Unit IV - The Nervous System I

The Nervous System

• The endocrine and nervous systems maintain internal coordination

  • Endocrine: chemical messengers (hormones) delivered to the bloodstream

  • Nervous: three basic steps

    • Sense organs receive information

    • The brain and spinal cord determine responses

    • The brain and spinal cord issue commands to glands and muscles

Subdivisions of the Nervous System

• Two major anatomical subdivisions

  • Central Nervous System (CNS)

    • The brain and spinal cord are enclosed in bony coverings

  • Peripheral Nervous System (PNS)

    • Nerve: bundle of axons in connective tissue

    • Ganglion: swelling of cell bodies in a nerve

Functional Divisions of the PNS

• Sensory (afferent) divisions (receptors to CNS)

  • Visceral sensory and somatic sensory division

• Motor (efferent) division (CNS to effectors)

  • Visceral motor division (ANS)

    • Effectors: cardiac, smooth muscle, glands

    • Sympathetic division (action)

    • Parasympathetic division (digestion)

  • Somatic motor division effectors: skeletal muscle

    • Effectors: skeletal muscle

Sensory (Afferent) Neurons

• Afferent Neurons

• Detect changes in the body and the external environment

• Information transmitted into brain or spinal cord

Interneurons

• Association Neurons

• Lie between the sensory and motor pathways in the CNS

• 90% of our neurons are interneurons

• Process, store, and retrieve information

Motor Neuron

• Efferent Neuron

• Send signals out to muscles and gland cells

• Organs that carry out responses called effectors

Properties of Neurons

• Excitability (irritability)

  • Ability to respond to internal and external environmental stimuli

• Conductivity

  • Produce traveling electrical signals

• Secretion

  • Secretion of a chemical neurotransmitters from the nerve termini in response to an electrical signal

Structure of a Neuron

• Cell Body - Perikaryon Soma

  • Single, central nucleus with a large nucleolus

  • Cytoskeleton of microtubules and neurofibrils (bundles of actin filaments)

  • Lipofuscin is a product of the breakdown of worn-out organelles -- more with age

• A vast number of short dendrites

  • For receiving signals

• A single axon (nerve fiber) arising from the axon hillock for rapid conduction

  • Axoplasm, axolemma, and synaptic vesicles

Multipolar Neuron

• Most common

• Many dendrites / one axon

• Very common in the cerebellum

Bipolar Neuron

• One dendrite / one axon

• Olfactory, retina, ear

Unipolar Neuron

Sensory from the skin and organs to the spinal cord

Anaxonic Neuron

• Many dendrites / no axon

• Help in visual processes

Axonal Transport

• Proteins made in soma must be transported to axon and axon terminal

  • Repairs axolemma, for gated ion channel proteins, as enzymes or neurotransmitters

• Fast anterograde axonal transport

  • Either direction up to 400 mm / day for organelles, enzymes, vesicles and small molecules

• Fast retrograde for recycled materials and pathogens

• Slow axonal transport or axoplasmic flow

  • Moves cytoskeletal and new axoplasm at 10 mm / day during repair and regeneration in damaged axons

• Can take anywhere from a few months to a few years

Axonal Transportation is Bidirectional

• Substances travel continuously along the axon in both directions

• Anterograde movement: movement AWAY from the cell body

  • Move substances needed to make neurotransmitters

  • Some neurotransmitters are made in the cell body, packaged into vesicles, then transported to axon terminals

• Retrograde movement: movement TOWARD the cell body

  • Return substances to be degraded or recycled by the cell body

  • Move molecules like nerve growth factor that activates certain genes that promote growth

Neurons

• Excitable nerve cells

• Respond to stimuli by changing their action potential

• Transmit electrical signals

Neuroglia

• Glial cells, Glia

• Far outnumber neurons

• Surround / wrap neurons

• Support, insulate, protect neurons

• Structure

  • Central cell body with branching “processes” (extensions)

  • Smaller in size and nuclei stain darker than neurons

Cells of the CNS

• Astrocytes - MOST IMPORTANT!

