Neural Control Mechanisms Section AJohn Paul L. Oliveros, MD

Neural Tissue• Neuron:

▫ basic unit of the nervous system

▫ Serves as integrators• Neurotransmitters:

▫ chemical messengers released by nerve cells

• Parts:▫ Cell body▫ Dendrites▫ Axon▫ Axon terminals

Neural Tissue• Parts of a neuron

▫ Cell Body Contains nucleus and

ribosomes Genetic information

and machinery for protein synthesis

▫ Dendrites Receive inputs from

other neurons Branching increases

the cell’s receptive surface area

▫ Axon AKA nerve fiber Single long process that extends

from the cell body to its target cells

INITIAL SEGMENT AKA axon hillock Portion of axon closest to the

cell body plus parts of the cell body

“Trigger zone” Collaterals

Main branches of the axon▫ Axon Terminal

Ending of each branch of axon Releases neurotransmitters

▫ Varicosities Bulging areas along the axon Also releases neurotransmitters

Neural Tissue• Myelin Sheath

▫ Layers of plasma membrane wrapped around the axon by a nearby supporting cell

▫ Speeds up conduction of electrical signals along the axons and conserves energy

▫ Oligodendroglia: CNS▫ Schwann cells: PNS

• Nodes of Ranvier▫ Spaces between adjacent

sections of myelin▫ Axons plasma is exposed

to ECF

Neural Tissue• Axon Transport

▫ Movement of various organelles and materials from cell body to axon and its terminal

▫ To maintain structure and function of the axon▫ Microtubules

Rails along which transport occurs▫ Linking proteins

Link organelles and materials to microtubules Function as motors of axon transport and ATPase enzymes Provide energy from split ATP to the motors

▫ Axon Terminalcell body Opposite route of transport Route for growth factors and other chemical signals picked up at

the terminals Route of tetanus toxins and polio and herpes virus

Neural Tissue

Neural Tissue• synapse

▫ Specialized junction between two neurons where one alters the activity of the other

• Presynaptic neuron▫ Conducting signals

toward a synapse• Postsynaptic neuron

▫ Conducts signals away from a synapse

Neural tissue• Glial Cells/Neuroglia

▫ 90% of cells in the CNS▫ Occupy only 50% of CNS▫ Physically and metabolically support neurons▫ Types:

Oligodendroglia Form myelin covering of CNS axons

Astroglia Regulate composition of ECF in the CNS Remove K+ ions and neurotransmitters around syapses Sustain neurons metabolically (provide glucose and remove ammonia) Embryo: guide neuron migration and stimulate neuron growth Many neuron like characteristics

Microglia Perform immune functions in te CNS

Schwann cells Glial cells of the PNS Produce myelin sheath of the peripheral nerve fibers

Neural Growth and degeneration• Embryo:

▫ Precursor cells: develop into neurons or glial cells▫ Neuron cell migrates to its final location and sends out processes▫ Growth cone: specialized tip of axons that finds the correct route and

final target of the processes▫ Neurotropic factors: growth factors for neural tissue in the ECF

surrounding the growth cone or distant target▫ Synapses are then formed once target tissues are reached▫ Neural development occurs in all trimesters of pregnancy and upto

infancy permanent damage by alcohol, drugs, radiation, malnutrition, and viruses

• Fine tuning:▫ Degeneration of neurons and synapses after growth and projection of

axons▫ 50-70% of neurons die by apoptosis▫ Refining of connectivity in the nervous system

Neural growth and regeneration• Neuron damage

▫Outside CNS Does not affect cell body Severed axon can repair itself and regain

significant function Distal axons degenerates Proximal axon develops growth cone and grows

back to target organ▫Within CNS

No significant regeneration of the axon occurs at the damage site

No significant return of function

Section BMembrane Potentials

Basic principles of electricity• Electric potential

▫ Potential of work obtained when separated electric charges of opposite signs are allowed to come together

