THE NERVOUS SYSTEM: NEURAL

TISSUE

• Nervous system– Swift, brief responses to stimuli

• Endocrine system– Adjusts metabolic operations– Directs long-term changes

Two organ systems coordinate and direct activities of body

An Overview of the Nervous System

Divisions of the nervous system

Anatomical Classification of the Nervous System

• Central Nervous System– Brain and spinal cord

• Peripheral Nervous System– All neural tissue outside CNS

Functional divisions of nervous system

• Afferent– Sensory information from receptors to CNS

• Efferent – Motor commands to muscles and glands– Somatic division

• Voluntary control over skeletal muscle

– Autonomic division• Involuntary regulation of smooth and cardiac muscle, glands

Histology of Neural Tissue

• Neurons

Cells in Nervous Tissue

• Neuroglia

• about half the volume of cells in the CNS

• smaller than neurons

• 5 to 50 times more numerous

• do NOT generate electrical impulses

• divide by mitosis

• two types in the PNS– Schwann cells

– Satellite cells

• Four types in the CNS– Astrocytes

– Oligodendrocytes

– Microglia

– Ependymal cells

Neuroglia (Glia)

• Largest of glial cells• Star shaped with many processes projecting from the cell body• Help form and maintain blood-brain barrier• Provide structural support for neurons• Maintain the appropriate chemical environment for generation of nerve impulses/action potentials• Regulate nutrient concentrations for neuron survival• Regulate ion concentrations - generation of action potentials by neurons• Take up excess neurotransmitters• Assist in neuronal migration during brain development• Perform repairs to stabilize tissue

Astrocytes

Oligodendrocytes

• Most common glial cell type

• Each forms myelin sheath around the axons of neurons in CNS

• Analogous to Schwann cells of PNS

• Form a supportive network around CNS neurons

• fewer processes than astrocytes• round or oval cell body

Microglia

• Small cells found near blood vessels• Phagocytic role - clear away dead cells• protect CNS from disease through phagocytosis of microbes• migrate to areas of injury where they clear away debris of

injured cells - may also kill healthy cells

• few processes• derived from mesodermal cells that also give rise to monocytesand macrophages

Ependymal Cells

• Form epithelial membrane lining cerebral cavities (ventricles) & central canal - that contain CSF

• Produce & circulate the cerebrospinal fluid (CSF) found in these chambers

• CSF = colourless liquid that protects the brain and SC against

chemical & physical injuries, carries oxygen, glucose and other necessary

chemicals from the blood to neurons and neuroglia

• epithelial cells arranged in asingle layer• range in shape from cuboidalto columnar

• Flat cells surrounding PNS cell bodies

• Support neurons in the PNS

PNS: Satellite Cells

PNS: Schwann Cells

• each cell surrounds multiple unmyelinated PNS axons with a single layer of its plasma membrane

• Each cell produces part of the myelin sheath surrounding an axon in the PNS

• contributes regeneration of PNS axons

Neurilemma

Representative Neuron

1. cell body or soma -single nucleus with prominent nucleolus-Nissl bodies

-rough ER & free ribosomes for protein synthesis-proteins then replace neuronal cellular components for growthand repair of damaged axons in the PNS

-neurofilaments or neurofibrils give cell shape and support - bundles of intermediate filaments-microtubules move material inside cell-lipofuscin pigment clumps (harmless aging) - yellowish brown

2. Cell processes = dendrites (little trees)- the receiving or input portion of the neuron-short, tapering and highly branched-surfaces specialized for contact with other neurons-cytoplasm contains Nissl bodies & mitochondria

Neurons

3. Cell processes = axons• Conduct impulses away from cell body-

propagates nerve impulses to another neuron

• Long, thin cylindrical process of cell

• contains mitochondria, microtubules & neurofibrils - NO ER/NO protein synth.