• Microglial cells

• Ependymal cells

• Oligodendrocytes

Cells of the PNS

• Satellite cells

• Schwann cells

CNS Neuroglia - Astrocytes

• Abundant, star-shaped cells

• Barrier between capillaries and neurons

• Control brain environment

• MOST IMPORTANT

CNS Neuroglia - Microglia

• Spiderlike phagocytes

• Dispose of debris

• SECOND MOST IMPORTANT

CNS Neuroglia - Ependymal Cells

• Line cavities of the brain and spinal cord

• Cilia assist with circulation of cerebrospinal fluid

CNS Neuroglia - Oligodendrocytes

• Wrap around nerve fibers in the central nervous system

• Produce myelin sheaths

Astrocytes

• Most abundant and versatile glial cell

• Forms the framework of the CNS

  • Support and brace neurons

  • Connect them to their nutrient supply lines

• Control the chemical environment around neurons

  • “Mop up” leaked potassium ions

  • Recapture and recycle released neurotransmitters

• Contribute to the BBB (blood-brain barrier)

  • Regulate the composition of brain tissue fluid

• Convert glucose to lactate to feed neurons

• Secretes nerve growth factor to promote synapse formation

• Respond to and influence synaptic signaling

• Sclerosis – hardened astrocyte mass replaces damaged neurons

Microglial Cells

• Small, ovoid cells with long “thorny” processes

• Monitor the status of nearby neurons

• Migrate toward damaged neurons

• Transform into specialized macrophages that phagocytose microbes and neuronal debris:

  • In the presence of invading microorganisms or dead neurons

  • e.g., in areas of infection, trauma, or stroke

• Important since immune cells have limited access to CNS

• Important for synapse elimination or pruning

Synaptic Pruning

• Our body’s way of maintaining more efficient brain function as we get older and learn new complex information

• Implicated in autism and schizophrenia

Ependymal Cells

• Ranges in shape from squamous to columnar—many are ciliated

• Line the central cavities of the brain and spinal cord

• Form a fairly permeable barrier between:

  • Cerebrospinal fluid (CSF) fills the CNS cavities

  • Interstitial fluid (ISF) tissues bathing the cells

• Beating of their cilia helps circulate CSF that cushions the brain and spinal cord

Oligodendrocytes

• Wrap around and insulate axons

• Branching cells with fewer processes than astrocytes

• Line up along the thicker nerve fibers in the CNS

• Wrap their processes tightly around the fibers

• Produce an insulating covering called a myelin sheath

PNS Neuroglia - Satellite Cells

• Like Microglia

• Surround, protect, and cushion neuronal cell bodies

• Thought to function similarly to astrocytes

PNS Neuroglia - Schwann Cells

• The live area of the cell

• Form myelin sheath in PNS

• Functionally similar to oligodendrocytes

• Vital to regeneration of damaged peripheral nerve fibers

Myelin

• Insulating layer around a nerve fiber

  • Oligodendrocytes in the CNS and Schwann cells in the PNS

  • Formed from wrappings of the plasma membrane

    • 20% protein and 80 % lipid (looks white)

  • All myelination is completed by late adolescence

• In PNS, hundreds of layers wrap the axon

  • The outermost coil is schwann cell (neurilemma)

  • Covered by basal lamina and endoneurium

• In CNS - no neurilemma or endoneurium

• Oligodendrocytes myelinate several fibers

  • Myelination spirals inward with new layers pushed under the older ones

• Gaps between myelin segments: Nodes of Ranvier

• The initial segment (area before 1st schwann cell) and the axon hillock form a trigger zone where signals begin

Speed of Nerve Signals

• Diameter of fiber and presence of myelin

  • Large fibers have more surface area for signals

• Speeds

  • Small, unmyelinated fibers = 0.5 - 2.0 m / sec

  • Small, myelinated fibers = 3 - 15.0 m / sec

  • Large, myelinated fibers = up to 120 m / sec

• Functions

  • Slow signals supply the stomach and dilate pupil

  • Fast signals supply skeletal muscles and transport sensory signals for vision and balance

Electrical Potentials and Currents

• Nerve pathway is a series of separate cells

• Neural communication: mechanisms for producing electrical potentials and currents