• Potential differences/potential▫ Difference in the amount of charge

between two points▫ Volts: unit of electric potential▫ Millivolts: measurement in

biological systems• Current

▫ Movement of electric charge▫ Depends on the potential

differences between charges and the material on which they are moving

• Resistance▫ Hindrance to electric charge

movement

• Ohms law: ▫ I= E/R

• Insulator▫ Materials with high

electrical resistance• Conductor

▫ Materials with low electrical resistance

▫ e.g. water

Resting Membrane Potential• Resting membrane

potential▫ The potential difference

across the plasma membrane under resting conditions

▫ Inside cell: negative charge (-70mV)

Resting membrane potential• Magnitude of membrane

potential is determined by:▫ Differences of specific ion

concentrations in the intracellular and extracellular fluids

▫ Differences in membrane permeabilities to the different ions

Resting membrane potential• Equilibrium potential:

▫ the membrane potential at which flux due to concentration gradient is equal to the flux due to electrical potential but at opposite directions

▫ No net movement of ion because opposing fluxes are equal

▫ Membrane potential will not undergo further change

▫ Its value depends on the concentration gradient of an ion across the membrane

Resting membrane potential

Resting Membrane Potential• In a resting cell, Na+ and K+

ion concentrations don’t change because the ions moved in and out by the Na+,K+-atpase pump equals that moved by the membrane channels electrical potential across membranes remain constant

• Electrogenic pump▫ Pump that moves net charge

across the membrane and contributes to the membrane potential

▫ Na+,K+-ATPase pump: Sends out 3 Na+ ions for

moving in 2K+ ions Makes the inside of the cell

more negative

Graded Potentials and Action Potentials• Nerve cells transmit and process

information through transient changes in the membrane potential from it s resting level

• Two forms of signals▫ Graded potential

Over short distances▫ Action potential

Long distance signals• Depolarized

▫ Potential is less negative than the resting level

• Overshoot▫ A reversal of the membrane potential

polarity▫ Cell inside becomes positive relative to

the outside• Repolarize

▫ When the depolarized membranepotential returns toward the resting value

• hyperpolarize▫ The potential is more negative than the

resting lavel

Graded potential• Changes in the membrane

potential confined to a relatively small region of the plasma membrane

• Die out within 1-2 mm of site• Produced by a specific

change in the cell’s environment acting on a specialized region of the membrane

• Magnitude of the potential change can vary

• Local current is decremental▫ Amplitude decreases with

increasing distance from the origin

Graded Potential

Graded Potential

Action Potentials• Rapid and large alterations in

the membrane potential • 100mV from -70mV then

reporalize to its resting membrane

• Excitable membranes: ▫ Plasma membranes capable

of producing action potentials

▫ e.g. Neurons, muscle cells, endocrine cells, immune cells, reproductive cells

▫ Only cells in the body that can conduct action potentials

• Excitability:▫ Ability to generate action

potentials

Ionic basis of action potentials• Resting state:

▫ K+ and Cl- ion membranes open▫ Close to K+ equilibrium

• Depolarizing phase▫ Opening of voltage-gated Na+

channels 100x▫ More + Na ions enter the cell▫ May overshoot: inside on the cell

becomes positvely charged• Short duration of action potentials

▫ Resting membrane returns rapidly to resting potential because Na+ channels undergo

inactivation near the peak of the action potential to then close

Voltage gated K+ channels begin to open

Ionic basis of action Potentials• Afterhyperpolarization

▫ Small hyperpolarization of the membrane potential beyond the resting level

▫ Some of voltage gated K+ ions are still open after all Na+ have closed

• Chloride permeability does’t change during action potential

• The amount of ions involve is extremely small and produces infinitesimal changes in the intracellular ion concentration

• Na+,K+-ATPase pump makes sure that concentration gradient of each ions are restored to generate future action potentials

