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NEUR 734

Computational Neurobiology
Wednesdays, 12:00 2:50 pm
Dr. Kim "Avrama" Blackwell
Krasnow Institute, Room 220
Office Hours: Wed 10:30-11:30
Book: Johnston and Wu, Foundations of
Cellular Neurophysiology, MIT Press, 1995
Bower and Beeman, The Book of GENESIS,
Telos, 2
nd
Edition, available online:
http://www.genesis-sim.org
Neur 734 Work Requirements
Homework: 10% of Grade
Due next class
Marked down one letter grade if late
Not accepted more than one week late
Midterm: 45% of Grade
Final: 45% of Grade,
NOT cumulative
Neur 734: Additional Information
Website:
http://www.gmu.edu/departments/krasnow/CENlab/classes

All students are expected to uphold the GMU honor
code, which prohibits Cheating, Plagiarism,
Stealing, and Lying.

In this class, working together on homework is
permitted, so long as such working together
does not take the form of copying each others
work.
Lecture 1: Outline
Introduction
Neurons as electrical devices
Equilibrium
Nernst equation and derivation
Donnan Equilibrium
Circuit model of Neuron
Goldman-Hodgkin-Katz Equation

Understanding the Brain
The brain is not a homogeneous structure
Different parts responsible for different functions
Picture
Which Neuron Properties are
Important for Behavior?
Networks / Connectivity / topographic maps
To what extent can connectivity explain
behavior?
Morphology
How is information processing influenced by
shape
Electrical Properties
How is information processing influenced by
channels
Intracellular signaling
Diversity in Connectivity
Local circuit interactions
Origin, number of pre-synaptic signals
Somatotopy
Retinotopy
Destination, number of fibers


Morphological Diversity
Soma size: few microns to tens of microns
Axons: none, or up to 1-2 meters
Dendrites: none, to vast branching pattern
Morphological Diversity
Diversity in Neuron
Communication
Electrical (gap junctions)
Proteins form channels
Bi-directional
Chemical (uni-directional)
Pre-synaptic vesicles
Mechanisms of vesicle release
Type of neurotransmitter in vesicle
Post-synaptic receptors
Location: spine vs dendrite vs soma vs axon
Density and properties of channel opening
Diversity of Membrane
Properties
Membrane channels differ by
Permeability (e.g. Na
+
vs K
+
)
Channel density
Gating properties (voltage vs calcium)
Intracellular signaling
Enzymes activated by substances such as
calcium
Enzymes modify different membrane proteins

Levels of Organization
Molecules (Small) Bioinformatics, Molecular
Biology, Biochemisty
Single Neurons Physiology, Anatomy,
Molecular Biology,
Bioinformatics
Small Networks (Medium) Physiology, Anatomy
Systems Physiology, Anatomy,
Psychology, Imaging
Whole Organism (Large)
(Behavior)
Psychologists,
Physiology, Functional
Imaging
Focus of this Class
Single Neurons
Information Processing
Some plasticity
Some molecules
Intracellular signaling

Neuronal function
Process incoming signals, and transmit signals
Signals arrive via Synapses
End of one neuron makes specialized contact with membrane of
another neuron.
Signals propagate down dendrites to soma
Channels in membrane affect how signals are combined in dendrites
Action potentials are generated
All-or-none signal which travels rapidly down axon
AP causes transmitter release at the end of the neuron
Transmitter carries signal to the next neuron for processing.
Neurons are Electrical Devices
Electrons flow in a circuit
Current flow:
milliAmps into your phone charger
nanoAmps across a cell membrane
Potential difference
AA batteries are 1.5 Volts between terminals
-70 millivolts across a cell membrane
Analogous to water flowing through a hose
Neurons are Electrical Devices
Water Flow Electricity Neurons
Quantity Liters, Drops Coulombs,
electrons
Coulombs,
ions
flow gallons/sec charge/sec
(Amperes)
charge/sec
(Amperes)
Driving
force
pressure
(lb/area)
Electrical
potential
(Volts)
Electrical
Potential
source Gravity/pum
p
Battery

Concentratio
n Gradient
resistanc
e
narrow pipes resistors Channels
Circuits: Quantity of Charge
Coulomb (C)
quantity of charge (q) that repels an identical charge, 1
meter away, with force of 9e
9
Newtons.
elementary charge: e = 1.602 e
-19
C
1 Coulomb = 6.24e
18
electrons
Faradays constant (F)
quantity of charge on one mole of electrons
F = N
A
e
N
A
= 6.023e
23
molecules/mol
F = 96,485 C/mol

