Nerves

BIEN 500

Steven A. Jones

Divisions of the Nervous System

• Higher brain/cortical level– Memory storehouse– Thought– Control of other parts of the nervous system

• Subconscious activities– Medulla– Pons– Mesencephalon– Hypothalamus– Thalamus– Cerebellum– Basal ganglia

• Spinal Cord– Reflex activities (walking, withdrawal from pain, leg support,

control of blood flow

Control of respiration & arterial pressure

Emotion

Neuron Anatomy

Dendrites

Axon

Cell Body

Brain

Spinal Cord

Signals from dendrites can be transmitted either to knobs on the cell body or knobs on the dendrites

Conduction generally occurs in one direction.

Signals

• Nerves deliver sequences of spikes.

• Spike frequency translates to signal strength.

Time

Signals

• Response threshold and maximum spike frequency depend on nerve type.

Excitatory State

Fre

quen

cy o

f di

scha

rge

(s-1)

100

300

400

500

600

200

Note: Threshold for Neuron 3 has a higher threshold, but ultimately has higher frequency of discharge.

Neuron 1

2

3

Fatigue

• Nerve is incapable of producing more action potentials

• Causes are:– Depletion of transmitter substances in the

presynaptic terminals– Inactivation of postsynaptic membrane

receptors– Buildup of abnormal amounts of ions at the

postsynaptic cell

Other Effects

• Post-tetanic facilitation – nerve becomes more excitable after resting from intense stimulation.

• pH– Alkalosis causes higher excitability– Acidosis causes lower excitability

• Hypoxia – reduces excitability

Drugs

Increases Excitability (Reduced Threshold)

Caffeine, theophylline, theobromide (coffee, tea and cocoa, respectively)

Decrease Inhibition Strichnine – can cause muscle spasms

Increase membrane threshold

Most anesthetics

Connections

• Synaptic cleft (2-3 nm wide)• Presynaptic Terminal has

– Mitochondria– Neural Transmitter Vesicles

• Postsynaptic Terminal (cell soma) has:– Receptor Proteins

Transmitter VesiclesMitochondria

Receptor Proteins

Soma

Causes of Synaptic Delay1. Discharge of neural transmitter.2. Diffusion of the transmitter across

the cleft.3. Response of membrane receptor to

the neural transmitter.4. Action of the receptor to increase

membrane permeability.5. Inward diffusion of sodium. Discharge

Receptor Response

Diffusion

Na+

Receptor Effect

Release of Neural Transmitter

• Voltage gated Ca++ channels release Ca++

• Ca++ causes release of neural transmitter.

• Each vesicle secretes transmitter by pinocytosis.

• Transmitter Acetylcholine– 2000-10000 molecules per vesicle– Enough vesicles for 10,000 action potentials

Ion Receptor Responses

• Cation Channels– Short term, excitatory– Allow passage of cations (Mostly Na+, but also

K+, Ca++)

• Anion Channels– Short term, inhibitory– Allow passage of anions (Mainly Cl-, inhibitory

hyperpolarization)

G Protein Receptors

Transmitter Substance

Portion affects the neuron (e.g. opening potassium channel, transcription, enzyme

activation)

Extracellular

Intracellular

Second Messenger Receptor Responses

• Long-term responses.• G Protein Channels have , and components. component is released, possibly causing:

– Opening of an ion channel– Activation of cyclic Adenosine Monophosphate (cAMP)

• Can alter cell structure and excitability.

– Activation of intracellular enzymes– Activation of gene transcription

• Formation of new proteins.• Change in metabolic machinery• Can be important in memory

Action Potential

Time (ms)

0

-70

Potential Inside (mV)

Excessive K+ Inside

Influx of Na+

Outflux of Na+, Influx of K+

Mechanisms of Excitation

• Opening of sodium channels– Makes inside potential less negative

• Depressed chloride or potassium channel conduction

• Metabolic changes– Direct impact– Increase in the number of excitatory receptors– Decrease in the number of inhibitory

receptors.

Mechanisms of Inhibition

• Opening of chloride channels– makes inside more negative

• Increasing K+ Conductance (K+ diffuses out)

• Activation of inhibiting receptor enzymes

Neural Transmitters

• Approximately 50 neural transmitters are known.