Mechanism of ion-channel changes

• 1st part of depolarization: ▫ Due to local current opens up

voltage gated channels sodium influx increase in cell’s positive charge increase depolarization (positive feedback)

▫ Delayed opening of K+ channels• Inactivation of Na+ channels:

▫ Due to change in the conformation channel proteins

• Local anesthetics▫ e.g. Procaine, lidocaine▫ Block voltage gated Na+ channels▫ Prevent sensation of pain

• Animal toxins:▫ Puffer fish: tetrodotoxin▫ Prevent na+ component of action

potential• In some cells: Ca++ gates open

prolonged action potential

Threshold and the all-or-none response• The event that initiates the

membrane depolarization provides an ionic current that adds positive charge to the inside of the cell

• Events:▫ K+ efflux increases

Due to weaker inside negativity

▫ Na+ influx increases Opening of voltage gated

channels by initial depolarization

As depolarization increaes mor voltage gated channels open

▫ Na+influx eventually exceeds K+ efflux positive feedback starts action potential

• Threshold potential▫ Membrane potential when the net

movement of positive charge through ion channels is inward

▫ Action potential only occurs after this is reached

▫ About 15mV less neative than • Threshold Stimuli

▫ strong enough to depolarize the membrane to threshold potential

• Subthreshold potentials▫ Weak depolarizations▫ Membrane returnsto resting level

as soon as stimuli is removed▫ No action potential generated

• Subthreshold stimulus▫ Stimuli that causes subthreshold

potentials

Threshold and the all-or-none response• Stimuli more than threshold

magnitude elicit action potentialswith exactly the same amplitude with that of a threshold stimulus▫ Threshold:

membrane events not dependent on stimulus strength

Depolarization generates action potential because the positive feedback is operating

• All-or-none response▫ Action potentials occur

maximally or they do not occur at all

• Firing of the gun analogy

Refractory periods• Absolute refractory period

▫ During action potential, a 2nd stimulus, no matter how strong, will not produce a 2nd action potential

▫ Na+ channels undergo a closes and inactive state at the peak of the action potential

▫ Membrane must be repolarized to return Na+ channels to a state which they can be opened again

• Relative refractory period▫ Interval followng the refractory

period during which a 2nd action potential can be produced

▫ Stimulus must be greater than usual

▫ 10-15ms longer in neurons▫ Coincides with the period of

hyperpolarization▫ Lingering inactivation of Na+

channels and increased number of potassium channels open

▫ Additional action potentials fired Depolarization exceeds the

increased threshold Depolarization outlasr the

refractory period

Action Potential Propagation• The difference in potentials

betwen active and resting regions causes ions to flow

• Local current depolarizes the membrane adjacent to the action potential site to its threshold potential producing another action potential action potential propagation

• Gunpowder trail analogy• Action potentials are not

conducted decrementally• Direction of the propagation is

away from a region of the membrane that has been recently active▫ Due to refractory period

Action potential propagation• Muscle cells

▫ Action potentials are initiated near the middle of these cylindrical cells and propagate towards the 2 ends

• Nerve cells▫ Initiation at one end and propagate

towards the other end• Velocity of action potential

propagation depends on▫ Fiber diameter

The larger, the faster▫ Myelination

Myelin is an insulator Action potential only in the nodes of

ranvier Concentration of Na+ channels is

high Saltatory conduction/ jumping of

action potentials from one node to the other as they propagate

Faster conduction

Initiation of action potential• Afferent neurons

▫ Initial depolarization threshold achieved by a graded potential (receptor potential) generated by sensory receptors at the peripheral ends

• Efferent neurons/ interneurons▫ Depolarization threshold due to

Graded potential generated by synaptic input

Spontaneous change in the neurons membrane potential (pacemaker potential) Occurs in absence of external

stimuli e.g. Smooth muscle, cardiac

muscles Contnuous change in membrane

permeability no stable resting membrane potential

Implicated in breathing, heart beat, GIT movements

Section CSynapses

Synapses• Anatomically specialized

junction between 2 neurons• Electrical activity of a

presynaptic neuron influences the elcetrical/metabolic activity of a postsynaptic neuron