  • Electrical potential - different concentrations of charged particles in different parts of the cell

  • Electrical current - flow of charged particles from one point to another within the cell

• Living cells are polarized

  • Resting membrane potential is -70 mV with a negative charge on the inside of membrane

The Role of Ion Channels

• Types of plasma membrane ion channels:

  • Passive, or leakage, channels – always open

  • Chemically gated channels – open with the binding of a specific neurotransmitter

  • Voltage-gated channels – open and close in response to membrane potential

Operation of a Chemically - Gated Channel

• Example: ACh Receptor channel

• Closed when a neurotransmitter (ACh) is not bound to the extracellular receptor

  • Na⁺ cannot enter the cell and K⁺ cannot exit the cell

Operation of a Voltage - Gated Channel

• Example: Voltage Gated Na⁺ channel

• Closed when the intracellular environment has negative voltage

• Na⁺ cannot enter the cell

Resting Membrane Potential ( I )

• Unequal electrolyte distribution between ECF (Extracellular Fluid) / ICF (Intracellular Fluid)

• Diffusion of ions down their concentration gradients

• Selective permeability of the plasma membrane

• Electrical attraction of cations and anions

• The membrane is very permeable to K⁺

  • Leaks out until an electrical gradient is created, attracting it back in

• Cytoplasmic anions can not escape due to size or charge (PO₄^2-, SO₄^2-, organic acids, proteins)

• The membrane is much less permeable to Na⁺

• Na⁺ / K⁺ pumps out 3 Na⁺ for every 2 K⁺ it brings in

  • Works continuously and requires a great deal of ATP

  • Necessitates that glucose and oxygen be supplied to nerve tissue

Resting Membrane Potential ( II )

• Resting Membrane Potential: potential difference across the membrane

• Basic Neuron: -70mV: negative inside, relative to outside

• Two factors generate the resting membrane potential:

  • Concentration—differences in ionic composition of intracellular and extracellular fluids

  • Permeability—differences in the plasma membrane’s permeability to those ions

• Cytosol has lower [Na⁺] and higher [K⁺] than the outside (extracellular fluid)

• Active transport by Na⁺ / K⁺ - ATPase sets concentration gradients

Local Potentials

• Local disturbances in membrane potential

  • Occurs when a neuron is stimulated by chemicals, light, heat, or mechanical disturbance

  • Depolarization decreases the potential across the cell membrane due to the opening of gated Na⁺ channels

    • Na⁺ rushes in down concentration and electrical gradients

    • Na⁺ diffuses for a short distance inside the membrane, producing a change in voltage called a local potential

• Differences from action potentials

  • Are graded (vary in magnitude with stimulus strength)

  • Are decremental (get weaker the farther they spread)

  • Are reversible as K⁺ diffuses out of cell

  • Can be either excitatory or inhibitory (hyperpolarize)

Changes in Membrane Potential

Graded Potentials

• Like a Ripple - the bigger the stimulus, the bigger the response!

• Voltage changes in graded potentials are decremental

• Current is quickly dissipated due to the leaky plasma membrane

  • Can only travel over short distances

Action Potentials

• More dramatic changes in areas of high density of voltage-gated channels occur

  • Trigger zone up to 500 channels / um2 (normal is 75)

2. If threshold potential (-55mV) is reached voltage-gated Na⁺ channels open (Na⁺ enters causing depolarization)

3. Past 0 mV, Na⁺ channels close: depolarization

4. Slow K⁺ gates fully open

5. K⁺ exits, repolarizing the cell

6. Negative overshoot produces hyperpolarization, excessive exiting of K⁺

Characteristics of AP

• Called a spike

• Follows an all-or-none law

  • Voltage gates either open or don’t

• Nondecremental (do not get weaker with distance)

• Irreversible (once started, it goes to completion and can not be stopped)

The Refractory Period

• Period of resistance to stimulation

• Absolute refractory period

  • As long as Na+ gates are open

  • No stimulus will trigger AP

• Relative refractory period

  • As long as K+ gates are open

  • Only especially strong stimulus will trigger new AP

• Refractory period occurs only to a small patch of membrane at one time (quickly recovers)

