The Nervous System

• Three Functions– Sensory Input (Afferent) **Affect– Integration (Processing/Interpretation)– Motor Output (Efferent) **Effect

Nervous System Organization

• Central Nervous System (CNS)– Brain– Spinal Cord

• Peripheral Nervous System (PNS)– Afferent Division (Sensory)– Efferent Division (Motor)

PNS Afferent (Sensory)

• Somatic afferent fibers– From skin, skeletal muscles and joints

• Visceral afferent fibers– From internal organs (viscera)

PNS Efferent (Motor)

• Somatic n.s. – impulses to skeletal muscles a.k.a. voluntary ns

• Autonomic n.s. – visceral motor fibers to smooth muscles, cardiac muscle, & glands a.k.a. involuntary ns– Sympathetic n.s. (“fight or flight”) = stimulate– Parasympathetic n.s. (“rest and repose”) = inhibit

NS Cell Makeup• Neurons – functional transmission cells• Neuroglia – Supporting cells that surround

neurons a.k.a. glial cells or “nerve glue”– CNS neuroglia

• Astrocytes • Microglia• Ependymal cells• Oligodendrocytes

– PNS neuroglia• Satellite cells• Schwann cells

Neuroglia

• Astrocytes - – most abundant – anchor to BV’s, assist nutrient transfer – glucose uptake, lactic acid delivery– guide migrating “young” neurons– synapse formation– capillary permeability– “mop up” K+ and recapture neurotransmitters

Cont.

• Microglia – “thorny” processes– neuron “health detectors” – transform to macrophages

• Ependymal cells – “wrapping” – squamous to columnar shape + cilia in central cavities

of the brain and spinal cord– Permeable barrier between CSF and tissue fluid of CNS

• Oligodendrocytes – – wrap the thick nerve fibers of the CNS to make

insulated coverings = myelin sheaths

Motor Neuron

Neurons• A.k.a. nerve cells• Have extreme longevity – up to 100+ years!• Essentially amitotic = cannot divide/regen.• Have high metabolic rate and need continuous

glucose and oxygen• Have two major anatomical structures

– Cell body– Processes

• Axons

• Dendrites

Axons• Transmitting portion – Action Potentials (AP’s)

(conducting component)– Anterograde movement

– Retrograde movement (abnormal w/ bacterial/viral agents)

• Profuse branching at terminal end (10,000 +)• Knob-like ends on the terminal branches (secretory

component – neurotransmitters - NT’s)– Axonal terminals (or)

– Synaptic knobs (or)

– Boutons

Myelin Sheath & Neurilemma

• Whitish fatty protein that is segmented

• Myelinated nerves conduct rapidly - larger

• Unmyelinated nerves conduct slowly- finer

• Neurilemma is the “husk” or external part of the Schwann cell

• Nodes of Ranvier

Classification of Neurons

• Structural – Multipolar– Bipolar– Unipolar

• Functional– Sensory / Afferent– Motor / Efferent– Interneurons

Neurophysiology

• Highly irritable• Electrical impulse generated and conducted = AP’s• Voltage or potential difference measured in mV and

generally a “resting” membrane of a neuron is ~ -70mV• Membrane Ions channels: “leakage/passive” and

“gated/active”– Chemical (ligand) gated – chemical stimuli– Voltage-gated – electrical stimuli– Mechanically – distortion stimuli

Resting Membrane Potential

Resting Membrane Potential

• - 70 mV across the membrane (varies - 40 to - 90mV) when the membrane is polarized

• Negative sign means inside (cytoplasmic side) is negatively charged

• Charge is based on differences in ionic concentrations in intra and extra-cellular fluids, and differences in permeability

• K+ is the most important ion in generating membrane potential

Membrane Potentials• Changes in these is involved with receiving,

integrating, and sending information.

• Caused by:– Anything altering ion permeability– Anything altering ion concentrations on either

side of the membrane.

• Produces either:– Graded potentials – over short distances– Action potentials – over long distances

Cont.

• Depolarization – relative to “resting” it is less negative/more positive (closer to “0”) on the inside of the neuron – which increases the probability of producing a nerve impulse

• Hyperpolarization – increased membrane potential, or more negative than resting potential – which decreases the probabilility of a nerve impulse.

Graded Potentials

Action Potentials (AP’s)• Principal form of neuron communication only in

excitable membranes of neurons and muscle cells• Brief reversal of membrane potential from -70 to

+30 mV• Depolarization followed by repolarization phase

and often a hyperpolarization period (msec’s)• AP’s are also called nerve impulses and only

axons can generate one.• Stimulus changes permeability via voltage-gated

channels on the axon

Generating AP’s• Three overlapping membrane permeability

changes by opening and closing active ion gates1) Resting State: Voltage-gated Na/K+ channels closed

2) Depolarizing phase: Increase in Na+ permeability and reversal of membrane potential – Na+ influx causes depolarization until threshold (-55 to -50mV)

3) Repolarizing phase: a) Decrease in Na+ permeability b) w/ increase in K+ permeability

