By: Dr. Khaled Ibrahim
Nervous System
Neurons
Neuroglia
Nerve
AXON
= Dendrites +
Nerve
soma + Axon
Fiber
= Nerve Cell
•Axon (myelinated
Or not) = Nerve fiber
• Nerve fibers are hold by
“endoneurium” forming
Fascicle.
• A fascicle is covered by
“perineurium”
• Fascicles are covered by
“epineurium” forming
NERVE TRUNK
Small artery ---> nerve trunk
Arteriole -----> fascicles.
capillaries -----> nerve fibers
Properties of Nerve Fibers
Respond to Changes
surrounding them
Detect the changes
From receptors to CNS
“Sensory Nerves”
Convert the changes
into electrical change called
“nerve impulse”
From CNS to Effector organs
“Motor Nerves”
1
2
Conduct nerve impulses
Along their length
Excitability
Conductivity
Stimulus
Definition: It is any change in the surrounding environment.
Types
1
Chemical
-Chemical transmitters
- Hormones.
- Drugs.
-Ions (Na+, K+, .... etc).
- Gases (O2 and CO2).
2
Physical
-Thermal.
e.g. cooling
or warming.
- Mechanical.
e.g. stretch, touch,
pressure and injury.
- Electromagnetic.
e.g. light rays
3
Electrical
- Galvanic Current:
Low intensity
Long Duration
- Faradic Current:
High intensity
Short duration
Electrical stimuli are commonly used for stimulation in
experimental work because they are:
- Easily applied.
- Accurately controlled as regard: strength & duration.
- Similar to the physiological process of excitation. So,
they cause no (or minimal) damage to the tissues &
can be repeated.
STIMULUS + NERVE = RESPONSE
Response of
NERVE
TO
STIMULUS
Depends on
Excitability
of
the nerve
Intensity of
Stimulus
Duration of
Stimulus
Effectiveness
of
The stimulus
Rate of rise
Maximal
Intensity of the Stimulus
Subminimal
Supermaximal
Minimal
Maximal stimulus:
Superminimal
(superthreshold)
Subminimal
stimulus:
It Minimal
is the least(threshold)
stimulus which
stimuli:
Supermaximal
stimuli:
(subthreshold)
stimuli:
It
is
the
weakest
stimulus
which
produces
a
maximal
response
and
Group of stimuli having intensities
They
areofall stimuli of greater
They
are all
stimuli
Superminimal
produces
a
response
&
below
above
which
there
is
no
further
higher than minimal & lower
than than the maximal
intensities
low
intensity
which
which no
response
occurs.
increase
in
the
response.
the maximal
which
showstimulus
gradual
produce no response but produce the same
increase in response withmaximal
gradual
even if applied for a response.
increase in the intensity.
very long time.
0.8
1
1.5
2
3
5
8
20
V
Duration of the Stimulus
Excitation time: It is the time needed by the stimulus to be effective
(to produce response).
Within limit, the stronger the stimulus, the shorter is
excitation time.
This is studied by Strength- Duration Curve
Strength – Duration Curve
Aim: to study the relation between the strength and
duration of a stimulus
Obtained by: stimulating the nerve with electrical stimuli
of different intensities and recording the time needed by
each stimulus to start the response.
Strength
The stronger the stimulus, the
ItThe
isbethe
intensity
shorter will
theminimal
duration(time
up factor):
chronaxia
time:
(threshold
intensity)
to a certain
duration,
below
- ItUtilization
is the time
neededoftoa
Timewhich
needed
forproduce
rheobase
to
stimulus
can
which no
response
cantissue
occur
stimulate
the
by a
produce
response.(=
response
ifwhich
applied
for
longthe
whatever
the
strength
of is
the
stimulus
double
rheobase
excitation
time).
period
of time
&
below
stimulus
may
be. This
is which
rheobase.
no response
occurs.
called the “minimal
time”.
2R
t
Rheobase
Chronaxia
Duration
The chronaxia (time factor):
- It is the time needed to stimulate the tissue by a stimulus which
is double the rheobase.
- It is used:
a- to compare the excitability of different tissues.
b- to compare the excitability of the same tissue under different
conditions.
The shorter the chronaxia, the greater the excitability and vice
versa.