• Small molecules– Fast-acting– Acute responses

• Large polypeptides– Slow-acting– Long-term responses

Neural Transmitters

• Factors in response– Amount of transmitter generated– Number of receptors– Transmitter uptake mechanisms– Transmitter inactivation– Receptor inactivation

Small Molecule Neural Transmitters

Class I: Acetylcholine Class III: Amino Acids

Class II: The Amines -Aminobutyric acid (GABA)

Norepinephrine Glycine

Epinephrine Glutamate

Dopamine Aspartate

Serotonin Class IV:

Histamine Nitric Oxide

Recycling of Transmitter Vesicles

Recycling of Transmitter Vesicles

Concentrating Proteins

Recycling of Transmitter Vesicles

Concentrating Proteins

Recycling of Transmitter Vesicles

Small Neural TransmittersAcetylcholine: Excitation (mostly)

Norepinephrine: Excitation (mostly)

Glutamate: Excitation

Dopamine: Inhibition

Glycine: Inhibition

GABA: Inhibition

Serotonin: Pain inhibition, Sleep

Nitric Oxide (NO):

Memory, Smooth muscle relaxation, inhibits platelets and cellular proliferation. NO is not stored.

Selected Neuropeptides• Hypothalamic

– Leuteinizing hormone• Pituitary

– Growth Hormone– Vasopressin– Oxytocin

• Acting on Gut and Brain– Insulin– Glucagon

• Others– Angiotensin II– Bradykinin– Sleep Peptides

Neuropeptides• Usually one type per neuron.• Must be removed

– By diffusion from synaptic cleft– By enzymatic destruction– By active transport into presynaptic terminal (recycling)

• Synthesized in cell body.• More “expensive” to generate.• Transmitted to synapse by streaming.• Vesicles are not reused.• More potent than small neural transmitters• More prolonged action.

Response Time for Neural Transmitter

DL2tCoefficienDiffusion

widthgap

D

L

If L is 3 nm and D is 3.45 x 10-6 cm2/s (D for serotonin), then:

sscmcm 2 8627 1087.01045.3/103

It follows that the transport of the neural transmitter across the synaptic cleft is not the time limiting factor in neural transmission.

Other Factors in Response Time

• Release of transmitter.

• Response time of receptors.

• Response time for action after receptor response.

Connections

• Facilitated (subthreshold or subliminal) Zone

• Discharge Zone– Transmitting nerve will trigger receiving nerve

Facilitated

Discharge

Connections

• Inhibition Zone– Exists when dendrites are inhibitory instead of

excitatory.

Inhibition Zone

(entire field of inhibiting neuron)

Simultaneous Excitation and Inhibition

• Different neural transmitters for excitation and inhibition.

• Intervening Inhibitory synapse

• Might be used to control opposing muscles

Inhibitory Synapse

Excitatory Synapse

Excitation

Inhibition

Divergence

• To increase the intensity on a given element:

• To cause the same effect on different elements:

Afterdischarge

• Response lasts longer than input

• Reverberatory (positive feedback-fig 46-13)

• Can add facilitation and inhibition (like FET?)

Time

Time (ms)

Potential Inside (mV) With Afterdischarge

Without Afterdischarge

Afterdischarge

Simplest case – neuronal signal feeds back on itself, causing re-triggering.

Afterdischarge with Facilitation/Inhibition

External neuron excites or inhibits the feedback connection.

External Neuron

Circuit Analogue to Oscillatory Pool

Integrator

Schmitt Trigger (has hysteresis, positive feedback)

Substitute FET transistor for R1 to get voltage (signal) controlled oscillator.

+-

+-

R1Time (s)

Vol

tage

(V

)

Vol

tage

(V

)

Time (s)

Saturation

Continuous Neural Signals

• Intrinsic Neuronal Excitability

• Reverberatig Circuits– Can be controlled by facilitation/inhibition– Dog scratching, breathing– Uncontrolled – epilepsy– Inhibition mechanisms

• Inhibitory feedback• Synaptic fatigue

Memory

• Mostly occurs in the cerebral cortex

• May also occur in basal sections of brain & spinal cord.

• Facilitation – The more often a synapse fires, the easier it is to fire again.

• Pathways can fire without the initial stimulus.

Ch. 47: Somatic Sensations• Categories of somatic senses

– Mechanireceptive somatic sensors• Tactile• Position

– Thermoreceptive senses– Pain sense

• Position senses– Rate of movement– Static position

• Tactile senses• Touch, pressure, vibration, tickle.

Tickle and Itch

• Receptors are almost exclusively in the superficial layers of the skin

• Transmitted by small, type C, unmyelinated fibers (similar to slow, aching pain).