4) Hyperpolarization: K+ permeability continues to produce undershoot

Action Potential: Resting State

• Na+ and K+ channels are closed• Leakage accounts for small movements of Na+ and

K+

• Each Na+ channel has two voltage-regulated gates – Activation gates –

closed in the resting state

– Inactivation gates – open in the resting state

Figure 11.12.1

Action Potential: Depolarization Phase

• Na+ permeability increases; membrane potential reverses

• Na+ gates are opened; K+ gates are closed• Threshold – a critical level of depolarization

(-55 to -50 mV)• At threshold,

depolarization becomes self-generating

Figure 11.12.2

Action Potential: Repolarization Phase

• Sodium inactivation gates close• Membrane permeability to Na+ declines to

resting levels• As sodium gates close, voltage-sensitive K+

gates open• K+ exits the cell and

internal negativity of the resting neuron is restored

Figure 11.12.3

Action Potential: Hyperpolarization

• Potassium gates remain open, causing an excessive efflux of K+

• This efflux causes hyperpolarization of the membrane (undershoot)

• The neuron is insensitive to stimulus and depolarization during this time

Figure 11.12.4

Action Potential: Role of the Sodium-Potassium Pump

• Repolarization – Restores the resting electrical conditions of the

neuron– Does not restore the resting ionic conditions

• Ionic redistribution back to resting conditions is restored by the sodium-potassium pump

Propagation of AP’s

• Process in unmyelinated nerves:– Away from its point of origin toward axon terminals

and then is self-propagating– Ea. segment repolarizes - restores resting potential

• Process in myelinated nerves:– Saltatory conduction

• Propagation of nerve impulse is a better term to use than nerve impulse conduction

Threshold & “All-or-None”

• Not all local (graded) potentials lead to AP’s– Reached when outward K+ = inward Na+ movement

• At threshold either Na+ gates open with more Na+ entering or close with more K+ leaving and return to resting potential

• Stronger stimuli cause threshold to be reached and begins positive feedback cycle

• The AP either happens or it does not

Stimulus Intensity

• AP’s are independent of stimulus strength, therefore the RATE of stimuli allow for the CNS to interpret intensity (i.e. more painful)

Refractory Period

• When an AP is being generated it can’t respond to another stimulus to create another AP = the absolute refractory period

• The relative refractory period follows the absolute while Na+ gates are still closed and neuron is repolarizing.

• A very strong stimulus in the relative period CAN cause another AP to be initiated

Conduction Velocity

1) Axon diameter – larger usually means faster, due to less resistance

2) Degree of myelinationa) Unmyelinated develop AP’s in adjoining

segments of a neuron, thus are slow moving

b) Myelinated are “insulated” by myelin and only allow current to pass at the nodes of Ranvier where voltage-gated channels are concentrated, thus are fast moving & are termed saltatory conduction (Abnormal = MS)

Saltatory Conduction

Multiple Sclerosis (MS)

• An autoimmune disease that mainly affects young adults

• Symptoms: visual disturbances, weakness, loss of muscular control, and urinary incontinence

• Nerve fibers are severed and myelin sheaths in the CNS become nonfunctional scleroses

• Shunting and short-circuiting of nerve impulses occurs

Multiple Sclerosis: Treatment

• The advent of disease-modifying drugs including interferon beta-1a and -1b, Avonex, Betaseran, and Copazone:– Hold symptoms at bay– Reduce complications– Reduce disability

Nerve Fiber Classification

• Group A = large diameter myelinated found in somatic sensory and motor fibers of the skin muscles and joints (150 m/s)

• Group B = lightly myelinated and intermediated diameter found in ANS motor fibers, visceral sensory fibers & smaller somatic sensory fibers (15 m/s)

• Group C = smallest and unmyelinated found in similar areas as B fibers (1 m/s)

Imbalances

• Alcohol, sedatives and anesthetics all impair Na+ permeability = no AP’s

• Cold and pressure interrupt blood flow and thus O2 delivery impairing AP generation and thus ability to conduct impulses

Synapses• Junction of one neuron (axonal terminals) with

another neuron or neuromuscular junction

• Presynaptic is before and postsynaptic is after

• There may be as many as 1000-10,000 synapses with each neuron

• Two varieties:– Electrical – sleep arousal, conscious perception,

emotion, memory, and early embryonic nervous tissue– Chemical (neurotransmitters)

Chemical Synapses1) Ca2+ channels open in presynaptic axonal

terminal and let in extracelluar Ca2+ 2) Neurotransmitter (NT) is released by Ca2+

causing vesicles of NT to empty into the cleft3) NT binds with postsynaptic receptors4) Ion channels open in postsynaptic membrane

causing current locally to cause either excitation or inhibition

* More NT or longer lasting presence of NT = greater response

Postsynaptic Potentials

• AP’s are not generated, only locally graded depolarization events called excitatory or inhibitory postsynaptic potentials

• EPSP – excitatory NT opens a single channel, with simultaneous flow of Na+ and K+ in both directions.

