Neurophysiology

I. Background

A. Cell Types

1. Neurons

2. Glia

B. Subtypes

1. Differ based on their structure, chemistry and function

C. Relative distribution

1. 100 billion neurons (give or take 100 million)

2. 10 times as many glia as neurons

D. Functional significance

1. Neurons confer the unique functions of the nervous system

 

II. Cellular Structure of Neurons

A. Neurons contain the same basic structures as most other cells

B. Structure of animal cells

1. Cell body (soma)

            a. 20 um in diameter

b. Surrounded by a membrane that separates the inside of the cell from the outside

i. 5 nm thick

2. Cellular contents

a. Everything within the cell membrane other than the nucleus is the considered cytoplasm

3. Nucleus

a. Contain the chromosomes that confer the heritable material—DNA

b. Gene expression

i. DNA to Protein

                        ii. DNA (transcription) mRNA (translation) Protein

3. Ribosomes

a. Site where protein is made

4. Endoplasmic reticulum

a. Rough

i. Have ribosomes

b. Smooth

i. Transport completed protein to other cellular sites

5. Mitochondria

a. Site where metabolic functions are performed

6. Golgi apparatus

a. Post-translational modification of proteins

7. Neuronal membrane

a. Cannot understand the function of the brain without understanding the structure and function of the membrane and its associated proteins

C. Unique features of neurons

1. Morphological regions

            a. Cell body (soma or perikaryon)

b. Neurites

2. Types of neurites

a. Axons

b. Dendrites

3. Axons

a. Cell body usually gives rise to a single axon

i. Conducts nerve impulse from one neuron to the next

ii. Up to 1 meter in length

iii. Speed of the nerve impulse is a function of the diameter of the axon

4. Dendrites

a. Small

i. Rarely more than 2mm

b. Organized symmetrically

i. Antennae

c. Dendritic tree

            i. Collective term for all neurites of a given neuron

D. Neural signals

1. Efferent

            a. Away from the cell body

2. Afferent

            b. Towards the cell body

E. Synapse

1. Site of neurotransduction

            a. Electrical to chemical signal

2. Structural elements

            a. Axon terminal

i. Site where axon comes in contact with another neuron

b. Presynaptic terminal

c. Postsynaptic terminal

            i. Usually found on dendrite

d. Cleft

            i. Space between the two sides of a synapse

3. Synaptic transmission

a. Process by which information is transferred from one side of the synapse to the other

b. Most adult vertebrate synapses are electrical

c. Electrical impulse that travels down the axon is converted to a chemical message

4. Neurotransmitter

a. Chemical signal

b. Different neurons use different types of neurotransmitters

5. Receptor

a. Specialized proteins responsible for detecting neurotransmitters

b. Involved in transduction of signal

 

III. Non-Neuronal Cells

A. Glia

1. Support neuronal function

2. Types

            a. Astrocytes

i. Regulate extracellular space

ii. Remove neurotransmitters, restrict movement of neurotransmitter from synapse, etc.

            b. Oligodendrocytes (Schwann Cells)

i. Myelinating glia

ii. Wrap around the axons

iii. Insulation

iv. Myelin sheath (what holds a sword)

v. Node of Ranvier: where the myelin sheath is interrupted

 

IV. Functional Activity of Neurons

A. Electrical current created by the movement of ions

1. Properties of ions differ from those of electrons

            a. Free electrons and more nearly at the speed of light

b. Electrons are good conductors and the air surrounding a wire is not

c. Ions in the cytosol of the nerve cell are less conductive than electrons

d. Fluid around neurons is also a conductor

2. Membranes are leaky

a. Current moving down an axon leaves passively

i. Like water in a leaky hose

3. Active process is needed to overcome passive current flow from neuron

a. Action potential

B. Properties of action potentials

1. Do not diminish

2. Fixed in size and duration (independent of the amount of current that evokes it)

3. All or nothing

C. Action potentials occur because of the properties of the neuronal membrane

1. Neuronal membrane is excitable

D. Functional states of a neuron

1. Rest

            a. Neurons do not fire continuously

b. When not generating action potentials, neurons are at rest

c. Cytosol along the inside of the membrane has a negative charge relative to the outside

2. Resting membrane potential

a. Difference in the electrical charge across the membrane

i. Difference is always negative

ii. Can be measured using an intracellular microelectrode

3. Action potential

a. Brief reversal of the resting membrane potential

b. Electrical signal created during action potential generation is the basic information unit of the nervous system

            i. Binary code (actually analogue)

            c. Result from the flow of current across the membrane

i. Current is supplied by other neurons

4. Current plot

a. Potential x time

i. Hyperpolarization

ii. Depolarization

iii. Threshold

 

V. Properties that Make Action Potentials Possible

A. Three questions

1. How does the neuronal membrane at rest separate electrical charge?

2. How is this charge rapidly redistributed across the membrane during an action potential?

3. How does the impulse (action potential) travel reliably down the axon?

 

(Properties that make it possible for a neuron to separate charge when at rest are the same factors that allow action potentials to occur and for that impulse to be propagated along the axon.)

