lecture 23

Question 1

What is the CNS?

Answer 1

brain and spinal cord

Question 2

What is the PNS?

Answer 2

afferent (carries signal to the CNS)
- sensory neurons

efferent (carries signals from the CNS)

• somatic (motor neuron/skeletal muscle)
• autonomic (innervate smooth muscle, cardiac muscle and glands)
• • sympathetic and parasympathetic

Question 3

What are key features of the brain?

Answer 3

• 1.5kg
• 20% cardiac output
• dependent on O2 for energy (ATP production)
• dependent on glucose for fuel
• blood flow stops - brain function stops in seconds, neurons die in minutes
• brain has no reserves of energy
• limited regenerative capacity (general principle)
• protected by skull, meninges, CSF, BBB

Question 4

What is brain topography?

Answer 4

• sensory gyrus
• motor cortex etc
• visual cortex at the back
• frontal lobe
• different areas of the brain perform different functions
• deeper regions in the brain also have specific functions

Question 5

What is the spinal column?

Answer 5

• primary pathway for communication between periphery and brain
• 45cm long
• protected by spinal column
• connected to brain through brain stem

Question 6

What are common CNS injuries?

Answer 6

• disease outcome depends on location of injury
  e. g.
• Multiple Sclerosis: lesions anywhere in CNS and induce a range of clinical manifestations (more of a syndrome)
• Prion disease: fatal familial insomnia, selective loss of thalamic nuclei causing hormone irregularities - disruption of sleep wake cycles
• spinal cord injury: C1-C2 - loss of involuntary function of breathing, cervical region-quadriplegia, thoracic nerves-paraplegia
• Parkinson’s disease: selective neuronal loss in substantia nigra - affecting motor function
• Alzheimer’s disease: selective loss in neurons in hippocampus, frontal, parietal, temporal lobes - affecting cognition and memory

Question 7

What protects the CNS? From what?

Answer 7

skull and vertebral column
- mechanical forces

meninges

• dura mater - tough
• arachnoid layer - space with vessels running through it
• pia mater - thin delicate meninges that cover the surface of the brain - runs close to the brain

CSF

BBB
- formed between the pia mater and the parenchyma

glia cells

Question 8

What is CSF?

Answer 8

• formed by choroid plexus of ventricle cavities
• enters subarachnoid space, flows between meningeal layers of brain and spinal cord, reabsorbed into the blood
• shock-absorbing to prevent brain from bumping against the skill
• contributes to the composition of interstitial fluid
• removal of excess fluid in the CNS occurs between the pia mater and blood vessels because typical lymphatics are not present
• The CSF circulating freely in the subarachnoid space over the whole CNS surface and in the ventricular system acts as a protective water bath

Question 9

What is the structure of the blood brain barrier?

Answer 9

• a highly specialised brain endothelial structure of the fully differentiated neurovascular system which separates components of blood from neurons
• 400 miles of capillaries in human brain
• neurovascular unit-1 capillary for each neuron

BBB

• endothelial cells
• tight junctions
• basement membrane
• pericytes
• astrocytes
• microglia

Question 10

What are pericytes?

Answer 10

• adjacent to endothelial cells, share common basement membrane, encircle
• contribute to microvascular stability – mechanical and biochemical, via matrix and signals endothelial cell differentiation
• release growth factors and angiogenic molecules
• • microvascular permeability, remodelling, angiogenesis
• smooth muscle cell lineage
• • contractile - regulate blood flow

Question 11

What does the blood brain barrier do?

Answer 11

• maintains the chemical composition of the interstitial space
• limits entry of plasma components, RBC and leukocytes
• precludes free exchange of solutes
• allows diffusion of small lipid soluble molecules (400Da)
• regulated active transport of ions and carrier mediated transport of glucose and amino acids
• provides a problem in terms of making drugs for the brain

Question 12

From what does the BBB protect the brain?

Answer 12

• foreign substances
• physiological substances in the systemic circulation
• drastic environmental fluctuations

Question 13

Of what is the BBB required for function?

Answer 13

• neural circuits
• synaptic transmission
• synaptic remodelling
• angiogenesis
• neurogenesis

Question 14

What happens when you get compromise of BBB (due to pathology)?

Answer 14

• generates neurotoxic products that compromise these functions
• compromise all the functions that the brain performs

Question 15

How can the brain be grossly separated?

Answer 15

grey matter

• cell bodies and dendrites
• glia
• blood vessels

white matter

• myelinated axons
• glia
• blood vessels

Question 16

What is the neuropil?

Answer 16

all the other cells supporting the neurons e.g. glial cells

Question 17

What are neurons?

Answer 17

• terminally differentiated
• • permanent tissue
• • can’t divide
• receive and transmit electrical impulses
• made up of neuronal cell body, axon and dendrites
• cell body
• • nucleus
• • nissl substance (rER)
• • neurofibrils: provide structure, transport proteins
• dendrites receive
• axons transmit

Question 18

What are types of neurons?

Answer 18

• sensory
• autonomic
• motor
• interneurons

while we draw them relatively stylistically depending on their functions they can have different functions
neuronal morphology varies greatly

Question 19

How are neurons arranged?

Answer 19

• e.g. in cortex - 6 layers
• neurons function in arrangements e.g. layers, ganglia, tracts
• different layers have different types of neurons performing different functions

Question 20

What are glial cells?

