how they receive and transmit
input. Those with a larger surface area provide more space capacity for neurotransmitter receptors and, thus,
generally form stronger, more stable synapses rather than the more transient, filopodial types. Spines are also
plastic and can increase in size during learning and memory.

Question 24

What are filopodia?

Answer 24

that function as antennae for cells to probe their environment. Consequently, filopodia have an important role in cell migration, neurite outgrowth and wound healing and serve as precursors for dendritic spines in neurons

Question 25

Why is glial morphology important?

Answer 25

Glial cells also vary in morphology. Here, microglia change morphology when they become activated, or ‘reactive’,
with increasing numbers of processes and progressively become more round and phagocytic.

Reactive microglial
release more cytokines to attract more microglia to the site of a perceived injury.

In phagocytic mode, they engulf
any perceived debris, which can include synapses.

Thus, microglial morphology can be used to score and infer
neuroinflammation.

Question 26

What is ‘astrocytosis’?

Answer 26

Astrogliosis (also known as astrocytosis or referred to as reactive astrocytosis) is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, autoimmune responses or neurodegenerative disease.

Question 27

Mouse with dementia experiment….

Answer 27

Here, we show an example of the scoring system in a mouse brain from a model of
frontotemporal dementia stained with a microglial marker, ‘Iba1’. You can see the scoring system goes from ‘1’,
ramified – which is normal; through ‘2’, reactive; ‘3’, ameboid; to ‘4’, phagocytic. This has then been used to show
progressive neuroinflammation in this model, compared to a non-transgenic mouse control.
Slide 7
Astrocytic morphology is highly heterogeneous even under normal conditions. Therefore, instead of morphology,
activation is often inferred from increased numbers of cells in a given location – this is often called ‘astrocytosis’.
An increased number of cells may be due to local recruitment or enhanced proliferation of astrocytes. In the
same mouse model of frontotemporal dementia as before, an increase in the number of astrocytes is quantified
by the percentage of the total area that is stained for the astrocytic marker, ‘GFAP’. In this case, progressive
astrocytosis is observed from 12 months of age, panel ‘E’, and quantification below.

Question 28

How are the organelles in a neuron similar to a standard eukaryotic cell?

Answer 28

Inside a neuron, the majority of specialised organelles are very similar to a standard eukaryotic cell, including the
following:

1. the nucleus – where all genetic information is stored; the endoplasmic reticulum – where some new
   proteins are produced, sorted and processed for delivery to their required location;
2. the Golgi apparatus – where
   additional sorting and processing occurs;
3. mitochondria – are the energy generator of the cell and also have key
   roles in calcium buffering and cell signaling;
4. lysosomes – are enzyme-filled vesicles for the degradation of proteins
   and other organelles when faulty; and the cell membrane – is a lipid bilayer containing receptors for cellular
   communication.

You can see a great video introduction to some of these concepts with this link provided
[https://www.youtube.com/watch?v=URUJD5NEXC8].

Question 29

What is a Eukaryote?

Answer 29

Eukaryote - any cell or organism that possesses a clearly defined nucleus.

Question 30

How are neurons different from other eukaryotic cells?

Answer 30

Neurons do, however, have some unique features that relate to their highly specialised function.

1. HIGH ENERGY DEMAND
   The first of these
   is that they have an unusually high energy demand. In a human, the brain comprises only 2% of body mass yet it
   uses about 20% of the oxygen consumed by the rest of the body. The majority of this is used to maintain the
   electrical equilibrium of the neuronal cell membrane by the sodium-potassium ATP pump which, as its name
   suggests, consumes ATP. Other main energy demands include the recycling of neurotransmitters and calcium
   buffering.
   Slide 10
   Due to their extended morphology, including both axons and dendrites, neurons also need to transport cargo
   along very long distances. Although some proteins are made locally, the vast majority of proteins – and
   mitochondria – are produced next to the nucleus. But they are often required at distant sites, such as synapses.
   Cargo, therefore, needs to be transported out to synapses and back to the soma for recycling or signalling. Cargo
   is mainly transported along microtubules, one of the key cytoskeletal components of the cell. This can be away
   from the nucleus – ‘anterograde’ – or towards the nucleus – ‘retrograde’.
2. SENSITIVITY TO BALANCE
   As for the majority of processes in neurons, neuronal transport lies in a delicate balance – where even a slight
   imbalance can lead to dysfunction. This is notable in most neurons, probably due to their really long axons. For
   example, a slight impairment in retrograde transport can lead to a build-up of dysfunctional components at
   synapses and a reduction in the supply of recycled components, blocking normal synaptic function.
3. LIMITIED CAPACITY TO GENERATE NEW NEURONS DURING ADULTHOOD
   The last key feature of a neuron is due to the fact that we have limited capacity to generate new neurons during
   adulthood and that neurons are post-mitotic and cannot undergo cell division for growth or repair. Thus, neurons
   become vulnerable with age – as cell components deteriorate and, thus, have a reduced resistance to cell stress.
   The key processes that often become dysfunctional with ageing are protein clearance, DNA repair and
   mitochondrial function. Selective neuronal vulnerability in disease is probably due to the varying vulnerability of
   specific neuronal populations to different cell and networks stresses.