Circuits: Current and Voltage
Current
rate of flow of electrical charge
C/sec = Amperes

Electromotive Force
Potential difference between two points, One volt
EMF requires 1 joule of work to move one
coulomb of charge between two points.
i =
dq
dt

Circuits: Resistance
Ohms law
current = conductance * voltage
V/I=R 1/R = g: conductance
Current results from ions flowing through
channels:
channels are open
concentration gradient or voltage difference exists,
driving potential = V E
k

I-V plot is Linear (Figure A.5)
Circuits: Capacitance
Capacitance
ability to store charge, C/Volt = Farads (F)
C = q/V, q=CV


Analogous to cup in line with a hose
Start water flowing, nothing flows through hose
until cup is full and water overflows into hose

i C
dV
dt
V
C
i dt = =
}
,
1
Circuits:
Kirchoffs laws
1. At node, sum of currents entering = 0
2. In loop, sum of voltages = 0
Figure A.7
Circuits: Resistors in Series
Figure A.9
Circuits: Resistors in Parallel

Circuits: Capacitors in Parallel
Figure A.6
Circuits: Capacitors in Series

Circuits: Resistors and
Capacitors

Neuron cytoplasm
Contains ions and proteins
Is at equilibrium with extracellular fluid (ECF)
No NET change in ion movement
No change in ionic concentrations
No net movement of water
Total concentration inside (cytoplasm) = outside (ECF)
But, relative concentrations differ between inside and
out
Electrical neutrality in each compartment
Why study steady state?
Equilibrium = steady state
The resting membrane potential of a cell is
membrane potential when cell is at steady
state.
Electrical signals (what we care about)
are departure from steady state (equilibrium)
are caused by changes in permeability

Equilibrium / Steady State
A cell is in equilibrium if
Osmolarity is in balance ( ions in = ions out)
No net flow of water (implied by above)
Charge is in balance (anions = cations)
No net flow of ions
Flow of ions to inside equals flow of ions to outside
How is no net flow achieved?
Osmolarity Balance
Osmolarity inside cell is equal to osmolarity
outside cell
[Na
+
]
in
+ [Ca
++
]
in
+ [K
+
]
in
+ [Cl
-
]
in
+ [A
-
]
in
=
[Na
+
]
out
+ [Ca
++
]
out
+ [K
+
]
out
+ [Cl
-
]
out
Membrane is permeable to water. If
osmolarity is different, water will flow to
equalize osmolarity.
Electrical Neutrality
Total charges of cations is approximately
equal to total charge on anions within a
volume:


z is valence; e is elementary charge; [C] is
concentration.
Both intracellular and extracellular solutions
are approximately electrically neutral
z e C z e C
j
j Anions
j i
i Cations
i
e e

=

[ ] [ ]
Electrical Neutrality
Charges in each compartment are balanced
Outside the cell, sum of anions = sum of cations
[Na
+
]
out
+ 2*[Ca
++
]
out
+ [K
+
]
out
= [Cl
-
]
out

Inside the cell, sum of anions = sum of cations
[Na
+
]
in
+ 2*[Ca
++
]
in
+ [K
+
]
in
= [Cl
-
]
in
+ [A
-
]
in

A
-
are other anions, which are mostly proteins
Anions are impermeant to the membrane
Electrical Neutrality
space charge neutrality is violated in
neurons
separation of charge at plasma membrane
due to capacitance & electric field
Number of unbalanced ions = q (total excess
charge) / e (elementary charge)
Total charge, q = C * membrane area *
voltage
Example
Ion Movement
Concentration gradient produces tendency
for ions to move from high concentration to
low concentration
Mechanism is diffusion
Ions move through ionic channels
Protein pores in membrane
At rest, pores for sodium and calcium are
closed
Membrane is selectively permeable to potassium
Ion Movement
Movement of potassium from inside to
outside causes imbalance in charge
Recall that protein anions are impermeable and
can't move with potassium
Excess of K
+
outside
Excess of A
-
inside
Ion Movement
Charge distribution creates an electrical field.
Produces a potential difference between inside
and outside.
Potential difference permitted by special
property of membrane.
Capacitance
Farad = Coulomb per Volt
Quantity of charge producing a 1 volt potential.
Ion Movement
Potential difference produces force of
attraction
Negative potential of cell attracts potassium ions
As potential decreases, the force that draws
potassium ions inside the cell increases
At some potential, electrostatic forces pulling
K
+
in equals diffusive tendency for K
+
to
move out.
At that potential and concentration gradient, no
net flow of K
+
occurs.
Potential is called Equilibrium potential
Steady State (Equilibrium)
Relative concentrations differ between inside
and out
Concentration gradient between inside and
outside
Flow of ions (charge) sets up electrical gradient
Equilibrium potential of an ion = voltage at
which no net movement of ions