• joins the soma at a cone-shaped elevation = axon hillock

• first part of the axon = initial segment

• most impulses arise at the junction of the axon hillock and initial segment = trigger zone

• cytoplasm = axoplasm

• plasma membrane = axolemma

• Side branches = collaterals arise from the axon

• axon and collaterals end in fine processes called axon terminals

• Swollen tips called synaptic end bulbs contain vesicles filled with neurotransmitters

Structural Classification of Neurons

• Based on number of processes found on cell body– multipolar = several dendrites & one axon

• most common cell type in the brain and SC

– bipolar neurons = one main dendrite & one axon• found in retina, inner ear & olfactory

– unipolar neurons = one process only, sensory only (touch, stretch)• develops from a bipolar neuron in the embryo - axon and dendrite fuse and then

branch into 2 branches near the soma - both have the structure of axons (propagate APs) - the axon that projects toward the periphery = dendrites

• Named for histologist that first described them or their appearance

Structural Classification of Neurons

•Purkinje = cerebellum•Renshaw = spinal cord

• others are named for shapese.g. pyramidal cells

Functional Classification of Neurons

• Sensory (afferent) neurons– transport sensory information from skin, muscles,

joints, sense organs & viscera to CNS

• Motor (efferent) neurons– send motor nerve impulses to muscles & glands

• Interneurons (association) neurons– connect sensory to motor neurons

– 90% of neurons in the body

The Nerve Impulse

Terms to know

• membrane potential = electrical voltage difference measured across the membrane of a cell

• resting membrane potential = membrane potential of a neuron measured when it is unstimulated– results from the build-up of negative ions in the cytosol along the inside

of the neuron’s PM– the outside of the PM becomes more positive– this difference in charge can be measured as potential energy – measured

in millivolts• polarization• depolarization• repolarization• hyperpolarization

The electric potential across an axonal membrane can be measured

• the differences in positive andnegative charges in and outof the neuron can be measured byelectrodes = resting membrane potential -ranges from -40 to -90 mV

Ion Channels

• ion channels in the PM of neurons and muscles contributes to their excitability

• when open - ions move down their concentration gradients

• channels possess gates to open and close them

• two types: gated and non-gated

2. Gated channels: open and close in response to a stimulusA. voltage-gated: open in response to change in voltage - participate in the AP

B. ligand-gated: open & close in response to particular chemical stimuli (hormone, neurotransmitter, ion)

C. mechanically-gated: open with mechanical stimulation

1. Leakage (non-gated) or Resting channels: are always open, contribute to the resting potential-nerve cells have more K+ than Na+ leakage channels -as a result, membrane permeability to K+ is higher-K+ leaks out of cell - inside becomes more negative-K+ is then pumped back in

• Resting membrane potential is -70mV

• triggered when the membrane potential reaches a threshold usually -55 MV

• if the graded potential change exceeds that of threshold – Action Potential

• Depolarization is the change from -70mV to +30 mV

• Repolarization is the reversal from +30 mV back to -70 mV)

Action Potential

• action potential = nerve impulse• takes place in two stages: depolarizing phase (more positive) and repolarizing

phase (more negative - back toward resting potential)• followed by a hyperpolarizing phase or refractory period in which no new AP

can be generated http://www.blackwellpublishing.com/matthews/channel.html

The action potential• 1. neuron is at resting membrane potential (resting MP)

• 2. neuron receives a signal– Neurotransmitter (NT)

• 3. NT binds ligand-gated sodium channel

• 4. LGNa channel opens

• 5. Na flows into neuron = depolarization– Inside of neuron (i.e. MP) becomes more positive

• 6. if neuron depolarizes enough to Threshold = Action Potential (AP)

• 7. 1st stage of AP – opening of voltage-gated Na channels

• 8. even more Na flows in through VGNa channels = BIG depolarization

– Membrane potential goes from negative to positive

• 9. closing of VGNa channels & opening of voltage-gated K channels

• 10. BIG outflow of potassium through VGK channels = repolarization

– Inside of neuron (MP) becomes more negative

• 11. neuron repolarizes so much – it goes past resting and hyperpolarizes

• 12. closing of VGK channels

• 13. all voltage-gated channels closed, Na/K pump “resets” ion distribution to resting situation