NERVE
FIBERS
MUSCLE
FIBERS
thick myelinated
0.1 m.sec.
thin myelinated
0.3 m.sec.,
unmyelinated
0.5 m.sec
skeletal muscles
0.25-1.0 m.sec.
cardiac muscle
1.0-3.0 m.sec.
smooth muscles
5.0 m.sec.
So, the effective stimulus (produce a response) is:
Intensity: minimal or higher than minimal.
Duration: enough excitation time according to the
intensity (longer time is better).
Resting membrane potential
(RMP)
Definition:
The difference in potential between the inside and outside of
the nerve fibers during resting states (no stimulation).
During rest, the nerve fiber membrane shows a polarized state
in which the inner surface of the membrane is negatively
charged compared with outer surface which is positively
charged.
Measurement of RMP:
 RMP is recorded by the use of two microelectrodes with very
fine tips (less than 1 µm) connected with a special voltmeter.
 If we put the two electrodes on the outer surface of the
membrane, there is no potential difference between them
indicating that all points on the outer surface of the membrane are
at the same potential.
 If one electrode is introduced inside the nerve fiber and the
other electrode is placed on its outer surface, a potential
difference is recorded (-70 m.v) which is the RMP. (the –ve
charge indicates that the inner surface is negatively charged
relative to the outer surface (interstitial fluid).
Causes of the resting membrane potential:
I- Unequal Distribution of ions inside and outside the nerve fiber:
Outside the nerve fiber
(Cations)
(Anions)
Na+
K+
Protein¯
(140 mEq./L)
(4 mEq./L)
(2 gm %)
Na+
K+
Protein¯
(14 mEq./L)
(140 mEq./L)
(16 gm %)
Inside the nerve fiber
Cl¯
(100 mEq./L)
Cl¯
(4 mEq./L)
II- Selective permeability of the cell membrane:
The cell membrane
is made up of double
layers of lipids
with specialized proteins
penetrating the double
Layers.
These proteins form pores or channels which regulate the
movements of water-soluble ions (Na+, K+, Cl¯) across the
membrane.
There are three basic types of ion channels:
1
Passive ion Channels
Site:
found in the membrane of the
whole nerve cell.
Gates:
no gates (just a pore)
Function:
involved in generation of RMP.
2
Chemically activated ion channels
Site:
found in the membrane of the
Dendrites and soma.
Gates:
has a gate-like process which
open by binding of a chemical
stimulus (transmitter) to a
specific site (receptor)
on the channel.
Function:
involved in neuromuscular
transmission.
3
Voltage activated ion channels
Site:
found in the membrane of the
Soma and axon.
Gates:
has a gate-like process which
open by when a certain change
In the membrane potential.
Function:
involved in generation of
Action potential
Passive ion channels Chemically-activated
ion channels
found
in
the
membrane of
the
whole nerve cell.
- no gates (just a pore).
the - found
in
the
membrane
of membrane of the axon
dendrites and soma.
and soma.
-has a gate-like process - has a gate-like process
which open by binding which
open
by
of a chemical stimulus detection of a certain
(transmitter)
to
a change
in
the
specific site (receptor) membrane potential.
on the channel.
- involved in neuromuscular
trans-involved in generation
- involved
in mission.
& propagation of
generation of RMP.
action potential.
-
-found
in
Voltage-activated
ion channels
So, the nerve membrane is:
 Freely permeable to lipid-soluble substances.
 Impermeable to proteins (organic anions), due to their large size.
 Semipermeable to water-soluble ions (regulated by ion channels)
N.B.: In the resting neuron, Na+ ions pass through the passive Na+ channels with
difficulty, while K+ ions pass through the passive K+ channels more easily. The cell
membrane is about 100 times more permeable for K+ ions than for Na+ ions.
Diffusion of ions through the cell membrane
K+
Protein
Na+
Cl-
Tend to diffuse:
from inside the cell
to outside
Tend to
diffuse:from inside
the cell to outside
following K+.
Tend to
diffuse:from
outside to inside the
cell.
Tend to
diffuse:from
outside to
inside the cell.
According to:
According to:
According to:
1) Concentration
gradient: (inside is
30-40 times more
than outside).
1) Concentration
gradient.
2) Electric gradient:
(attracted to the
+ve charges
outside).
1) Concentration
gradient: (out-side
is 10-15 times than
in-side).
2) Electric gradient
(inside is electronegative).
According to:
Concentration
gradient:
(outside is 25
times more
concentrated
than inside).