 

B. Resting membrane potential

1. Important considerations

            a. Nature of the fluids on the two sides of the membrane

            b. Structure of the neuronal membrane

            c. Proteins that span the membrane

C. Cytosol and extracellular fluid

1. Fluids are aqueous

            a. Water distribute charges unevenly

                        i. Oxygen attracts more negative charge than hydrogen

b. Water is held together by polar covalent bonds

i. An effective solvent for charged molecules

2. Ions

            a. An atom or molecule with a net electrical charge

            b. Types

                        i. Cation (+)

                        ii. Anion (-)

3. Ionic bond

a. Molecule held together by the electrical attraction of oppositely charged atoms

4. Charged portion of water has a greater attraction for the ions than they have for each other

a. Ionic bond is broken

D. Phospholipid membrane

1. Terms

            a. Hydrophilic: water loving

i. Polar compounds and ions

2. Hydrophobic: water fearing

a. Nonpolar covalent bonds

i. Do not interact with water

3. Lipids

a. Water insoluble biological molecule

4. Phospholipid bilayer

a. Tail

i. Long chain of carbons

ii. Nonpolar

            b. Head

i. Polar end

ii. Comprised of P plus 3 O's

5. Functional consequence

            a. Tails arrange themselves in a bilayer

                        i. Tails do not like water

                        ii. Tails are inside

                        iii. Heads are outside

E. Proteins associated with the membrane

1. Background

a. Proteins are the product of gene expression

b. Type and distribution of protein molecule distinguish neurons from other cells

c. Resting and action potentials depend on the special proteins that span the lipid bilayer

            d. Protein chemistry

i. Primary structure: aa chain

ii. Secondary structure: certain types of organizations such as helices and sheets result when certain aa's are combined in the primary structure

iii. Tertiary structure: individual protein molecules can fold and form a more highly organized structure (e.g. globule)

iv. Quaternary structure: when different polypeptides combine to for a larger molecule

2. Ion channels

a. Number of individual protein molecules organized to create a pore in the membrane

i. Membrane spanning protein

            b. Diameter of the pore limits what can pass through the channel

c. Selectivity is also conferred by the nature of the amino acids that line the inside of the pore

                        i. Positively charged amino acids will attract negatively charged ions

ii. Negatively charged amino acids will attract positively charged ions

            d. Gating

i. Unique micro-environmental conditions that alter the selectivity of an ion channel changes (e.g., when voltage changes)

ii. Only when the membrane is within a particular voltage range does the channel open

e. Function

i. Permit and control movement of charged molecules across the neural membrane

ii. Movement is selective: size, charge and environmental condition

 

F. Diffusion (One of two primary forces that create resting membrane potentials)

1. Net movement of ions from a higher concentration to a lower concentration

2. Ions will not pass through the membrane

            a. Can diffuse through ion channels selective for that particular ion

3. Concentration gradient

            a. Difference in concentration between one side and the other

            b. Solute will move down its concentration gradient

4. Factors necessary for diffusion of ions across the neuronal membrane

            a. Ion channel for that ion

            b. Concentration gradient

5. Ions will flow down a concentration gradient

 

G. Electric field (One of two primary forces that create resting membrane potentials)

1. Ions can also move as a result of an electric field

2. Background

a. Opposite charges attract and like charges repel. (Na+ moves towards negative field and Cl- moves towards positive field)

b. Anode

i. Positive pole of a battery

ii. Negative flow to here

            c. Cathode

i. Negative pole of a battery

ii. Negative flow away

            d. Electric current

i. Movement of charges

            e. Electrical potential (voltage)

i. Difference in charge between the anode and the cathode

ii. Reflects the force exerted on a charged particle

            f. Electrical conductance

i. Ease with which a charged particle can move

            g. Resistance

i. Difficulty with which a charged particle can move

3. Factors necessary for charged particles to move across the neuronal membrane

            a. Ion channel for that ion

            b. A potential difference across the membrane

 

Example: K+ of differing concentration separated by a semi-permeable membrane. This difference generates an electrical potential. The side with the higher concentration is negative. If the ions were allowed to freely move, the movement will stop at some point, but not when the concentrations are equal. As positive charges accumulate on one side, the positivity makes it less attractive to positive ions-the potential charge across the membrane offsets the concentration gradient. The point at which this occurs is known as electrochemical equilibrium. This relationship is described by the Nernst equation.

