lecture 23 Flashcards
1
Q
What is the CNS?
A
brain and spinal cord
2
Q
What is the PNS?
A
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
3
Q
What are key features of the brain?
A
- 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
4
Q
What is brain topography?
A
- 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
5
Q
What is the spinal column?
A
- primary pathway for communication between periphery and brain
- 45cm long
- protected by spinal column
- connected to brain through brain stem
6
Q
What are common CNS injuries?
A
- 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
7
Q
What protects the CNS? From what?
A
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
8
Q
What is CSF?
A
- 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
9
Q
What is the structure of the blood brain barrier?
A
- 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
10
Q
What are pericytes?
A
- 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
11
Q
What does the blood brain barrier do?
A
- 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
12
Q
From what does the BBB protect the brain?
A
- foreign substances
- physiological substances in the systemic circulation
- drastic environmental fluctuations
13
Q
Of what is the BBB required for function?
A
- neural circuits
- synaptic transmission
- synaptic remodelling
- angiogenesis
- neurogenesis
14
Q
What happens when you get compromise of BBB (due to pathology)?
A
- generates neurotoxic products that compromise these functions
- compromise all the functions that the brain performs
15
Q
How can the brain be grossly separated?
A
grey matter
- cell bodies and dendrites
- glia
- blood vessels
white matter
- myelinated axons
- glia
- blood vessels
16
Q
What is the neuropil?
A
all the other cells supporting the neurons e.g. glial cells
17
Q
What are neurons?
A
- 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
18
Q
What are types of neurons?
A
- sensory
- autonomic
- motor
- interneurons
while we draw them relatively stylistically depending on their functions they can have different functions
neuronal morphology varies greatly
19
Q
How are neurons arranged?
A
- 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
20
Q
What are glial cells?
A
- ‘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
21
Q
What are oligodendrocytes?
A
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
22
Q
What is the function of myelin?
A
- 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
23
Q
What are astrocytes?
A
- 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
24
Q
How are astrocytes organised?
A
- not randomly distributed
- highly organised into non-overlapping domains
- unique little niches
- every part of blood vessel, node etc has contact with an astrocyte
25
What are astrocytes characterised by?
- presence of numerous processes
| - ability to make multiple contacts with other CNS elements and express large numbers of receptors
26
What are endfeet?
- 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
27
How do astrocytes contribute to CNS function?
- 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
28
What are emerging roles of astrocytes?
- modulation of synaptogenesis/synaptic activity
- regulation/modulation of neurogenesis
- modulation of post-injury repair
- modulation of memory formation
29
What are microglia?
- 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
30
What is the normal function of microglia in healthy brain?
- 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
31
What are the four different phenotypes of microglia?
- ameboid microglia - during development and perinatal period
- ramified, under normal conditions - in mature CNS
- reactive, non-phagocytic microglia - sublethal injury
- phagocytic microglia
32
What is immune privilege?
- 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
33
What is specialised immune privilege?
- 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
34
What are neural progenitor cells? Do we have neural stem cells?
- 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
35
Have neural stem cells been isolated?
yes
- neural stem cells isolated from adult mouse brain
- form neurospheres (fast dividing neuroprogenitor cells)
- induced to differentiate into astrocytes, oligodendrocytes and neurons