Impulse Conduction in Unmyelinated Fibers

• The threshold voltage in the trigger zone begins the impulse

• Nerve signal (impulse) - a chain reaction of sequential opening of voltage-gated Na⁺ channels down the entire length of the axon

• Nerve signal (nondecremental) travels at 2m / sec

• The signal is like a wave / ripple

Saltatory Conduction

The rapid propagation of action potentials along myelinated axons, jumping between gaps called Nodes of Ranvier

Saltatory Conduction - Myelinated Fibers

• Voltage-gated channels needed for APs

  • Fewer than 25 per um² in myelin-covered regions

  • Up to 12,000 per um² in nodes of Ranvier

• Fast Na⁺ diffusion occurs between nodes

Multiple Sclerosis

• An autoimmune disease that mainly affects young adults - mainly women

• Symptoms include 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 occur

• Treatments include injections of methylprednisolone and beta interferon

Synaptic Transmission

• Action Potential (AP) arrives at the axon terminal

• Calcium Influx - voltage-gated Ca²⁺ channels open and Ca²⁺ enters the axon terminal

• Neurotransmitter (NT) Release - Ca²⁺ entry causes synaptic vesicles to release NT by exocytosis

• Diffusion - NT diffuses across the synaptic cleft

• Receptor Binding / Response - binding of NT opens ion channels, leading to graded postsynaptic potentials

• Termination - NT effects are terminated via reuptake, degradation, or diffusion from the synapse

Synapses between Neurons

• First neuron releases neurotransmitter onto second neuron that responds to it

  • 1^st neuron is presynaptic neuron

  • 2^nd neuron is postsynaptic neuron

• Synapse may be axodendritic, axosomatic or axoaxonic

• Number of synapses on postsynaptic cell variable

  • 8,000 on spinal motor neuron

  • 100,000 on neuron in cerebellum

Electrical Synapses

• Electrical Synapses:

  • Are less common than chemical synapses

  • Correspond to gap junctions found in other cell types

  • Contain intercellular protein channels

  • Permit ion flow from one neuron to the next

  • Are found in the brain and are abundant in embryonic tissue

Chemical Synapses

• Specialized for the release and reception of neurotransmitters

• Typically composed of two parts:

  • Axonal terminal of the presynaptic neuron, which contains synaptic vesicles

  • Receptor region on the dendrite(s) or soma of the postsynaptic neuron

Types of Neurotransmitters

• Acetylcholine

• Amino Acids:

  • GABA

  • Glycine

  • Aspartic Acid

  • Glutamic Acid

• Monoamines:

  • Epinephrine

  • Norepinephrine

  • Dopamine

  • Serotonin

  • Histamine

Neuropeptides

• Chains of 2 to 40 amino acids

• Stored in axon terminal as larger secretory granules (called dense-core vesicles)

• Act at lower concentrations

• Longer-lasting effects

• Some are released from non-neural tissue

  • Gut - Brain peptides cause food cravings

• Some function as hormones

  • Modify actions of neurotransmitters

Ionotropic NT Receptors

• Direct

• Rapid signaling (ligand-gated ion channel)

Metabotropic NT Receptors

• Indirect

• Slower, longer-lasting changes with diverse responses (G-protein coupled receptors)

Synaptic Transmission

• 3 kinds of synapses with different modes of action

  • Excitatory cholinergic synapse = ACh

  • Inhibitory GABA-ergic synapse = GABA

  • Excitatory adrenergic synapse = NE

• Synaptic delay (0.5 m / sec)

  • Time from the arrival of the nerve signal at a synapse to the start of an AP in the postsynaptic cell

Excitatory Cholinergic Synapse

• A nerve signal opens voltage-gated calcium channels in the synaptic knob

• Triggers the release of ACh, which crosses synapse

• ACh receptors trigger the opening of Na+ channels, producing local potential (postsynaptic potential)

• When it reaches -55mV, it triggers AP in the postsynaptic neuron

Inhibitory GABA-ergic Synapse

• Nerve signal triggers the release of GABA (y-aminobutyric acid), which crosses the synapse