Nernst Equation
Equilibrium potential is determined by
Concentration outside, C
out
Concentration inside, C
in
Temperature of solution in Kelvin, T
Valence of ion, z
Work required to separate charge, R
Nernst Equation
R is the ideal gas constant
8.32 joules/Kelvin/mole
F is Faraday's constant
96,485 Coulombs per mole
E
RT
zF
C
C
R
out
in
=
|
\

|
.
|
ln
Squid Axon
Ion Conc in Conc out Equilibrium Potential
Na+ 50 440 55
K+ 400 20 -76
Cl- 40 560 -66
Ca++ 0.4 10 145
Concentration in millimoles,
potential in millivolts.
Mammalian Neuron
Ion Conc in Conc out Equilibrium Potential
Na+ 18 145 56
K+ 135 3 -102
Cl- 7 20 -76
Ca++ 0.0001 1.2 125
Concentration in millimoles,
potential in millivolts.
Calcium in cell is much higher, but is heavily buffered.
Thus this value represents free calcium.
Reversal Potential
Equilibrium potential also called reversal
potential, E
R
If membrane potential (V
M
) is greater than E
R
,
then potassium ions flow out
Diffusional tendency greater than electrostatic force
If V
M
is lower than E
R
, then potassium ions flow
in.
Diffusional tendency less than electrostatic force
If V
M
= E
R
, then forces balance, no net flow
Derivation of Nernst Equation
Ficks law for diffusion
Based on physical laws governing movement of ions in
biological systems
D: cm
2
/sec
Brownian motion = random movements, but
Molecules appear to flow down concentration gradient
Flux is proportional to magnitude of gradient
When derived, applied strictly to
Non-charged particles
Charged particles with no electrical field
J D
C
x
diff
=
c
c
[ ]
Derivation of Nernst Equation
Ohms law for drift
Units
Electric Field E: V/cm = cV/cx
: mobility (cm
2
/V-sec)
Z: dimensionless valence
[C]: concentration (molecules/cm
3
)
Charged particles drift down the electric potential
gradient
Drift is proportional to magnitude of gradient
Field is a true driving force
J Z C
V
x
drift
=
c
c
[ ]
Derivation of Nernst Equation
Einsteins relation
Diffusion is random movement produced by thermal
agitation, depends on temperature
Frictional resistance exerted by fluid medium is the same
for drift as for diffusion
Diffusion coefficient and mobility are related:
K: Boltzmans constant (1.38e-23 joule/deg K)
T: absolute temperature, q: charge
Units: joule / C cm
2
/V-sec = cm
2
/sec
Recall that 1 volt = 1 joule per Coulomb
This implies that diffusional and drift processes are
additive
D
kT
q
=
Derivation of Nernst Equation
Nernst-Planck Equation (NPE)
Nernst and Planck originally added the two fluxes


Recall:
ion transporters in membrane and selective
permeability of membrane results in concentration
gradient, which leads to
Diffusion, which leads to
Charge separation, which leads to
Electrical field
J J J Z C
V
x
D
C
x
drift diff
= + =
c
c
c
c
[ ]
[ ]
Derivation of Nernst Equation
Substitute Einsteins relation into NPE


Divide by N
A
=> moles / sec cm
2
Multiply by molar charge (zF) to obtain current
density (Coulombs/sec-cm
2
)

J Z C
V
x
kT
q
C
x
=
c
c
c
c
[ ]
[ ]
Derivation of Nernst Equation
I: ionic current flow driven by electrochemical
potentials
F: Faradays constant, 96485 C/mol
R: ideal gas const, 1.98 cal/K-mol = F k / q
u=/N
A
I
zF
N
J uz F C
V
x
uzRT
C
x
A
= =
2
[ ]
[ ] c
c
c
c
Derivation of Nernst Equation
At equilibrium, I=0

Cancel like terms

Divide by zF[C]
integrate
uz F C
V
x
uzRT
C
x
2
[ ]
[ ] c
c
c
c
=
z F C V RT C [ ] [ ] c c =
c
c
V
RT
zF
C
C
1
2
1
2
}
=
}
[ ]
[ ]
Donnan Rule of Equilibrium
Concentration gradients can be maintained
solely by selective permeabilities
At passive equilibrium, Nernst equation
holds for each permeable ion
No net current flow; thus, membrane potential =
Nernst potential
Reversal potentials are equal for each permeable
ion
E
RT
F
Cl
Cl
E
RT
F
K
K
RCl
out
in
RK
out
in
=
|
\

|
.
|
= =
|
\

|
.
|
ln ln
Donnan Rule of Equilibrium
Equation solved for ratio of concentrations


