|Blood Brain Barrier|
It has been know for over a century that if certain dyes were injected into the bloodstream of an animal, the tissues of the whole body EXCEPT the brain and spinal cord would be coloured.
Similarly if the dye was injected into the brain, the brain would be coloured, but the colour would not cross into the body.
So the concept of a "Blood-Brain Barrier" (BBB) which prevents materials in the blood from entering the brain, and vice versa, came into existence. More recently, the cellular structures associated with this barrier have become more understood.
The main functions of the blood-brain barrier are to protect the brain from circulating organisms or chemicals that might interfere with brain function and to maintain a stable environment for the neurones to perform their functions.
Interference with brain function could arise from entry of neurotransmitters, metabolites, osmolality, hormones and toxins, and of organisms such as bacteria and viruses; so it is important that these are not allowed to have access to neurones and synapses.
Brain Capillaries are made of endothelial cells that are tightly bound together, at 'tight junctions', and these vessels prevent large molecules from crossing to the extracellular fluid of the brain. Outside the endothelial cells is the basement membrane which may be thickened in brain capillaries.
|Astocytes and the Blood Brain Barrier|
Astrocytes have processes ('end feet') which terminate on the outside of the capillaries, and others that make contact with the neurone. These numerous projections anchor neurons to their blood supply.
One of the functions of astrocytes is to be selective in the transfer of materials from the blood to the neurones of the brain; in doing so they control the environment around nerve cells and synapses.
Astrocytes are able to take up various chemicals released at synapses and help to recycle them; one example would be the neurotransmitters released during synaptic transmission.
Astrocytes are believed to be an essential part of the blood–brain barrier, and may release substances that regulate local blood flow, so that local blood flow is matched to the metabolic activity of neurones in that area.
Astrocytes are connected to each other by gap junctions, and communicate using calcium and other chemical messengers.
The BBB is not fully formed at birth, so brain development is particularly vulnerable to pathophysiological events in infants.
The BBB can be breached in certain pathophysiological states including: hypertension, hyperosmolality, infection, trauma, ischaemia, inflammation, radiation, and raised intracranial pressure.
Should the BBB be breached, microglia are activated and become phagocytic in nature, removing cellular debris, invading organisms etc.
|Some Exceptions: Locations where the BBB is defective|
Some sites within the brain however do monitor the levels of chemicals, such as hormones, within the blood. The hypothalamus is an example where the blood brain barrier is defective; others include a number of sites around the cerebro-ventricular system, and are given the name 'circumventricular organs'.
Circumventricular organs have an extensive blood supply and fenestrated capillaries; they occur mainly around the Third Ventricle and in the area postrema of the medulla, where toxic substances can enter the brain and give rise to vomiting.
Other sites of circumventricular organs have special functions including the regulation of body fluid balance, cardiovascular control, immune responses, thirst, feeding behaviour and sexual behaviour.
|Cerebral Blood Volume and Brain Swelling|
The Munro-Kelly Doctrine deals with the constancy of the sum of the brain and CSF volumes, being equal to the volume of the skull, which cannot expand. Venous sinuses (which can be compressed) are included in the volume of the brain.
Elevation of CSF pressure as a result of a swelling of the brain or because of development of a extra-dural haematoma or other 'space-occupying lesion' compresses the venous system, raising venous pressure and causing increased filtration in brain capillaries.
One consequence of this is that the brain swells, and intracranial pressure is elevated progressively with time.
It is important to recognise this vicious circle, because it is the cause of gradual deterioration in brain function. Papilloedema is an important sign of raised CSF pressure; tissue swelling and venous obstruction are evident in this condition.
|Cerebral Blood Flow|
Blood FLOW (volume/minute as opposed to the volume of blood present in the brain) to the brain tissue can change, and the diameter of small vessels below the pia mater can change, and regulate LOCAL blood flow
One of the main factors that determines local blood flow within regions of the brain depend upon the metabolic rate of neurones in that area.
Examples include a rise in blood flow:
The diameter of pial vessels is affected by changes in pCO2 and pO2.
In addition, astrocytes can respond to glutamate released at synapses; astrocytes communicate with each other through gap junctions using calcium ions as a mediator, and these can release prostanoids at the end feet, causing vasodilatation. Prostanoids are thought to be involved as the response is blocked by non-steroidal anti-inflammatory agents.
|Metabolism of Neurotransmitters|
Neurone terminals synthesise glutamate from glutamine. After release, glutamate needs to be removed from the synapse quickly because accumulation of extracellular glutamate is associated with neuronal toxicity.
Astrocytes play a role in recycling glutamate, by converting it to glutamine, which can be re-used by nerve endings.
The glutamate-glutamine cycle is recognised as an important metabolic pathway for mopping up excess glutamate from the synapse.
Excess glutamine is transported away from the brain in the blood stream.
Astrocytes and GABA Metabolism
A similar process occurs for GABA, a major inhibitory neurotransmitter within the CNS.
Following its release into the synaptic cleft it is taken up by astrocytes and converted into glutamine which is reused (see the right hand side of the diagram).
Astrocytes are connected to each other using gap junctions - electrical synapses - which allow the spread of current from one astrocyte to the next.
It is known that many glial cells have glutamate reeptors and respond to glutamate by generating a calcium current that spreads to adjacent astrocytes through gap junctions.
The idea that glia - astrocytes - can also release transmitters and influence synaptic activity between nerve cells is the subject of much speculation, but has produced the concept of 'gliotransmission'.
Gliotransmitters released from glial cells could potentially alter the sensitivity of post-synaptic neurones to neurotransmitters.
Potential gliotransmitters included glutamate and ATP.
Component of the Blood Brain Barrier
The cellular barrier between blood and neurones
Active involvement in the regulation of local blood flow
Selective movement of chemicals between blood and neurones
|Gap Junctions||Connexins - protein pores - connect adjacent astrocytes||Coordination of neighbouring astrocytes||calcium ions|
Glutamine Cycle: Glu and GABA are taken up and converted to glutamine.
Glutamine passes either into the blood or into nerve endings for synthesis into Glutamate or GABA
|Gliotransmission||release of neurotransmitter by glial cells||?glutamate; ?ATP|