Microanatomy of the nervous system

Question 1

Why did Santiago Ramon y Cajal and Camillo Golgi were jointly awarded the Nobel Prize of physiology and medicine in 1906?

Answer 1

For their discovery that the brain is not a single continuous system, but composed of individual cell units

We now know those are Neurons and supporting glial sub-types

Question 2

How Neurons communicate?
What makes the different types of neurons?
What are these types?

Answer 2

Neurons communicate by passing electrical signals along their elongated form and then converting these into chemical signal to activate an electrical signal in the next neuron

Many forms of neurons specialised for their particular function within the nervous system

• Model neuron: receives signals from / sends signals to other neurons and has a long extended shape
• Sensory neurons: can be activated by changes in skin cells
• Motor neurons: stimulate muscle movement
• Local interneurons: send and receive signals with multiple other neurons

Question 3

What are the glial subtypes?

Answer 3

• Astrocytes
• Microglia
• Oligodendrocytes
• Ependymal cells

Question 4

What is the role of ependymal cells?

Answer 4

Line the ventricles of the brain and the central canal of the spinal cord.

Question 5

What is the relation between neurons and glial cells?

Answer 5

Neurons are supported by different types of glia.

Question 6

What is the role of astrocytes?

Answer 6

• Physical scaffolding framework for neurons
• Distribute nutrients from the blood supply to neurons
• Help maintain blood-brain barrier
• Tissue repair -> glial scars
• Regulation of synaptic activity by direct contact with synapses (tripartite synapse)
• Astrocyte-astrocyte signalling via gap junctions
• Help maintain optimal microenvironment around neurons
• potassium (K) buffer after depolarisation
• metabolize and recycle NTs: especially Glu (toxic extracellularly)

Question 7

What is the role of microglia?

Answer 7

• Smaller than the astrocytes (as per name)
• CNS macrophages
• Resident immune cells of brain = immunosuppressed stable population
• Clear cellular debris -> degrade synapses
• essential for synaptic pruning during development, BUT makes matters worse by preventing recovery when neurons undergo chronic stress during disease
• apoptosis
• Recruit other cells to sites of damage
• assist activated T cells
• Aid in tissue repair

Question 8

What are macrophages?

Answer 8

Primary mediators of granulomatous inflammation
- M1 macrophages are activated for cell mediated immune response to provide host defence

Question 9

What are T cells?

Answer 9

T cells are central regulators of the immune response

• modulate the function of other immune cells
• affect the behaviour of endothelial and parenchymal cells
• express membrane-bound molecules and secrete soluble mediators -> control antibody responses, activate innate immune cells, and lyse target cells

Question 10

What is the role of oligodendrocytes?

Answer 10

• Support and insulate neuronal axons by generation of myelin sheath in CNS (vs. Schwann cells in PNS)
  
  • increased speed of neuronal signaling through saltatory conduction
• Provide metabolic support to neurons (aided by their proximity)

Question 11

What is the difference between oligodendrocytes and Schwann cells?

Answer 11

> Oligodendrocytes form myelin sheath on neuronal axons in the Central Nervous System (CNS)
> Schwann cells form myelin sheath on neuronal axons in the Peripheral Nervous System (PNS)

Question 12

What is the impact of demyelinating diseases, such as multiple sclerosis?

Answer 12

Cause degeneration of the myelin sheath, which prevents the brain from communicating properly with the body.

Question 13

What is characteristic of the difference between acute and chronic neuroinflammation?

Answer 13

There is a delicate balance between:

• an Acute neuroinflammation inducing a defence response,
• and a Chronic neuroinflammation inducing an over/aberrant activation of astrocytes and microglia

Altered function of glial cells -> disturbed synaptic transmission

=> Dysfunction can result in vulnerability to neurodevelopment and neurodegenerative diseases

Question 14

What does the extent of dendritic branching reflect?

Answer 14

The neurone’s required level of input: dendrites are the main site of neuronal input

Question 15

What does axonal length determine?
Which neurons have long axons?

Answer 15

The distance of ouput in the network: motor neurons have long axons
e.g. longest axon from lower motor neuron cell body in spinal cord to control the muscles in your big toe = 1m

Question 16

What are dendritic spines?