Favored by:
the high
permeability of the
membrane to K+
ions.
K+
Antagonized by:
Protein
Prevented by:
Na+
Limited by:
ClPrevented by:
* Repulsion forces:
between the
diffusing ions and
the +ve charges
outside the
membrane.
* Na+ - K+ pump.
the impermeability
of the membrane
to proteins.
the low
permeability of
the resting
membrane to
these ions.
* Repulsion force:
by the –ve
charges inside.
* Attraction force:
between Cl- ions
and Na+.
Net diffusion:
Net diffusion:
Net diffusion:
K+ ions diffusion
continue until an
equilibrium occurs
between the
diffusion force and
the antagonistic
forces
Protein ions (-ve)
are held on the
inner surface of the
membrane.
& K+ ions (+ve)
are held on the
outer surface
attracted to the
proteins inside.
Small amounts
of Na+ ions
diffuse inside
then pumped
again to outside
the cell by Na+
- K+ pump.
Sodium-potassium pump (Na+- K+ATPase) 0
Site: present in the cell membranes.
 Function:
- Transports Na+ from ICF to ECF & K+ from ECF to ICF; it maintains low
intracellular [Na+] and high intracellular [K+].
Energy used:
- It utilizes about 40% - 50% of energy of basal metabolic rate (BMR).
Composition:
- Formed of 4 subunits (2α and 2β).
- The α subunit has an ATPase activity (can cleave ATP and release energy).
- It contains binding sites for 3 Na+ and an ATP molecule on its
intracellular face & 2 K+ on its extracellular face.
Operation of the pump:
Step 1:
* Attachment of 3 ions of Na+ causes cleavage ATP molecule into ADP +
Pi + Energy.
* Pi + Aspartic acid residue of the α-subunit in the presence of energy
causes formation of “α-subunit P” (Aspartic acid-phosphate bond).
* The addition of high-energy phosphate group to the α-subunit causes
conformational change in that unit transporting 3Na+ to the exterior.
Step 2:
* Attachment of 2 ions of K+ to the α-subunit causes the Aspartic acidphosphate bond to hydrolyze (dephosphorylation).
* This dephosphorylation causes another conformational changes to occur
resulting in transport of 2K+ ions to the interior.
Activation of the pump:
1- High intracellular [Na+].
2- High extracellular [K+].
3- Availability of energy (ATP).
Inhibition of the pump:
1- Too low intracellular [Na+].
2- Too low extracellular [K+].
3- Too low intracellular ATP.
4- Cardiac glycosides as: digitalis and Ouabain, which are used in treatment
of heart failure. They cause specific inhibition of Na+-K+ ATPase.
They bind to the extracellular face of the pump (preventing binding to K+)
thereby interfere with dephosphorylation process.
Action potential
Definition: It is the electrical changes which occur in the resting membrane
potential as a result of its stimulation by an effective stimulus
These electrical changes propagate along the nerve fibers to the effector
organ producing the response or action (hence the name action potential).
 The electrical changes of the action potential are:
A- Depolarization.
B- Repolarization.
C- Redistribution of ions.
A) Depolarization:
Definition:  negativity of the membrane potential.
Mechanism:
The stimulus  the permeability of the cell membrane
(several hundred fold) to Na+ ions through opening of voltage-activated Na+
channels.
Na+ channels:
Has 2 gating particles:
- an m gate covers the extracellular surface (activation gate) .
- an h gate covers the intracellular surface (inactivation gate).
* Both the m and the h gate must be open for Na+ to flow through the Na+
channels.
* When m gate is open, Na+ ions can pass (the channel is said to be activated).
* When h gate is closed, Na+ ions can not pass the channel is said to be
inactivated.
Na+ diffusion (Na+ influx):
1) At first, Na+ influx is Slow until the threshold potential due to gradual
opening of Na+ channels
Change of the membrane potential form
the resting potential (-70 m.v.) to the threshold potential (-55 m.v.)
2) Then, Na+ influx becomes Rapid after the threshold potential due to
sudden opening of most of voltage-gated Na+ channels
Changes
the membrane potential to zero.
3) With continuous Na+ influx, the membrane potential becomes positive (+
35 m.v.) causing momentary reversal of polarity or Na+ overshoot.
B) Repolarization:
Definition: Restoration of the resting membrane potential.