Answer 20

• ‘glia’ comes from the word glue
• include cell types that are neither neurons nor blood vessels
• • oligodendrocytes (myelin forming)
• • astrocytes (homeostasis)
• • microglia (immune surveillance)
• • ependymal cells (lining of ventricles and central canal)
• • adult progenitor cells

Question 21

What are oligodendrocytes?

Answer 21

under normal homeostatic conditions:

• cells with numerous processes
• small amount of cytoplasm

structure
- support neuron

function

• produce myelin which wraps most axons in CNS
• 1 oligodendrocyte myelinates 4-40 axons depending on axon size and position
• surrounds axons in segments along length
• • internode
• segments are separated by gap
• • node of Ranvier

Question 22

What is the function of myelin?

Answer 22

• enables saltatory conduction - node to node
• acts as insulator
• decreases current leakage across internodal axonal membrane
• increases conduction velocity
• > miniaturisation of nervous system - large fibre diameter, high conduction velocity
• saves space, metabolic and synthetic energy
• very metabolically active - e.g. proteins continually phosphorylating

Question 23

What are astrocytes?

Answer 23

• support and maintain the CNS
• 2 major morphological types of astrocytes:

protoplasmic (grey matter)
- processes spread radially

fibrous (white matter)

• arranged in rows between axon bundles
• send processes to nodes of adjacent myelinated axons

Question 24

How are astrocytes organised?

Answer 24

• not randomly distributed
• highly organised into non-overlapping domains
• unique little niches
• every part of blood vessel, node etc has contact with an astrocyte

Question 25

What are astrocytes characterised by?

Answer 25

- presence of numerous processes | - ability to make multiple contacts with other CNS elements and express large numbers of receptors

Question 26

What are endfeet?

Answer 26

- at the end of astrocyte processes - contact blood vessels - interact with ependymal cells (CSF-brain barrier) - are associated with the Node of Ranvier - ensheath synapses - are associated with nerve cell bodies - communicate with nerve cell bodies - communicate with other astrocytes - communicate with oligodendrocytes and microglia

Question 27

How do astrocytes contribute to CNS function?

Answer 27

- almost every CNS function described involves astrocytes - CNS development: neuronal path finding oligodendrocyte maturation (growth factors) - maintenance of environment at the synapse (removal and recycling of neurotransmitters) - synthesis of precursors for transmitters (glutamate and GABA) - maintenance of the environment at the node of ranvier - supply of energy to neurons - brain water homeostasis - maintenance of blood brain barrier integrity (glia limitans) - regulation of extracellular pH

Question 28

What are emerging roles of astrocytes?

Answer 28

- modulation of synaptogenesis/synaptic activity - regulation/modulation of neurogenesis - modulation of post-injury repair - modulation of memory formation

Question 29

What are microglia?

Answer 29

- resident macrophages - 10 - 20% glial cell population - from mesoderm - mononuclear phagocyte precursors - enter brain during early development, before the formation of the blood brain barrier - distributed equally in grey and white matter - but there are regional differences, reason/mechanism not known - in adult brain - - low turnover - - down regulated phenotype

Question 30

What is the normal function of microglia in healthy brain?

Answer 30

- homeostasis, first-line of defence against viruses, bacteria, parasitic CNS infections - present at the blood brain barrier - remove debris - moving around the tissue, not static - unique functions and some overlapping functions with astrocytes

Question 31

What are the four different phenotypes of microglia?

Answer 31

- ameboid microglia - during development and perinatal period - ramified, under normal conditions - in mature CNS - reactive, non-phagocytic microglia - sublethal injury - phagocytic microglia

Question 32

What is immune privilege?

Answer 32

- limited penetration of the BBB by immune system from the systemic circulation - a lack of lymphatic vessels in the brain parenchyma - inability of microglial and astroglial cells to sustain immune responses, lack of DCs in the parenchyma - traditional adaptive immune response doesn't occur within the parenchyma of the brain - low levels of major histocompatibility complex expression in the brain HOWEVER not quite as cut and dry as that - the work of Peter Medawar in 1948 on graft rejection demonstrated that skin transplants in the brain of naïve animals did not provoke an immune response, but if animals were first exposed to graft antigens in the periphery, grafts would be rejected - graft specific adaptive immune response that is primed in the periphery can access the CNS and mediate rejection of the foreign tissue

Question 33

What is specialised immune privilege?

Answer 33

- leukocyte penetration into the CNS is specialised - under homeostatic conditions leukocyte trafficking is relatively low and the cells rarely enter the neuropill - leukocyte trafficking can increase considerably in inflammation and disease - memory T cells are found in the CSF under steady-state conditions and microglial cells respond to injury

Question 34

What are neural progenitor cells? Do we have neural stem cells?

Answer 34

- microglia arise from mesoderm - neurons, astrocytes, oligodendrocytes and ependyma arise from neuroectoderm - adult neural stem cells (neural progenitor cells) - - discrete regions of brain (neurogenic niche) - - appearance and markers of radial glial cells (glial cells present during development) - - have potential to differentiate into neurons, astrocytes and oligodendrocytes

Question 35

Have neural stem cells been isolated?

Answer 35

yes - neural stem cells isolated from adult mouse brain - form neurospheres (fast dividing neuroprogenitor cells) - induced to differentiate into astrocytes, oligodendrocytes and neurons