• 100 quadrillion synapses in the CNS

• Excitatory synapse▫ Membrane potential of

postsynaptic neurons is brought closer to the threshold

• Inhibitory synapse▫ Postsynaptic neuron

membrane potential is brought further away from the threshold or stabilized

• Convergence▫ Neural input from many

neurons affect one neuron

• Divergence▫ Neural input from one

neuron affects many other neurons

Functional anatomy of synapses• 2 types of synapses:

▫ Electrical synapses Pre and postsynaptic cells joined by

gap junctions Numerous in cardiac and smooth

muscle cells Rare in mammalian nervous system

▫ Chemical synapses Synaptic cleft

Separates pre and post synaptic neurons

Prevents direct propagation of electric current

Signals transmitted by means of neurotransmitter

Co-transmitters Additional neurotransmitter

simultaneously released with another neurotransmitter

Synaptic vesicles Store neurotransmitter in the

terminals

Functional anatomy of synapses

• Presynaptic cell:▫ Action potential axon terminal

depolarization voltage-gated Ca++ channels open Ca++ enters fusion of synaptic vesicles to PM release of transmitters by exocytosis

• Postsynaptic cell:▫ Binding of neurotransmitters to

receptors opening or closing of specific ligand sensitive -ion channels

• One way conduction across synapses in general

• Brief synaptic delay (0.2 sec) from action potential at presynaptic neuron to membrane potential changes in post synaptic cell

Functional anatomy of synapses

• Fate of unbound neurotransmitters1. Are actively transported back to the axon

terminal/glial cells2. Diffuse away from the receptor site3. Enzymatically transformed into

ineffective substances • 2 kinds of chemical synapse

▫ Excitatory Response is depolarization Open postsynaptic-membrane ion channels

permeable to positvely charged ions Excitatatory postsynaptic potential (EPSP)

Potential change wherien there is net movemnt of positively charge ions into the cell to slightly depolarize it

Graded potential to bring the postsynaptic neuron closer to threshold

▫ Inhibitory Lessens likelihood for depolarization and

action poterntial Opening of Cl- or sometimes K+ channels Inhibitory postsynaptic potential (IPSP)

Hyperpolarizing graded potential

Activation of a postsynaptic cell• In most neurons, one

excitatory synaptic event by itself is not enough to cause threshold to be reached in the postsynaptic neuron

• Temporal summation:▫ Axon stimulated before the

1st EPSP has died away▫ The 2nd EPSP adds to the

previous one and creates a greater input than from 1 input alone

▫ Input signals arrive at the same cell at different times

▫ The potentials summate because there is a greater number of open ion channels

• Spatial summation:▫ 2 inputs occured at different

locations on the same cell

Activation of a postsynaptic cell

Synaptic effectiveness• A presynaptic terminal does

not release a constant amount of neurotransmitters everytime it is activated

• Presynaptic synapse (axon-axon synapse)▫ Axon terminal of one ends on

an axon terminal of another ▫ Effects:

Presynaptic inhibition Decrease the amount of

neurotransmitter secreted Presynaptic facilitation

Increase the amount of neurotransmitter secreted

Modification of Synaptic transmission by Drugs and Disease

• All synaptic mechanisms are vulnerable to drugs

• Agonist:▫ Drugs that bind to a receptor and

produces a response similar to normal activation of a receptor

• Antagonis:▫ Drugs that bind to the receptor but

aren’t able to activate it• Diseases:

▫ Tetanus toxin Protease that destroys certain

proteins in the synaptic-vesicle docking mechanism of inhibitory neurons to neurons supplying the skeletal muscle