Mechanism:
1- Stoppage of Na+ influx:
Due to:
a- Closure of the voltage-activated Na+ channels by closure of h (inactivation)
gate which close at threshold potential but after a certain delay time.
b- Reversal of the electrical gradient as the inside becomes +ve charged which
repel the diffusing Na+.
2- Opening of voltage-activated K+ channels:
At the threshold potential (-55 m.v), the voltage-activated K+ channels open
but after a slight delay time.
 K+ channels:
* In case of K+ channels, there is only one gate on the intracellular side
called n-gate.
* The n-gate must be open for K+ to flow through the channel.
K+ diffusion (K+ efflux):
1) At first, K+ efflux is rapid due to sudden opening of most (about 70%) of
K channels
the membrane is 70% repolarized.
2) Then, K+ efflux becomes slow due to slow opening of the remaining of
K+ channels
RMP is restored (-70 m.v).
3) With continuous K efflux due to continuous opening (delayed closure) of
K+ channels
the membrane becomes hyperpolarized.
C) Redistribution of ions:
 After passage of an action potential (depolarization and repolarization), the
ionic composition inside and outside the cell membrane is slightly disturbed
(some Na+ ions go inside during depolarization and some K+ ions go outside
during repolarization).
 Redistribution of Na+ and K+ ions to the normal resting condition is
established by the Na+-K+ pump which actively transports sodium out and
potassium into the cell.
Propagation of the action potential
Conductivity
Definition: It is the propagation (transmission) of action potential along the
axon from the region of the initial segment down to the terminal ending.
Significance: The action potential must be propagated in order to transfer
information from one place in the nervous system to the other.
 Direction:
- Inside the body (in vivo): in one direction (unidirectional)
* mostly: away from the cell body (orthodromic)
* to less extent: in the opposite direction (antidromic).
- Outside the body (in vitro): in both directions (bidirectional).
 Mechanism:
The action potential generated at one site on the axon, acts as a stimulus for the
production of another action potential in the adjacent sites of the axon.
Continuous conduction
Saltatory conduction
- It is propagation in unmyelinated - It is propagation in myelinated nerve
nerve fibers.
fibers.
- Mechanism:
- Mechanism:
1- Stimulation of the nerve fiber by an
effective stimulus
generation of
an action potential at the site of
stimulation.
1- Stimulation of the nerve fiber by an
effective stimulus
generation of
an action potential at the nearest node
of Ranvier.
2- During the action potential, the
stimulated area becomes depolarized
(membrane potential becomes
+35m.v).
2- During the action potential, the
nearest node becomes depolarized
(membrane potential becomes
+35m.v).
Continuous conduction
Saltatory conduction
3- This creates a potential difference
between the depolarized (active) area
(+ 35 mv) and the adjacent polarized
(resting) area (- 70 m.v).
3- This creates a potential difference
between the depolarized (active) node
(+ 35 mv) and the next polarized
(resting) node (- 70 m.v).
4- Because of this potential difference,
local circuits of current flows between
the two areas (in which the charges
move) causing the polarized (resting)
area to become depolarized to the
threshold level.
4- Because of this potential difference,
local circuits of current flows between
the two nodes (in which the charges
jump) causing the polarized (resting)
node to become depolarized to the
threshold level.
5- This generates an action potential at
the resting area, which by turn becomes
the stimulus for the adjacent region &
so on.
5- This generates an action potential at
the resting node, which by turn
becomes the stimulus for the adjacent
nodes & so on.
Continuous conduction
 Velocity of conduction:
slow (0.5-2.0 meter/sec)
Saltatory conduction
 Velocity of conduction:
fast (may reach up to 120 met/sec).
The greater the distance between nodes
of Ranvier, the greater the velocity of
conduction of the action potential.
Significance of Saltatory conduction and myelin sheath :
a) It increases the velocity of conduction because the action potential occurs
only at the nodes of Ranvier which is transmitted by jumping (saltatory
conduction).
b) It decreases the energy needed for the Na+ - K+ pump which is restricted to
the nodes of Ranvier. Myelinated fibers use about 1% of the energy used by
the unmyelinated fibers.
Monophasic action potential
 Definition: It is the action potential recorded when one micro electrode
(recording electrode) is introduced inside the nerve fiber and the other
electrode (reference electrode) is placed in the extracellular fluid away form
the excited region.