• Useful in detecting fleas, flies, etc.

• Pain inhibits itch by lateral inhibition

Somatic Sensory Pathways• Dorsal Column

– Touch signals for localization– Touch sensations for fine intensity– Phasic (e.g. vibratory) sensations– Position Sensations– Fine Pressure

• Anterolateral System– Pain– Warm and Cold– Crude touch and pressure– Tickle and Itch– Sexual Sensations

Somatic Sensation II, Pain, Headache, and Thermal Sensations• Fast Pain

– Sharp/pricking/acute/electric pain– As when stuck by a needle or electric shock

• Slow Pain– Types of slow pain

• Slow burning pain• Aching pain• Throbbing pain• Nauseous pain• Chronic pain

– Usually indicates tissue destruction

Purpose of Pain

Patient: “Doctor, it hurts when I do this.”

Doctor: “Well, don’t do that!”

Pain Receptors• All pain receptors are free nerve endings.• Pain receptors are found in:

– Superficial skin layers– Periosteum– Arterial walls– Joint surfaces– Falx and tentorium of cranial vault– Other areas are sparsely populated

• Any widespread tissue damage can cause slow, chronic aching pain.

Types of Pain Stimuli

• Mechanical

• Thermal

• Chemical– Caused by bradykinin, serogonin, histamine,

K+, acetylcholine, proteolytic enzymes– Enhanced by prostaglandins, substance P.

Causes of Pain

• Rate of tissue damage– Pain is felt at about 45 degrees.– This is the temp at which tissue becomes

damaged.

• Extracts from damaged tissue will induce pain.

• Ischemia (possibly because of lactic acid)

Pain Fibers• Fast pain

– Transmitted by type A fibers (6 to 30 m/s)– Probably transmitted by glutamate– Tells you to take immediate action (take hand off of burner)– Highly localized– Passes through neospinothalamic tract

• Slow, chronic pain– Transmitted by type C fibers (0.5 to 5 m/s)– Probably transmitted by Substance P– Becomes more painful over time– Reminds you that you did something stupid– Poorly localized– Transmitted through paleospinothalamic pathways

Analgesia System

• Stimulation of the periaqueductal gray area or the raphe magnus nucleus can suppress strong pain from the dorsal spinal roots.

• Enkephalins and serotonin (neurotrans-mitters) are involved.

• Opiate system – Endorphins and Enkephalins

• Inhibition by tactile sensory signals– E.g. rubbing the skin

Referred Pain

• Classic example is heart attack– Pain may be felt in arm, or masked as

indigestion.

• Pain receptors follow pathways to other areas of the body (cross-wiring).

Visceral Pain

• Gut Pain – not so much acute, but highly sensitive to diffuse pain.

• Some viscera do not feel pain– Parenchyma of the liver– Alveoli of the lungs

• Causes are– Ischemia– Chemical stimuli– Spasm (e.g. of ball bladder, bile duct, ureter)

Abnormal Pain• Hyperalgesia (excitable pain pathway)

– Excessive sensitivity of pain receptors (e.g. sunburned skin)

– Facilitation of sensory transmission• Thalamic syndrome• Herpes Zoster (Shingles)

– Herpes virus infects dorsal ganglia– Also causes skin rash

• Tic Douloureux– Felt in one side of the face– Feels like electric shock

Headache

• Brain is insensitive to pain

• Regions around the brain are sensitive– Meninges– Nasal Sinuses– Venous sinuses– Tentorium– Dura

Types of Headache• Migrane

– Cause is not well understood– May result from vessel spasm – vessel expands after the vessel is

exhausted.

• Meningitis– Infection of meninges– West Nile virus

• Low cerebral spinal fluid (brain impinges on dural surfaces)• Alcoholic Headache (“don’t drink that poision!)• Constipation headache (occurs even if spinal cord is cut).• Muscle spasm headache (muscles attached to scalp & neck)• Sinus Headache (inflammation, pressure)

Thermal SensationsIm

puls

es p

er S

econ

d

Temperature (ºC)

Cold Pain Heat Pain

Cold Receptors

Warmth Receptors

5 25 45 60

Thermal Sensation

• If temperature is too cold, subject stops feeling pain.

• Cold pain and hot pain feel similar.• Receptors are more sensitive to rates of

change of temperature, rather than temperature itself.– Pool water seems colder when you first get in.– Nerves adapt to the cooler temperature.– Eventually loss of heat will cause shivering.