▫ Botulinum toxin and spider venom Affect neurotransmitter release from

synaptic vesicles Interfere with docking proteins Act on axons different from those

acted upon by tetanus toxin

Synaptic effectiveness

Neurotransmitters and Neuromodulators• Neuromodulators

▫ Messengers that cause complex responses/modulation

▫ Alter effectiveness of synapse▫ Modify postsynaptic cell’s response

to neurotransmitters▫ Change the presynaptic cell’s

release, release, re-uptake, or metabolism of a transmitter

▫ Receptors for neuromodulators bring about changes in the metabolic processes in neurons via G-proteins

▫ Changes occur within minutes, hours, or days enzyme activity Protein synthesis

▫ Associated with slower events Learning Development Motivational states Sensory/motor activities

Neurotransmitters and neuromodulators• Acetylcholine (ACh)

▫ Synthesized from choline and acetyl coenzyme A

▫ Reducing enzyme: acetylcholinesterase

▫ Mostly in the PNS, also in CNS

▫ Nerve fibers: cholinergic▫ Receptors: nicotinic,

muscarinic▫ Function: attention,

learning, memory▫ Pathology: Alzheimers

• Biogenic amines▫ Synthesized from AA and

contain an amino group▫ MC: dopamine,

norepinphrine, serotonin, histamine

▫ Epinephrine: biogenic amine hormone secreted by adrenal medulla

▫ Norepinephrine: important neurotransmitter in CNS and PNS

Neurotransmitters and neuromodulators• Catecholamines

▫ Dopamine, norepinephrine, epinephrine

▫ Contain a catechol ring and an amine group

▫ Synthesized from tyrosine▫ Reducing enzyme: Monoamine

oxidase ▫ Catecholamine releasing

neurons mostly in brainstem and hypothalamus but axons go to all parts of the CNS

▫ Function: state of consciousness, mood, motivation, directed attention, movement, blood-pressure regulation, and hormone release

• Catecholamines▫ Fibers: adrenergic,

noradrenergic▫ Receptors: Alpha, Beta

Further divide in Alpha1, alpha2, Beta1 and Beta2 receptors

Neurotransmitters and neuromodulators

Neurotransmitters and neuromodulators• Serotonin

▫ Biogenic amine synthesized from trytophan

▫ Effects have slow onset and innervate virtually every structure of the brain and spinal cord.

▫ Has 16 different receptor types▫ Function:

Motor: excitatory Sensation: inhibitory

▫ Lowest activity during sleep and highest during alert wakefulness

▫ Motor activity, sleep, food intake, reproductive behavior, mood and anxiety

▫ Present in non-neural cells (e.g. Platelets, GI tract, immune system)

• Amino Acid Neurotransmitters▫ Amino acids that function as

neurotransmitters▫ Most prevalent neurotransmitter in

the CNS and affect virtually all neurons there

▫ Excitatory Amino Acids Glutamate Aspartate Function: learning, memory, neural

development Pathology: epilepsy, alzheimers,

parkinsons disease, Neural damage after stroke, brain

trauma Drugs: phencylidine (angel dust)

▫ Inhibitory Amino Acids GABA (gamma-aminobutyric acid) Glycine Drugs: valium

Neurotransmitters and neuromodulators• Neuropeptides

▫ Composed of 2 or more AA linked together by peptide bonds

▫ Function as hormones or paracrine agents

▫ Synthesis: from large proteins produced by ribosomes

▫ Fibers: peptidergic▫ Endogenous opioids

B-endorphin, dynorphins, enkephalins

Receptors are site of action of opiate drugs (morphine, codeine)

Function: analgesia, “jogger’s high”, eating and drinking behavior, CVS regulation, mood and behavior

▫ Substance P Released by afferent neurons Relay sensory information into the

CNS

• Nitric Oxide▫ Diffuse into the intracellular

fluid of nearby cells from cells of origin

▫ Messenger between neurons and effector cells

▫ Activate cGMP▫ Function: learning,

development, drug tolerance, penile erection, sensory and motor modulation

• ATP▫ Very fast acting excitatory

transmitter• Adenine