topic #2:

interstitial fluids in CNS & PNS

choroid plexus
blood-brain barrier
recall that the nervous system
a) transduces environmental stimuli into electrical signals
b) sends electrical signals to various tissues
rationale for todays lecture:
a) these signals result from changes in the permeability of nerve cell
membranes to ions inside & outside these cells.
b) before studying how these signals are generated, & because
incorrect ion concentrations can result in abnormal electrical
activity, lets look at how extracellular fluid is formed.
similar to Figs 9-1 & 10-1
imagine Na
+
& glucose
enter your blood (after a
meal).
how would these reach
the fluid surrounding your
brain, spinal cord, &
nerves in your arm?
1) first, notice the blood
flow from the heart to
capillaries in the head
& brain and arms
2) next, ask yourself
hmm what happens
at capillaries?
Fig 10-18
in the arm, leg, torso:
a) small ions (inorganic and organic), sugars, and amino acids are
physically small enough to diffuse through small openings
(fenestrae) between neighboring endothelial cells that form the
walls of the capillaries.
b) these materials can diffuse freely between the blood and the fluid
surrounding these capillaries.
c) these capillaries are therefore said to be leaky.
leaving
capillary
entering
capillary
thus, material can
leave fenestrated
capillaries 2 ways:
a) lipid-soluble species
can diffuse through
the endothelial cell
membranes
b) water-soluble
species diffuse
through fenestrae
(labeled pores here)
Fig 10-18
y: amount in brain vs standard
x: oil/water partition coefficient
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cross-section thru capillary
lipid soluble: O
2
, CO
2
, H
2
O, some drugs
H
2
O crosses lipid bilayers, although
slowly (Zeidel et al 1994 Agres lab)
e.g., heroin, nicotine, valium, & ethanol
cross easily, Na
+
doesnt
how does material leave the
capillaries & reach
peripheral nerves?
1) materials leak out of
fenestrated capillaries
(labeled blood vessels here)
2) both lipid- and water-soluble
materials diffuse through a leaky
connective tissue (perineurium) to the
extracellular space around nerve
fibers.
we will see a similar connective tissue in the brain.
Fig 5-30
circulatory system
fenestrated capillary
peripheral nerve bundle
extracellular fluid
summary:
Netters Atlas of the Human Body (2006), p.90
in the head:
1) 2 major arteries carry blood to the brain: one passing in front of
the bones of the neck (internal carotid artery) & one passing along the
side of these (basilar artery). this allows them to enter the skull and
extend upwards into the brain.
2) there, they branch into arterioles, then into capillaries.
back side
basilar
artery
internal
carotid
artery
Perezs Atlas of Human Anatomy (2006), p.163
unlike the arm, etc:
1) most capillaries in the brain are not fenestrated: the neighboring
endothelial cells are fused together at tight junctions
2) because the membranes block the free diffusion of water-soluble
material (from the blood to the extracellular space, and vice-
versa), we say there is a blood-brain barrier.
tight-junctions
-- part of the blood-
brain barrier
cross-section thru capillary
7
th
ed: p.141
8
th
ed: p.142
unlike the arm, etc:
1) most capillaries in the brain are not fenestrated: the neighboring
endothelial cells are fused together at tight junctions
2) because the membranes block the free diffusion of water-soluble
material (from the blood to the extracellular space, and vice-
versa), we say there is a blood-brain barrier.
3) but remember, this barrier does not block the transport and
diffusion of some materials through endothelial membranes.
diffusion
transport
ability to cross BBB generally
determined by lipid solubility.
higher rate implies transport
lower rate if bound to plasma proteins
7
th
ed: p.141
8
th
ed: p.142
so, how do water-soluble materials move from the blood into the fluid
surrounding the brain?
by a combination of diffusion and transport, at structures (each called
a choroid plexus) facing cavernous spaces (called ventricles)
formed by folds of the brain
Fig 5-5
so, how do water-soluble materials move from the blood into the fluid
surrounding the brain?
by a combination of diffusion and transport, at structures (each called
a choroid plexus) facing cavernous spaces (called ventricles)
formed by folds of the brain
choroid plexus
Fig 5-6
choroid plexus
add choroid plexus
to ventricle wall
push a large pocket
into the side of the
brain
narrow-down the
opening between this
pocket & the fluid
outside the brain
start with a brain
CSF outside brain
& inside ventricle
ions etc reach cells
in the brain by
diffusing from
the CSF, via the
outer & inner
surfaces
CSF outside brain
& inside ventricle
ventricle
brain extracellular
uid
brain
where are the ventricle, choroid plexus, CSF, and extracellular fluid?
ions etc reach cells
in the brain by
diffusing from
the CSF, via the
outer & inner
surfaces
next... rotate 90
o
& look at transport... (next slide)
so, how do water-soluble materials move from the blood into the fluid
surrounding the brain?
by 3 steps at secretory structures, each called a choroid plexus
1) diffusion out of fenestrated capillaries
2) transport across a special epithelium (the choroid epithelium) into
the cerebrospinal fluid (abbreviated CSF)
3) diffusion from the CSF, through a thin layer of connective tissue
(fibroblasts & collagen) into the extracellular fluid immediately
surrounding cells of the brain.
cerebrospinal fluid
fenestrated
capillary
schematically
choroid plexus
choroid
epithelium
.
brain surface
2
3
1
diffuses
between
capillaries
whats in cerebrospinal fluid??
salts, glucose, protein also vitamins, amino acids, hormones.
note: transporters can be used to move pharmacological agents (e.g. for chemotherapy)
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Kandel00 TableB-1
brain & spinal cord marinate
interneuronal space: 30-70 nm
.