• GABA receptors trigger the opening of Cl^- channels, producing hyperpolarization

• The postsynaptic neuron is now less likely to reach threshold

Excitatory Adrenergic Synapse

• Neurotransmitter is NE (norepinephrine)

• Acts through 2^nd messenger systems (cAMP)

  • Receptor is an integral membrane protein associated with a G protein, which activates adenylate cyclase, which converts ATP to cAMP

• cAMP has multiple effects

  • Binds to ion gate inside of membrane (depolarizing)

  • Activates cytoplasmic enzymes

  • Induces genetic transcription and production of new enzymes

• Its advantage is enzymatic amplification

Cessation and Modification of a Signal

• Mechanisms to turn off stimulation

  • Diffusion of neurotransmitter away into the ECF

    • Astrocytes return it to neurons

  • Synaptic knob reabsorbs amino acids and monoamines by endocytosis

  • Acetylcholinesterase degrades ACh

    • Choline is reabsorbed and recycled

• Neuromodulators modify transmission

  • Raise or lower the number of receptors

  • Alter neurotransmitter release, synthesis, or breakdown

Neural Integration

• The more synapses a neuron has, the greater its information-processing capability

  • Cells in the cerebral cortex with 40,000 synapses

  • The cerebral cortex is estimated to contain 100 trillion synapses

• Chemical synapses are decision-making components of the nervous system

  • The ability to process, store, and recall information is due to neural integration

• Based on the types of postsynaptic potentials produced by neurotransmitters

Excitatory Postsynaptic Potentials (EPSP)

• A positive voltage change causes the postsynaptic cell to be more likely to fire

  • Result from Na⁺ flowing into the cell

• Glutamate and aspartate are excitatory neurotransmitters

• ACh and norepinephrine may excite or inhibit, depending on the cell

Inhibitory Postsynaptic Potentials (IPSP)

• A negative voltage change causing postsynaptic cell to be less likely to fire (hyperpolarize)

  • Result of Cl^- flowing into the cell or K⁺ leaving the cell

• Glycine and GABA are inhibitory neurotransmitters

• ACh and norepinephrine may excite or inhibit depending upon cell

Postsynaptic Potentials

• EPSPs are graded potentials that can initiate an action potential in an axon

  • Use only chemically gated channels

  • Na⁺ and K⁺ flow in opposite directions simultaneously

• Postsynaptic membranes do not generate action potentials

• Neurotransmitter binding to a receptor at inhibitory synapses:

  • Membrane becomes more permeable to K⁺ and Cl^-

  • The charge on the inner surface is negative

  • Reduces the postsynaptic neuron’s ability to produce an action potential

Summation - Postsynaptic Potentials

• Net postsynaptic potentials in trigger zone

  • Firing depends on net input of other cells

    • Typical EPSP voltage = 0.5 mV and lasts 20 msec

    • 30 EPSPs needed to reach threshold

  • Temporal Summation

    • Single synapse receives many EPSPs in short time

  • Spatial Summation

    • Single synapse receives many EPSPs from many cells

Pain Regulation

Presynaptic Inhibition

• One presynaptic neuron suppresses another

  • Neuron I releases inhibitory GABA

    • Prevents voltage-gated calcium channels from opening -- it releases less or no neurotransmitter

Neural Coding and Integration

• Qualitative information (taste or hearing) depends upon which neurons fire

  • Labeled Line Code: the brain knows what type of sensory information travels on each fiber

• Quantitative information depends on:

  • Different neurons have different thresholds

    • Weak stimuli excite only specific neurons

  • Stronger stimuli cause a more rapid firing rate

    • CNS judges stimulus strength from the firing frequency of sensory neurons

    • Absolute refractory periods vary

Neural Pools and Circuits

• Neural Pool: interneurons that share specific body function

  • Control rhythm of breathing

• Facilitated vs. Discharge Zones

  • In Discharge Zone: a single cell can produce firing

  • In Facilitated Zone: single cell can only make it easier for the postsynaptic cell to fire