• IPSP – inhibitory as NT binding causes hyperpolarization by ↑ K+ and/or Cl- entry

Summation by Postsynaptic Neuron• Single EPSP doesn’t cause AP, but 1000’s firing will or

if a small number are firing, but rapidly it will• Thus EPSP summate in one of two ways:

– Temporal – one or more presynaptic neurons firing rapidly add together

– Spatial – multiple neurons simultaneously firing on one neuron

• IPSP’s can also do this and inhibit it more• Or they can do it together and the axon hillock will sort

it all out

Synaptic Modifications• Synaptic Potentiation – continuous use of a

synapse enhances its PSP’s related to ↑ Ca2+ via NMDA receptors on postsynaptic side– A.k.a. post-tetanic potentiation that increases the

efficiency of NT’s – long duration seen in the hippocampus involved w/ memory/learning

• Presynaptic inhibition and neuromodulation- the ‘pre’ side excitatory NT is inhibited by another neuron forming smaller EPSP– Differs from postsynaptic inhibition that just ↓

excitability of post synaptic neuron

Cont.

• Neuromodulation – presynaptic event acting on postsynaptic membrane. Some of these influence: – Synthesis– Release– Degradation or . . .– Reuptake of NT’s at presynaptice neuron

• Others alter sensitivity of postsynaptic membrane to the NT – act like hormones

Neurotransmitters

• > 50 different types with different NT’s released at different stimulation frequencies

• ACh – (acetylcholine) most plentiful, found at all neuromuscular junctions (NMJ) and some neurons of the ANS– Contained in synaptic vesicles– Degraded by Acetylcholinesterase or AChE on

the postsynaptic membrane– Converts it back into choline to be reused

NT cont.

• Biogenic amines – catecholamines like dopamine, norepinephrine (NE), epinephrine (EP), and the indolamines histamine & serotonin– Plays a significant role in emotional behaviors– Biological clock– Dopamine and NE are made from AA tyrosine, but

cells that release each have only the enzymes needed to make the NT they release

– Same pathway used to create EP– Serotonin made from AA tryptophan (sleep cycle)– Histamine from AA histidine

Synthesis of Catecholamines

• Enzymes present in the cell determine length of biosynthetic pathway

• Norepinephrine and dopamine are synthesized in axonal terminals

• Epinephrine is released by the adrenal medulla

Figure 11.21

NT cont.

• Amino Acids – GABA, glycine, glutamate, aspartate found only in CNS thus far– Glutamate is excitatory in CNS & important in

learning and memory, but stroke victims suffer excitotoxicity and die

– GABA and Glycine are CNS & spinal cord inhibitory – decline in visual/auditory processing with age and are enhanced by alcohol & TQZ

• Peptides – neuropeptides include:– Substance P for pain mediation– Endorphin, dynorphin & enkephalins act as natural

opiates to decrease pain sensation• Enkephalins increase in pregnant women in labor• Endorphins increase in competition “runner’s high”

NT cont.

• Novel messengers – include:– ATP – produces fast excitatory response or slow

second messengers – provokes pain receptors– Adenosine acts outside of cells as inhibitor in the brain

• Caffeine works by blocking those inhibitor receptors

• Dissolved gases– Nitric oxide (NO) – may be involved in retrograde

messenger in memory and learning, smooth muscle relaxation (vasodilation), but toxic release in stroke victims causes damage

– Carbon monoxide (CO) – may help mental alertness and acts similarly to NO

Neurotransmitter Function Classification

• Excitatory vs. Inhibitory – some groups do both and some NT’s individually cause opposite actions (e.g. ACh excites skeletal m. and inhibits cardiac m.)

• Direct vs. Indirect – open ion channels directly with rapid response (e.g. ACh) or promote longer-lasting effects w/ intracellular 2nd messengers “G protein-linked receptors such as cyclic AMP or cyclic GMP using heightened Ca2+ influx/sensitivity (Ch.3 p.84)

Neural Integration

• Neuronal pools – some incoming signals are directly excitatory (discharge), while others are more peripheral and only facilitate possible excitation (or inhibition)

Types of Circuits

• Diverging – amplifying, and common in both sensory and motor circuits

• Converging – concentrating, and are also common in sensory and motor circuits

• Oscillating – reverberating causing positive feedback, seen in rhythmic cycles like sleep-wake, breathing, etc.

• Parallel after-discharge – to common output cell at different times (~15ms) seen in complex problem solving mental processes

Spinal Reflex Arc

Development of Neurons

• The nervous system originates from the neural tube and neural crest

• The neural tube becomes the CNS

• There is a three-phase process of differentiation:– Proliferation of cells needed for development– Migration – cells become amitotic and move

externally– Differentiation into neuroblasts

Axonal Growth

• Guided by:– Scaffold laid down by older neurons– Orienting glial fibers– Release of nerve growth factor by astrocytes– Neurotropins released by other neurons– Repulsion guiding molecules– Attractants released by target cells

N-CAMs

• N-CAM – nerve cell adhesion molecule

• Important in establishing neural pathways

• Without N-CAM, neural function is impaired

• Found in the membrane of the growth cone