Answer 16

Small protrusions on dendrites which form the postsynaptic side of a synapse, receiving input from another neuron

• their shape and size will affect the receive and transmit input
• spines with larger surface area form stronger, more stable synapses
• spines are ‘plastic’: increase in size during learning and memory

Question 17

What is characteristic of microglial morphology?

Answer 17

Microglial change morphology when they become activated or ‘reactive’:

• progressively become round and phagocytic
• reactive microglia release more cytokine to attract more microglia to the site of perceived injury
• in phagocytic mode, they consume any perceived debris, which can include synapses

Morphology can be used to score and infer neuroinflamation

Question 18

What is a phagocyte?

Answer 18

Type of cell with ability to ingest and digest foreign particles (e.g. bacteria, dust, dye)

Question 19

What are cytokines?

Answer 19

Polypeptides secreted by leukocytes and other cells that act principally on hematopoietic cells

• the effects of which include modulation of immune and inflammatory responses
• their concentrations vary during the course of a disease
• pro- or anti-inflammatory effects, and these effects can be contextual

Question 20

What is characteristic of astrocytic morphology?
What is astrocytosis?

Answer 20

Astrocytic morphology is highly variable, even at rest

Activation is therefore often inferred through astrocytosis: an increased number of cells in a given location (due to recruitment or proliferation of astrocytes)

Question 21

How can microglial and astrocytic morphologies be used?

Answer 21

To score and infer neuroinflammation (Ghazi-Noori et al., 2012):
> the mouse model of frontotemporal dementia shows progressive neuroinflammation (vs. non-transgenic mouse control) when stained with anti-microglial (Iba1) antibody

> Increased coverage of staining for an astrocytic marker (GFAP) infers astrocytosis in a mouse model of frontotemporal dementia (vs. non-transgenic mouse control)

Question 22

What is common of all cells? What are the 2 broad categories of cells?

Answer 22

All cells have a cell membrane, a cytoplasm (belly fluid), and DNA

1. Eukaryotic cells
   - they have a nucleus and membrane-enclosed organelles (‘little organs’)
   - they are complex cells found in plants and animals
   (e. g. neurons)
2. Procaryotic cells -> unicellular organisms (e.g. bacteria)
   - no nucleus or membrane-enclosed organelles
   - they have DNA, but not contained in a nucleus

Question 23

What are the neuronal substructures (organelles)?

Answer 23

• Nucleus - genetic information store
• Endoplasmic reticulum - proteins produced, sorted and processed for delivery to their required location
• Golgi apparatus - additional sorting and processing centre
• Mitochondria - energy generator (synthesise ATP molecules for energy); also has roles in calcium buffering and cell signaling)
• Lysosome - degrades proteins and organelles when faulty; “garbage collectors”: filled with enzymes that breakdown cellular debris
• Cell membrane - lipid bilayer containing receptors for cellular communication

Question 24

What are the two types of endoplasmic reticulum?
What is its function?

Answer 24

• Rough endoplasmic reticulum (rER): with ribosomes
• Smooth endoplasmic reticulum (sER): no ribosomes
• Produce proteins, sort and process them for delivery to their required location

Question 25

What is the process of protein synthesis?

Answer 25

Proteins emerge in vesicles from the endoplasmic reticulum ; the Golgi apparatus receives them and renders them usable by the cell - by folding them into usable shapes or adding material to them (lipids or carbohydrates)

Question 26

What are the 3 unique features of a neuron?

Answer 26

1. Unusually high energy demand - brain uses 20% of the consumed oxygen - biggest ATP (energy) demand -\> sodium-potassium ATP pump (Na+ / K+-ATPase) which maintains electrical equilibrium of its membrane - other demands: recycling NTs ; calcium (Ca2+) buffering 2. Need to transport cargo along long distances (due to its extended morphology) - proteins and mitochondria are produced next to nucleus, BUT required at distant sites (e.g. synapses) - cargo needs to be transported back to the soma for recycling and signaling - transport occurs along microtubules, in a balance between anterograde and retrograde transport - \> anterograde transport = away form cell body - \> retrograde transport = towards cell body 3. Vulnerable to stress - we have a limited capacity to generate new neurons - neurons cannot undergo cell division for growth or repair - neurons become vulnerable with age as cell components deteriorate

Question 27

What is adenosine triphosphate (ATP)?