General form of equation (example calculation)



C
+m
is cation of valence m; A
-n
is anion of valence
n
Cl
Cl
K
K
in
out
out
in
|
\

|
.
|
=
|
\

|
.
|
A
A
C
C
in
n
out
n
n
out
m
in
m
m

+
+
|
\

|
.
| =
|
\

|
.
|
|
1
1
/
/
Donnan Equilibrium
What if equilibrium is disrupted, e.g. change
in extracellular ionic concentration (picture)
Initial conditions:
Potassium flux down concentration gradient
produces electrical potential:
E mV
K
K
mV
K
out
in
=
|
\

|
.
|
= 58 90
10
log
[ ]
[ ]
Ion Movement with Change in Cl
-
Decrease in external chloride concentration
Immediate increase in E
R
of Chloride to 55
Smaller increase in V
M
(between E
K
and new E
Cl
)
Chloride and potassium flow out, equal quantities
New equilibrium values calculated from Donnan Eqn
Water flows out to maintain osmotic balance
Proportional change in [K]
i
is trivial, decrease in
[Cl]
i
is significant
New equilibrium has lower [Cl]
i
, same [V
M
]
Ion Movement with Change in K
+
Increase in external Potassium concentration
Increase in E
R
of Potassium, to 55 mV
Smaller increase in V
M
of membrane
Chloride and potassium flow in, in equal
quantities
New equilibrium values calculated from Donnan Eqn
Water flows in to maintain osmotic balance
Proportional change in [K]
i
is trivial, change in
[Cl]
i
is significant
New equilibrium has higher [Cl]
i
, higher [V
M
]
Resting Potential
If membrane is permeable to K
+
, then ions
flow until V
M
= E
K

Experimentally, V
M
is close to potassium
reversal potential
Use Nernst eqn to determine theoretical
effect of [K
+
]
ext
on V
M
, compare to
experiments

Picture
Resting Potential
Effect of [K
+
]
ext
on V
M
:
Linear for high [K
+
]
ext

Departure from linearity at low [K
+
]
ext

Membranes permeability to other ions
Cl
-
Na
+
Permeability is less than K
+
To accurately compute V
M
, need Goldman-
Hodgkin-Katz
Goldman-Hodgkin-Katz Equation
Resting potential depends on concentration
of all ions to which membrane is permeable
No assumption of passive equilibrium
Relative contribution of each ion depends on
Concentration gradient
Permeability (relative to potassium)
V
RT
F
P K P Na P Cl
P K P Na P Cl
M
K out Na out Cl in
K in Na in Cl out
=
+ +
+ +
+ +
+ +
ln
[ ] [ ] [ ]
[ ] [ ] [ ]
Goldman-Hodgkin-Katz Equation
If p
Na
= p
Cl
= 0, GHK equation reduces to
Nernst Equation
In squid, p
K
: p
Na
: p
Cl
= 1.0 : 0.04 : 0.45
At 20

C, V
M
= -62 mV
In mammals, p
Cl
is lower, p
Na
is lower,
Thus V
M
is lower, -80 to 90 mV
Circuit Model of Membrane
Figure 3.1
phospholipids (lipid bilayer) => capacitance
proteins = channels = aqueous pores =>
resistance

Passive Ionic Currents
Current = rate of flow of electrons
Each ion has either
Extra proton (missing an electron)
Extra electron
Flow of ions creates flow of electrons
Rate of flow of electrons rate of flow of ions
Exactly equal for Na
+
, K
+
, Cl
-
Double for Ca
2+
Ohmic Ionic Currents
Rate of flow of ions depends on
Concentration gradient
Voltage difference
Conductance of ion channels
Ease of ion moving through channels
Analogous to permeability
Think of water moving through hose
Ohmic Ionic Currents
Relation between voltage difference,
concentration gradient, conductance
Larger conductance = larger current
Larger difference between V
M
and E
R
= larger
current
Larger conductance = larger current
I G V E
V E
Rj
j j M R
M R
= =

( )
( )
Ohmic Ionic Currents
Resistance is opposite of conductance : R =
1/G
High resistance to flow = low conductance and
low permeability
Driving force or Driving potential
Difference between membrane potential and
reversal potential: AV = V
M
- E
R
Each current has simple relation (Ohm's
Law) to Voltage difference: I = AV/R
Ohmic Ionic Currents
Define chord conductance as:

Define slope conductance as:

If linear, these are identical
If non-linear, these are not identical, but
depend on voltage at which they are
measured
G
I
V E
i
j
M R
=
( )
G
dI
dV
i
=
Circuit Model of Membrane
Assume a single type of pore
Resistor in parallel with capacitor
Solve Equations again?
Passive Ionic Currents
I is total current flowing across membrane-fig
3.4
Sum of currents due to each ion is the total
current
In equilibrium, total current is zero
Some current positive, some currents negative
I I I I I C
dV
dt
tot C Na K Cl
= + + + = +
G V E G V E G V E
Na M Na K M K Cl M Cl
( ) ( ) ( ) + +
Passive Ionic Currents
Steady state = net current = 0
Can solve for V
M
algebraicly
V
M
is weighted sum of reversal potentials:



Sample calculation of V
M
V
G E G E G E
G G G
M
Na Na K K Cl Cl
Na K Cl
=
+ +
+ +
Membrane Permeability
Movement of ions across biological
membranes
Defined empirically as
P units cm/sec
Recall, flux is also proportional to gradient:


Fig 2.3
J P C = A[ ]
J D
d C
dx
=
[ ]
Membrane Permeability
Within membrane, if assume [C] drops
linearly with respect to x, then

Where | is the water-membrane partition
coefficient (dimensionless); D* is membrane
diffusion
Use | A[C] because concentration within the
membrane is different than in solution
d C
dx
C
l
[ ] [ ]
=
A
|
J D
C
l
P
D
l
= =

*
[ ]
,
* A
|
|
Membrane Permeability
Further derive permeability using Einsteins
relation
Recall, R= F k / q
Or, K/q=R/F
Thus, permeability is related to mobility,
water membrane partition, width of
membrane and temperature
D
kT
q
RT
F
* * * = =
P
RT
F l
=
| *
Goldman-Hodgkin-Katz
What if ionic current is not ohmic?
Derive equation for ion movement through
pore
Uses permeability just derived
Assumptions
Nernst-Planck equation holds
Ions move independently and dont interact
Electric field in membrane is constant (-dV/dx = -
V/l)
I is defined to be positive flowing in to out
Goldman-Hodgkin-Katz
Recall, from Nernst derivation (u* for
membrane permeation):


Define (-dV/dx = -V/l) y =

Then,
I u z F C
V
x
u zRT
C
x
= * [ ] *
[ ]
2
c
c
c
c
I u z F C
V
l
* [ ]
2
dy
dx
dI
dx
u z FV
l
d C
dx
=
* [ ]
2
Goldman-Hodgkin-Katz
With I in steady state, dI/dx = 0, thus


Substitute into equation for y:
dC
dx
l
u z FV
dy
dx
=

*
2
y u zRT
d C
dx
u zRT
l
u z FV
d y
dx
= =

*
[ ]
*
*
2
Goldman-Hodgkin-Katz
Simplify:

Separate variables:

Integrate from inner to outer membrane
(x=0,l)
y
RTl
zFV
d y
d x
=
zFV
RTl
dx
d y
y
=
zFV
RTl
l y y x l x = = = ln( ) ln( ) ( ) ( ) 0
Goldman-Hodgkin-Katz
Substitute I-u*z
2
FV|[C]
out
for y(x=l), etc.



Algebra to isolate I:
=

|
\

|
.
|
|
zFV
RT
I C
I C
u z FV
l
out
u z FV
l
in
ln
[ ]
[ ]
*
*
2
2
|
|
I
e C C
e
u z FV
l
zFV
RT
out in
zFV
RT
=

|
\

|
.
|
|
|

*
[ ] [ ]
2
1
|
Goldman-Hodgkin-Katz
Replace |u*/l using

and introducing an additional F/RT:



This equation describes current flow through
membrane for single ion
I
e C C
e
Pz F V
RT
zFV
RT
out in
zFV
RT
=

|
\

|
.
|
|
|

2 2
1
[ ] [ ]
P
u RT
F l
=
| *
Goldman-Hodgkin-Katz
Picture
Membrane current is non-linear function of
membrane potential
If [C]
out
= [C]
in
, current is linear
If [C]
out
< [C]
in
, I-V plot shows outward rectification
Slope increases with voltage
If [C]
out
> [C]
in
, I-V plot shows outward rectification
Slope decreases with voltage
At rest, current flow for multiple ions must balance