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Continuous versus Saltatory Conduction

• Continuous conduction (unmyelinated fibers)– An action potential spreads

(propagates) over the surface of the axolemma

– as Na+ flows into the cell during depolarization, the voltage of adjacent areas is effected and their voltage-gated Na+ channels open

– step-by-step depolarization of each portion of the length of the axolemma

http://highered.mcgraw-hill.com/sites/0072437316/student_view0/chapter45/animations.html#

Saltatory Conduction

• Saltatory conduction (myelinated fibers)

-depolarization only at nodes of Ranvier - areas along the axon that are unmyelinated and where there is a high density of voltage-gated ion channels

-current carried by ions flowing through extracellular fluid from node to node

http://www.blackwellpublishing.com/matthews/actionp.html

• Properties of axon

• Presence or absence of myelin sheath

• Diameter of axon

Rate of Impulse Conduction

Synaptic Communication

SynapsesSynapse: Site of intercellular communication between 2

neurons or between a neuron and an effector (e.g. muscle – neuromuscular junction)

• Permits communication between neurons and other cells– Initiating neuron = presynaptic neuron– Receiving neuron = postsynaptic neuron

• You can classify a synapse according to:

– 1. the action they produce on the post-synaptic neuron – excitatory or inhibitory

– 2. the mode of communication – chemical vs. electrical

• If the NT depolarizes the postsynaptic neuron = excitatory– The depolarization event is often called an excitatory

postsynaptic potential (EPSP)– Opening of sodium channels or other cation channels (inward)

• Some NTs will cause hyperpolarization = inhibitory– The hyperpolarization event is often called an inhibitory

postsynaptic potential (IPSP)– Opening of chloride channels (inward) or potassium channels

(outward)

• Neural activity depends on summation of all synaptic activity– Excitatory and inhibitory

Synapses – Excitatory vs. Inhibitory

• Electrical

– Direct physical contact between cells required

– Conducted through gap junctions

– Two advantages over chemical synapses• 1. faster communication – almost instantaneous

• 2. synchronization between neurons or muscle fibers– e.g. heart beat

Synapses

Chemical Synapse

http://www.lifesci.ucsb.edu/~mcdougal/neurobehavior/modules_homework/lect3.dcr

• Synapse• Most are axodendritic axon -> dendrite• Some are axoaxonic – axon > axon

Synapses – Chemical vs. Electrical

http://www.blackwellpublishing.com/matthews/nmj.html

• Chemical – Membranes of pre and postsynaptic neurons do not touch– Synaptic cleft exists between the 2 neurons – 20 to 50 nm– the electrical impulse cannot travel across the cleft – indirect

method is required – chemical messengers (neurotransmitters)– Most common type of synapse– The neurotransmitter induces a postsynaptic potential in the PS

neuron – if the potential is an EPSP – excitatory and an AP results (e.g. glutamate)

• If the potential is an IPSP – inhibitory and NO AP results (e.g. glycine or GABA)

– Communication in one direction only

The Events in Muscle Contraction1. AP generated at trigger zone in

pre-synaptic neuron2. AP arrives in end bulb – causes entry

of calcium into end-bulb – releaseof Ach

3. Binding of Ach to ligand-gated Nachannels on muscle PM (Ach receptors)

4. Na enters muscle cell – depolarization5. Muscle membrane potential reaches

threshold = Action Potential6. AP travels through PM of muscle cell into

T-tubules7. AP “passes by” sarcoplasmic reticulum –

release of calcium into muscle cell8. Ca binds troponin-tropomyosin complex &

“shifts” it off myosin binding site9. Cross-bridging between actin and myosin,

pivoting of myosin head = Contraction(ATP dependent)