Answer 27

* Energy transfer molecule * Phosphate donor * Signaling molecule

Question 28

Which key neuronal processes become dysfunctional with ageing?

Answer 28

* Protein clearance * DNA repair * Mitochondrial dysfunction

Question 29

What is the possible reason why there is selective vulnerability of distinct neuronal populations / brain regions in different neurological diseases?

Answer 29

Differences in the resistance of particular neurons to different cell/network stressors

Question 30

Why do neurons have a high protein content?

Answer 30

The neurone's ability to renew protein content is essential for maintaining cell health and allowing plasticity - protein renewal can occur through protein synthesis and recycling

Question 31

What is neuronal plasticity?

Answer 31

A high protein content means that the neuron’s ability to renew protein content is essential for maintaining cell health → The key ability of neurons to adapt to stimuli.

Question 32

What is gene expression?

Answer 32

The process by which a gene (DNA) is used to synthesise the product it encodes: mostly protein, but also functional ribonucleic acids (RNAs) e.g. transfer RNA (tRNA) and ribosomal RNA (rRNA)

Question 33

What is protein synthesis?

Answer 33

How gene expression generates new protein from the genetic code.

Question 34

What are the steps of protein synthesis?

Answer 34

* *Transcription**: photocopying DNA into RNA (mRNA) - \> DNA is preserved in the nucleus \> RNA splicing **Translation**, the literal translation of the genetic code on the mRNA photocopy into protein

Question 35

What happens during the transcription phase of protein synthesis?

Answer 35

\> RNA polymerase enzyme copies DNA code (A, G, C, T) into mRNA (A, G, C, U) \> DNA structure is normally condensed and must be relaxed so the transcription factors can bind and initiate transcription - epigenetics, e.g. DNA methylation, can control whether DNA structure can be relaxed (DNA methylation; addition of methyl group to DNA)

Question 36

What is the role of RNA splicing? What does alternative splicing allow?

Answer 36

Processing prior to translation \> messenger RNA contains both coding (exons) and non-coding regions (introns) \> Splicing machinery cuts out introns -\> Mature RNA (mRNA) contains only protein-coding regions * *Alternative splicing** can produce different proteins from a single mRNA - \> DNA can increase the number of potential proteins it makes \> Mature mRNA is then exported from the nucleus to the cytoplasm for translation into protein

Question 37

What is the role of RNA sequencing?

Answer 37

Assesses gene expression at the mature RNA level - informs which genes are actively transcribed and how they spliced

Question 38

What happens during the translation phase of protein synthesis?

Answer 38

* Ribosomes translate RNA into protein * 3 base-pair code = 1 amino acid (ATG = start) * Transfer RNA (tRNA) brings amino acids into the ribosome where they are bound together to form a polypetide chain = protein * when folded into the correct structure becomes a functional protein

Question 39

What is local translation?

Answer 39

Translation occurring far away from the nucleus, at sites with high demand, such as synapses | (translation normally occurs close to the nucleus)

Question 40

What are amino acids?

Answer 40

Natural compounds composed of an amine group (–NH2) and a carboxylic acid group (–COOH), linked to the same carbon atom - key elements: carbon, hydrogen, oxygen, nitrogen

Question 41

What are polypeptides?

Answer 41

Polypeptides are biomaterials composed of repeating amino acid units linked by a peptide bond.

Question 42

What are peptides?

Answer 42

Peptides are short chains made up of amino acid monomers linked by amide bonds - often obtained from the breakdown of proteins

Question 43

What is protein folding?

Answer 43

* Occurs as soon as a protein is made * Folding undergoes quality control to ensure it is correct: misfolded proteins -\> degradation * Post-translational modification of proteins can modulate their folding and function (e.g. phosphorylation) increasing diversity of protein functionality -\> different protein activity during different cellular activities

Question 44

What is the consequence of protein misfolding and accumulation?

Answer 44

Major cause of neurodegenerative disease - increase in disease due to genetic mutations, cellular stress, and impairment of protein clearance