2
3
1
choroid plexus
(1) diffusion thru fenestrated capillaries, (2)
transport of water-soluble material across choroid
epithelium. (3)diffusion of lipid-soluble material
across choroid epithelium.
blood-brain barrier
(4) diffusion across lipid bilayers of endothelial
cells
4
cerebrospinal fluid (CSF)
brain surface
where does the CSF go?
1) it enters the subarachnoid space between two layers of
connective tissue covering the brain: the arachnoid membrane &
the pia mater.
Fig 5-6
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where does the CSF go?
1) it enters the subarachnoid space between two layers of
connective tissue covering the brain: the arachnoid membrane &
the pia mater.
Fig 5-6
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2) the subarachnoid space around the brain is continuous with space
between the same connective tissues covering the spinal cord.
3) the total volume of this space is 125 - 150 mL.
dura mater
arachnoid
pia mater
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compare with Fig 5-25
4) 500 mL of CSF is made per day.
5) therefore, CSF moves away from
the choroid plexi by fluid pressure
-- it moves between folds in the
brain, then between the spinal
cord & the vertebrae, and then
between the brain & skull (follow
#1-4 in the figure).
6) because the 150-mL space is a
fixed volume, CSF must leave at
the same rate that it is produced:
if it leaves more slowly than it is
produced, it would accumulate,
resulting in hydrocephaly (a.k.a.
water-on-the-brain).
7) it leaves by entering the veinous
blood through sinuses (@ #5 in the
figure).
Fig 5-6
http://www.brainmaps.org/index.php?action=viewslides&datid=17
Homo sapiens, adult, whole brain, MRI, coronal, SM-cor2
http://www.brainmaps.org/index.php?action=viewslides&datid=17
Homo sapiens, adult, whole brain, MRI, horizontal, s_nk_T1
transverse (horizontal) coronal (front)
enlarged lateral
ventricles (LV)
http://www.sciencedaily.com/releases/2007/07/070722203858.htm
The man was 44-years-old at the time, married with two children, and worked as a civil servant. He went to hospital after suffering mild left leg weakness. He
was treated by Dr Lionel Feuillet and colleagues, Hpital de la Timone and Facult de Mdecine, Universit de la Mditerrane, Marseille, France, who
authored the clinical update. Analysis of the mans medical history revealed at the age of six months, he had had a shunt inserted into his head to drain away
hydrocephalus (water on the brain), of unknown cause. At the age of 14, he had complained of unsteadiness and left leg weakness, which cleared up after the
shunt was revised. His neurological development and medical history were otherwise normal. Neuropsychological testing revealed the man had an intelligence
quotient (IQ) of 75, his verbal IQ was 84 and his performance IQ was 70. A CT scan showed severe dilation of the brains lateral ventricles, while an MRI scan
revealed massive enlargement of the lateral third and fourth venricles, a very thin cortical mantle and a posterior fossa cyst.
sagittal
(side)
(transverse)
the major sinus is the superior sagittal sinus -- under the dura
mater, between the cerebral hemispheres. the CSF moves by bulk
flow (thru villi) into this space & thus returns to the veinous blood.
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the major sinus is the superior sagittal sinus -- under the dura
mater, between the cerebral hemispheres. the CSF moves by bulk
flow (thru villi) into this space & thus returns to the veinous blood.
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the major sinus is the superior sagittal sinus -- under the dura
mater, between the cerebral hemispheres. the CSF moves by bulk
flow (thru villi) into this space & thus returns to the veinous blood.
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the major sinus is the superior sagittal sinus -- under the dura
mater, between the cerebral hemispheres. the CSF moves by bulk
flow (thru villi) into this space & thus returns to the veinous blood.
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fluid inside skull & vertebral column fluid outside skull & vertebral column
summary: interstitial fluids in the CNS & PNS are different
inside skull & vertebral column:
diffusion from cerebrospinal fluid
outside skull & vertebral column:
leakage from fenestrated capillaries
four end results:
1) cerebrospinal fluid (CSF) is formed by combination of water; materials
transported by choroid plexus; materials passing thru the blood-brain-
barrier. This includes both water- & lipid-soluble material. CSF flows
over the surface of the brain & spinal cord. Small molecular-weight
materials diffuse from CSF into the space between CNS cells,
forming the extracellular fluid of CNS neurons.
2) the CSF volume is small (125-150 mL), but it is constantly produced. if an
equal volume does not constantly leave, fluid accumulates: hydrocephaly!
The CSF leaves by being absorbed into the venous system, at the superior sagittal sinus on the
underside of the skull. The fluid moves through herniations in the arachnoid membrane called
"arachnoid villi".
3) the density of CSF & the brain are roughly equal: the brain tends to float
in the CSF, helping to protect it in case of sudden movements of the skull.
4) the BBB protects CNS against fluctuations in chemical composition of
blood (especially [K
+
]).
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inject K into blood, then measure K @
1) superior sagittal sinus
2) cortex
3) skeletal muscle in neck
WHAT WOULD YOU EXPECT TO SEE?
next slide: why K
spikes in the sinus
a) however, many drugs have rapid effects
on CNS because they are highly lipid-
soluble: barbiturates, nicotine, caffeine,
alcohol (Vander et al, p. 202 & 323)
b) these can have prolonged effects on CNS
if they change into less permeable forms.
example: heroin diffuses freely across
BBB. it is then de-acetylated into
morphine which is much less permeable.
this traps morphine in the CNS.
c) clinically important. for example, L-dopa
is lipid permeable: it is a precursor for
dopamine synthesis. when administered
to persons afflicted with Parkinsons
disease, it can alleviate some symptoms.
ability to cross BBB determined by
a) lipid solubility
b) transport
c) binding to plasma proteins
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4) the BBB protects CNS against fluctuations in chemical composition of
blood (especially [K
+
]).