The Neuromuscular Junction• end of neuron (synaptic terminal or axon bulb) is in very close association with the muscle fiber• distance between the bulb and the folded sarcolemma = synaptic cleft• nerve impulse leads to release of neurotransmitter (acetylcholine)• N.T. binds to receptors on myofibril surface• binding leads to influx of sodium, potassium ions (via channels)• eventual release of calcium by sarcoplasmic recticulum = contraction

• Acetylcholinesterase breaks down ACh• Limits duration of contraction

Motor Units• Each skeletal fiber has only ONE

NMJ

• MU = Somatic neuron + all the skeletal muscle fibers it innervates

• Number and size indicate precision of muscle control

• Muscle twitch – Single momentary contraction

– Response to a single stimulus

• All-or-none theory – Either contracts completely or not at

all

• Muscle fibers of different motor units are intermingled so that net distribution of force applied to the tendon remains constant even when individual muscle groups cycle between contraction and relaxation.

• Motor units in a whole muscle fire asynchronouslysome fibers are active others are relaxed delays muscle fatigue so contraction can be sustained

Motor Tone

• Resting muscle contracts random motor units– Constant tension created on tendon– Resting tension – muscle tone

• Stabilizes bones and joints

• More than 100 identified

• Some bind receptors and cause channels to open

• Others bind receptors and result in a second messenger system

• Results in either excitation or inhibition of the target

Neurotransmitters

1. small molecules: Acetylcholine (ACh)-All neuromuscular junctions use ACh-ACh also released at chemical synapses in the PNS and by some CNS neurons-Can be excitatory at some synapses and inhibitory at others-Inactivated by an enzyme acetylcholinesterase

2. Amino acids: glutamate & aspartate & GABA– Powerful excitatory effects

– Glutamate is the main excitatory neurotransmitter in the CNS

– Stimulate most excitatory neurons in the CNS (about ½ the neurons in the brain)

– Binding of glutamate to receptors opens calcium channels = EPSP

– GABA (gamma amino-butyric acid) is an inhibitory neurotransmitter for 1/3 of all brain synapses

– MSG – monosodium glutamate• flavor enhancer since 1900’s

• used as a purified salt of L-glutamic acid or in a mixture of amino acids

• intermediate in amino acid metabolism, energy source for cardiac myocytes

• can cause Chinese Restaurant syndrome – numbness, muscle weakness and heart palpitations – similar to effects seen upon Ach administration

• MSG can be converted into ACh via the Citric acid cycle

• ACh in the CNS is involved in memory, arousal and reward – excitatory NT

Neurotransmitters

Neurotransmitters3. Biogenic amines: modified amino acids

– catecholamines: norepinephrine (NE), epinephrine, dopamine (tyrosine)– serotonin - concentrated in neurons found in the brain region = raphe

nucleus• derived from tryptophan• sensory perception, temperature regulation, mood control, appetite, sleep

induction• feeling of well being

– NE - role in arousal, awakening, deep sleep, regulating mood– epinephrine (adrenaline) - flight or fight response– dopamine - emotional responses and pleasure, decreases skeletal muscle

tone

Removal of Neurotransmitter

• Enzymatic degradation– acetylcholinesterase

• Uptake by neurons or glia cells– neurotransmitter transporters

• NE, dopamine, serotonin

GABA

• GABA action is affected by a broad range of drugs called benzodiazepines– e.g. lorazepan – Ativan– e.g. diazepam - Valium

• Various uses: hynoptic, sedative, anxiolytic, anticonvulsant, muscle relaxant, amnesic

• Short lasting – half life is less than 12 hours– hypnotic effects– insomnia

• Long lasting – half life is more than 24 hours– anxiolytic effects (anti-anxiety drug)