 

In biological systems, there multiple ions involved, each governed by a separate permeability factor. This relationship is described by the Goldman equation.

 

H. Equilibrium state

1. Diffusional and electrical forces are equal and opposite

2. For neurons, when these forces are balanced, the resting membrane potential is negative (see below)

 

Overview:

1. Neuronal membrane acts as a barrier to charges

a. Permits generation of concentration gradients

b. Permits generation of electric fields

2. Membrane has ion channels that are selective for ions of different ions

            a. Specific ions can move under particular condition

 

I. Sodium-potassium pump

1. Necessary for the inside of the neuron to become negative relative to the outside of the neuron

2. Membrane associated protein

a. Transfers ions across the membrane at the expense of metabolic energy

i. 70% of all brain energy is consumed by this pump

3. Net movement of ions

a. 3 Na+'s from the inside to the outside

b. K+'s are moved into the neuron

4. Result

            a. Both electrical and a concentration gradients are created

            b. Na+ is greater outside

            c. K+ is greater inside

            d. More positive ions outside than inside

                        i. Inside of the neuron is negative relative to the outside

 

J. Control of ionic movement

1. K+

            a. K+ wants to move out based on the difference in concentration

            b. K+ is attracted to the relative negative charge inside the neuron

            c. Balance of these forces creates the resting potential

2. Na+

            a. Na+ wants to move in based on the difference in concentration

            b. Na+ is attracted to the relative negative charge inside the neuron

            c. Tightly gated Na+ channels prevent the movement of Na+

            d. Channels will not open unless a certain voltage range exists

                        i. Threshold (see below)

 

VI. Action Potentials

A. Definition

1. Rapid reversal of the resting potential

a. For an instant the inside of the neuron becomes positive relative to the outside

B. Voltage versus time plot

1. Terms

a. Rising Phase

b. Overshoot

c. Falling Phase

d. Undershoot

e. Depolarization

i. Less negative

            f. Threshold

i. Critical level of depolarization needed for an AP

            g. Hyperpolarization

i. More negative

C. Permeability changes underlie the action potential

1. Selective increase in Na+ conductance coincident to the rising phase

a. Na+ is responsible to AP initiation

b. Positive feedback loop causes increased Na+ conductance

c. Na+ conductance slowly activates K+ conductance

d. Na+ conductance inactivates (see below)

2. Selective increase in K+ conductance coincident to the falling phase

D. Refractory periods

1. Absolute refractory period

a. Time period during which it is not possible to generate an AP

2. Relative refractory period

a. Time period during which additional depolarizing current is necessary to generate an AP

3. Absolute and relative refractory periods are dependant on the properties of the ion channels that are involved in the AP (see below)

E. Initiation of an action potential

1. At rest:

            a. Na+ channels are closed

b. A concentration gradient and an electrical potential exist because of the Na+/K+ pump

c. K+ channels are closed but leaky

i. Diffusional and electrical forces in balance (K+ wants to stay and leave at the same time)

2. Effect of opening Na+ channels

a. Na+ would move down its concentration gradient and towards the negative potential

b. Inside of the neuron becomes positive relative to the outside

c. Na+ influx accounts for the rising phase of the action potential

F. Falling phase of the action potential

1. Leaky K+ channels open

a. K+ leaves by flowing down its concentration gradient, away from the now positive (inside) side of the membrane towards the more negative side of the membrane

G. Voltage gated Na+ channels

1. Highly selective for Na+

2. Opened and closed by changes in the electrical potential of the membrane

            a. When the resting potential is changes from -65mV to -45mV

i. Channels opens

b. Channels inactivate (close) spontaneously after approximately 1msec (inactivate)

c. Cannot “de-inactivate” until the neuron returns to its resting membrane potential

i. Responsible for the absolute refractory period

 

H. Voltage gated K+ channels

1. Opening is delayed

a. Coincides with the closing of the Na+ channels

2. K+ channels do not inactive

3. K+ continues to flow out of the neuron until it reaches its ionic equilibrium

4. Voltage inside the neuron will briefly be hyperpolarized

a. Less negative than the resting potential

b. Relative resting membrane potential

i. Additional current (more depolarizing current) would be required to reach threshold