1- Latent period:
Definition: It is the time passed between the stimulation of the nerve and
the start of the action potential.
 Cause: It represents the time taken by the impulse to travel from the site
of stimulation to the site of recording electrodes.
 Duration: is affected by:
- The distance between the stimulating and recording electrodes.
- The velocity of conduction of the nerve fibers.
Thus, the velocity of conduction of a nerve fiber can be calculated as follow:
Velocity of conduction =
Distance between the stimulating and recording electrodes
Duration of the latent period
2- Spike potential:
 Definition: It is large wave of a short duration (Its magnitude & duration
depends on the type of the nerve fiber).
It consists of:
Ascending limb
Descending limb
- Represents the process of depolarization.
- Represents 70% of
repolarization.
- Due to Na+ influx which occurs in two stages:
- Due to:
* Stoppage of Na+ influx
(see before).
* K+ efflux which occurs
at first rapid due to the
sudden opening of most
(about 70%) of the
voltage activated K+
channels.
1- Slow until the threshold
potential
2-Rapid after the threshold potential
* Due to gradual Na+
influx due to slow
opening of some Na
channels.
* Changes the
membrane potential
form the resting
potential (-70 m.v.) to the
threshold potential (-55
* Due to rapid Na+ influx
due to sudden opening of
most of voltage activated Na
channels.
* Changes the membrane
potential to zero & with
continuous Na+ influx, the
membrane potential becomes
positive (+ 35 m.v.). This is
3- After potentials:
Definition: They are small waves with relatively longer durations.
a) Negative after potential
(after depolarization)
- Relatively short. (4 m. sec)
b) Positive after potential
(after hyperpolarization)
- relatively prolonged (40 m. sec)
- Caused by slow opening of the - Caused by prolonged opening of the
remaining voltage-activated K channels.
K+ channels (delayed closure) which
cause a continuous K+ efflux.
- The membrane is partially depolarized.
- The membrane is hyperpolarized.
- known as negative after potential due to - known as positive after potential due to
presence of the some negative charges on the presence of more positive charges on
outer surface of the membrane.
the outer surface of the membrane.
- the negative charges are gradually - The excess K+ ions return back again
neutralized by the outward diffusion of inside the nerve fiber by Na+-K+ pump.
K+ ions at the end of this phase.
Excitability changes
i) Temporal rise of excitability:
* Corresponds to the slow depolarization of the nerve fiber before firing
level which is called the “local response”.
* The nerve can respond to another Subminimal stimulus applied to it during
this phase.
ii) Absolute
refractory period
(ARP)
- the excitability of
the nerve fiber is
completely lost.
i.e., the nerve is
refractory to further
stimulation
iii) Relative
refractory period
(RRP)
iv) Supernormal
phase of
excitability
v) Subnormal
phase of
excitability
- the excitability of - the excitability is - the excitability is
the nerve is partially above normal.
below normal.
recovered (but still
below normal)
- no other stimulus - Stronger stimuli are - weaker stimuli - stronger stimuli
whatever its strength needed to excite the can excite the are needed to
can excite the nerve.
nerve.
nerve.
excite the nerve.
- corresponds to: the
ascending limb of the
spike potential (after
the firing level) and
the early part of the
descending
limb
(initial
1/3
of
repolarization).
- corresponds to the - corresponds to - corresponds to
late part of the the negative after the positive after
descending limb of potential.
potential.
the spike potential
till the start of the
negative
after
potential.
ii) Absolute refractory
period (ARP)
iii) Relative
refractory period
(RRP)
iv)
Supernormal
phase of
excitability
v) Subnormal
phase of
excitability
Mechanism:
Mechanism:
Mechanism:
Mechanism:
- During the ascending
limb of the spike: the
gates of the voltage
activated Na+ channels
are already opened (by
the first stimulus) . If a
second
stimulus
is
applied, it can not have
any effect (the gates are
opened).
- During the early part
of the descending limb:
the gates are just closed
& need a sufficient
period of repolarization
to be re-opened.
- During this period,
the membrane is
partially repolarized &
Strong stimuli can
reopen many (not all)
of the gates of the
Na+ channels.
- This leads to
depolarization of the
membrane
and
production
of
a
second waeker action
potential (not all Na+
gates are opened).
- The membrane
is still partially
depolarized
&
near
to
the
threshold level.
- The
membrane is
hyperpolarized
& away from
the threshold
level.