• Acts to enhance GABA– GABA – major inhibitory NT in the CNS– GABA binds to GABA receptors – several types– Benzodiazepines bind and modulate the activity of the GABAA receptor which is

the most prolific NT receptor in the brain• GABAA receptor is comprised of 5 protein subunits• One subunit is the alpha subunit• BZ’s bind to the alpha subunit only and increase its affinity for binding the GABA

neurotransmitter• The GABAA receptor is a ligand-gated chloride channel• Binding of GABA increases the inward flow of chloride ions which hyperpolarizes the

neuron and inhibits its ability to make a new action potential• Therefore BZ’s potentiate the inhibitory effects of GABA

Valium

• top selling drug from 1969-1982– GABA agonist– Also decreases the synthesis of neurosteroid hormones (e.g.

DHEA, progesterone) which may regulate emotional state– Acts on areas of the limbic system, the thalamus and the

hypothalamus (anti-anxiety drug)– Metabolized by the liver into many metabolites– Gives rise to a biphasic half live of 1-2 days and 2-5 days!– Lipid-soluble and crosses the blood-brain barrier very easily– Stored in the heart, the muscle and the fat– Some drugs (barbituates), anti-depressants and alchohol can

enhance its effect– Smoking can increase the elimination of valium and decrease its

effects

Dopamine• Involved in feelings of pleasure, strength• Also mediates skeletal muscle contraction• Neurotransmitters like dopamine, serotonin, glutamate, acetylcholine

etc… are secreted and then rapidly internalized by transporters in order to control their levels within the nervous system

• Many drugs affect these transporters• Ritalin = methylphenidate

– 1954 – initially prescribed in adults for depression and narcolepsy - stimulant

– 1960 – prescribed to children with ADD, ADHD - depressant– Reason?? Might be due to an imbalance in dopamine– Binds both dopamine and norepinephine transporters and inhibits their

ability to take these NTs back up (keeps their levels high in the synapse)– Dopamine transporters (DAT) found in the PM of neurons (presynaptic)

• Transports dopamine back into the neuron along with sodium ions (symporter)• This terminates the dopamine signal• Chloride ions are also required to enter the neuron to prevent depolarization• In adults – these transporters regulate dopamine levels

• Cocaine – binds and inhibits DATs – increasing dopamine in the synapse

• Amphetamines – binds amphetamine receptors on a neuron which causes the internalization of the DAT into the neuron – increasing dopamine in the synapse

Neuropeptides• widespread in both CNS and PNS• excitatory and inhibitory• act as hormones elsewhere in the body

-Substance P -- enhances our perception of pain-opioid peptides: endorphins - released during stress, exercise

-breaks down bradykinins (pain chemicals), booststhe immune system and slows the growth of cancercells-binds to mu-opioid receptors-released by the neurons of the Hypothalamus and by the cells of the pituitary

enkephalins - analgesics -breaks down bradykinins (200x stronger than morphine) -pain-relieving effect by blocking the release of substance P

dynorphins - regulates pain and emotions

**acupuncture may produce loss of pain sensation because of release of opioid-like substances such as endorphins or dynorphins

Morphine• Opiate analgesic• Principal agent in opium

– Acts on the CNS – Acts on the GI tract – decrease motility, decrease gastric secretion,

decreases gastric empyting, increases fluid absorption• Other opiates: heroin, codeine, thebaine• Acts on the neurons of the CNS (specifically the nucleus accumbens

of the basal ganglia)• Binds to the mu-opioid receptor

– Found throughout the brain – especially in the posterior amygdala, the hypothalamus and thalams, the basal ganglia, the dorsal horn of the spinal cord and the trigeminal nerve

– Relieves the inhibition of GABA release by presynaptic neurons– Also relieves the inhibition of dopamine release (addiction)– Binding activates the receptor and gives rise to: analgesia, euporia,

sedation, dependence and respiratory and BP depression.• Acts on the immune system! – increase incidence of addiction in those

that suffer from pneumonia, TB and HIV– Activates a type of immune cell called a dendritic cell – decrease their

activation of B cells – decreased antibody production – decrease immune function