Neural Circuits

• Diverging Circuit: one cell synapses on another, and each synapse on others

• Converging Circuit: input from many fibers on one neuron (respiratory center)

• Reverberating Circuits: neurons stimulate each other in a linear sequence, but one cell restimulates the first cell to start the process all over

• Parallel After-Discharge Circuits: input neuron stimulates several pathways, which stimulate the output neuron to continue firing for a longer time after the input has truly stopped

Serial Processing

• Input travels along one pathway to a specific destination

• One neuron stimulates the next and so on to cause specific, anticipate response

• Predictable all-or-nothing manner

• Reflexes: rapid, automatic responses to stimuli, to produce a stereotyped and dependable response

Parallel Processing

• Input travels along several different pathways to be integrated in different CNS regions

• Inputs are segregated into many pathways

• Different parts of the neural circuitry deal with the information delivered by each pathway simultaneously

• Extremely important for higher-level mental functioning to put all parts together to understand the whole

Synaptic Plasticity

• Synaptic Strength:

• The amount or magnitude of the post-synaptic potential caused by activation of the pre-synaptic terminal

• Plasticity: ability of brain to change synaptic strength as a result of experience

• Plasticity: ability to learn and remember

Synaptic Plasticity Mechanisms

• More Strength: Up Regulation:

  • Increase vesicles or transmitter

  • Increase Post-synaptic receptors

• Less Strength: Down Regulation

  • Decrease vesicles or transmitter

  • Decrease post-synaptic receptors

Two Kinds of Synapses in the Brain

• Compensatory:

  • Regulatory

  • Homeostatic

  • Underlies Addiction

• Hebbian:

  • Intensifies with use!

  • Important for consolidating memory

Memory and Synaptic Plasticity

• Physical basis of memory is a pathway

  • Called a memory trace or engram

  • New synapses or existing synapses modified to make transmission easier (synaptic plasticity)

• Synaptic potentiation

  • Transmission mechanisms correlate with different forms of memory

    • Immediate, short and long-term memory

Immediate Memory

• Ability to hold something in your thoughts for just a few seconds

  • Essential for reading ability

• Feel for the flow of events (sense of the present)

• Our memory of what just happened “echoes” in our minds for a few seconds

  • Reverberating circuits

Short-Term Memory

• Lasts from a few seconds to several hours

  • Quickly forgotten if distracted

• Search for keys, dial the phone

  • Reverberating circuits

• Facilitation causes memory to last longer

  • Tetanic stimulation (rapid,repetitive signals) cause Ca²⁺ accumulation and cells more likely to fire

• Post-tetanic potentiation (to jog a memory)

  • Ca²⁺ level in synaptic knob stays elevated

  • Little stimulation needed to recover memory

Long-Term Memory

• Types of long-term memory

  • Declarative: retention of facts as text

  • Procedural: retention of motor skills

• Physical remodeling of synapses

  • New branching of axons or dendrites

• Molecular changes: long-term

  • Tetanic stimulation causes ionic changes

    • Neuron produces more neurotransmitter receptors

    • More protein synthesizes for synapse remodeling

    • Releases nitric oxide, then presynaptic neuron releases more neurotransmitter

Alzheimer’s Disease

• 100,000 deaths / year

  • 11% of population over 65; 47% by age 85

• Memory loss for recent events, moody, combative, lose ability to talk, walk, and eat

• Diagnosis confirmed at autopsy

  • Atrophy of gyri (folds) in cerebral cortex

  • Neurofibrillary tangles and senile plaques

• Degeneration of cholinergic neurons and deficiency of ACh and nerve growth factors

• Genetic connection confirmed

Parkinson’s Disease

• Progressive loss of motor function beginning in 50’s or 60’s -- no recovery

  • Degeneration of dopamine-releasing neurons

    • Prevents excessive activity in motor centers

    • Involuntary muscle contractions

      • Pill-rolling motion, facial rigidity, slurred speech, illegible handwriting, slow gait

• Treatment: drugs and physical therapy

  • Dopamine precursor crosses brain barrier

  • MAO inhibitor slows neural degeneration

  • Surgical technique to relieve tremors