PARTICULARLY HIGH PROTEIN AND LIPID CONTENT.
Compared to other cells and organisms, neurons have a particularly high protein and lipid content due to their
specialisation and elongated form.

Question 31

How does a neuron renew its protein and why is it important?

Answer 31

Compared to other cells and organisms, neurons have a particularly high protein and lipid content due to their
specialisation and elongated form.

Renewing the protein content of a neuron is essential for maintaining neuronal
cell health and plasticity, a key feature of neurons.

By plasticity, we mean the ability of a neuron to adapt to stimuli,
such as the growth of existing or new synapses during memory formation.

Renewal of proteins can occur by
protein synthesis or the recycling of existing proteins.

Question 32

What is gene expression? What product does it encode?

Answer 32

Gene expression is the process by which a gene is used to synthesise the product it encodes.

This is most
commonly protein but can also include functional RNAs, such as transfer RNA and ribosomal RNA.

Question 33

How does gene expression result in the generation of new proteins from the genetic code?

Answer 33

Protein
synthesis is how gene expression results in the generation of new proteins from the genetic code. For those of
you that are already familiar with this process, I hope this serves as a succinct refresher course.

Question 34

What are the two steps in gene expression?

Answer 34

Gene expression occurs via two key steps:

1. transcription – the photocopying of DNA into messenger RNA. This is
   a clever evolutionary step that keeps the DNA in the nucleus where it can be protected from damage.
2. The second
   step is translation – the literal translation of the genetic code on the mRNA photocopy into protein. These
   processes are highly regulated so that proteins are only made when they are needed.

Question 35

How does gene transcription occur?

Answer 35

Transcription occurs by the enzyme RNA polymerase moving along the DNA, copying it from the DNA code (‘A’,
‘G’, ‘C’ and ‘T’) into messenger RNA (‘A’, ‘G’, ‘C’ and ‘U’).

Note the changing of ‘T’s to ‘U’s from DNA to RNA. DNA is
normally kept in a condensed structure, which needs to be relaxed so that transcription factors can bind and
initiate transcription.

Epigenetic factors, such as DNA methylation, can control when the DNA structure can be
relaxed.

Question 36

What is DNA methylation?

Answer 36

Epigenetic factor that can control when the DNA structure can be
relaxed. DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription.

Question 37

What are RNA processing steps before translation?

Answer 37

Before being ready for translation, RNA undergoes several processing steps,

1. including RNA splicing. The splicing
   machinery chops out non-coding regions – ‘introns’ – of the messenger RNA, thus leading only protein-coding
   regions. Alternative splicing can chop out different regions, producing different mature RNA transcripts, which
   encode different proteins, which may have different functions within a cell. This is a way in which the genetic code
   can increase the number of potential proteins it makes.

This mature RNA is then exported from the nucleus to
the cytoplasm for translation into protein.

Question 38

What is RNA

sequencing?

Answer 38

Gene expression is often assessed at the mRNA level by ‘RNA

sequencing’. This informs which genes are being actively transcribed and how they are spliced.

Question 39

How are genes translated?

Answer 39

In the cytoplasm, ribosomes read mRNA code and translate this into protein.

The ribosome recognises a 3 basepair code on the mRNA and brings in a transfer RNA carrying the appropriate amino acid.

It binds sequential
amino acids together to form a polypeptide which, when folded into the correct structure, becomes a functional
protein.

Translation begins at the start code of an mRNA, which is AUG – or ATG on DNA – encoding the amino
acid ‘methionine’.

Translation normally occurs close to the nucleus, where the RNA is made, but in neurons this
also occurs at sites with high protein demand, such as synapses.

This is called local translation.

Question 40

What is local translation?

Answer 40

Translation normally occurs close to the nucleus, where the RNA is made, but in neurons this
also occurs at sites with high protein demand, such as synapses.

This is called local translation.

Question 41

Why is protein processing important? What happens if it doesn’t happen correctly?

Answer 41

Processing of proteins is essential for their correct folding and cellular targeting.

Protein folding occurs as soon
as a protein is made and then undergoes quality control to ensure it is correct.

Thus, misfolded proteins can be
targeted quickly and efficiently for degradation.

Proteins also often have post-translational modifications that
modulate their folding (such as phosphorylation), again, greatly increasing the diversity of protein functionality.

This can allow different protein activity during different cellular activities.

Protein misfolding is a major cause of
disease, especially in neurodegenerative disorders.

This can be due to genetic mutations, cellular stress or
impairment of clearance mechanisms and often leads to a build-up of aggregated protein in the brain.

Question 42

Summary of Week 1 topic 3

Answer 42

In summary, I hope this topic has guided your understanding into the foundations of the complex microanatomy
of the nervous system.

In Part 1, we learned how the nervous system is comprised of neurons and glia which
come in many different forms with specific functions.

In Part 2, we explored how neurons and glia have specialised
morphologies which enable them to carry out their function and that neurons share many substructures with a
standard eukaryotic cell, but also have their unique features and demands.

And, finally, in Part 3, we delved into
the totally critical cellular process of protein expression.