I.  Introduction
Examples of neurological/neuromuscular diseases that you will gain some understanding of:
  *Demyelinating diseases such as multiple sclerosis,      Guillain-Barre syndrome
  *Neurotoxic poisons such as organophosphates, curare
  *Neuromuscular diseases such as myasthenia gravis
  *Reflexes as a diagnostic tool

 B.  Functions
  1.  Forms a selective barrier to most water-soluble substances
  2.  Specialized functions of proteins

 C.  Types of Transport across the membrane
  1.  Diffusion:  movement of molecule always a non-energy requiring process
   a. Simple diffusion
    molecules pass through the lipid bilayer  directly  (lipid soluble molecules) OR
    through open protein channels
     e.g. water (special case of diffusion  termed osmosis)
    Discuss leak channels vs. gated channels
     -Na/K leak channels in membrane
     -Voltage gated channels
      e.g. sodium channels in action  potential
 
     -Ligand or chemical gated channels
      e.g. synaptic transmission
 
   b.  Facilitated diffusion
    molecules pass through the bilayer by binding to specialized carrier proteins
 
   c.  Factors Affecting Diffusion
    1.  Concentration gradient
     -difference in concentration of the substance in the ECF and ICF
     -the greater the gradient the more diffusion will occur
    2.  Electrical gradient
     -opposites attract, like charges repel. Therefore, charged molecules will move  toward opposite charge.
     -the greater the electrical gradient the more diffusion will occur
    3.  Membrane permeability
     -how soluble is the molecule in the lipid  bilayer or how many channels are available.  For many ions depends on  how many ion channels are open.
     -the greater the permeability the more diffusion
    4.  Surface area of membrane
     -increasing surface area increases diffusion
    5.  Molecular weight of substance
     -increasing MW decreases diffusion
    6.  Thickness of membrane
     -increasing thickness decreases  diffusion
   d.  Concept of equilibrium
    1.  Balance of forces such that no further “net" diffusion occurs
    2.  Occurs when:
     -concentration gradient is abolished
     -electrical gradient “                                “
     -the electrical and chemical gradients  are balanced
     -hydrostatic pressure prevents further  osmosis
 
  2.  Active Transport
   a.  Always an energy requiring process
    Energy source=ATP
   b.  Examples:
    i.  Proton pump
     (H+=proton=acid)
     Many proton pumps located in the stomach
     Purpose: pump acid into stomach
     Intuitively, considering  concentration gradients, should this require energy?

    ii. Na+-K+-ATPase pump
     -One of the most important pumps in the body
     -Necessary to maintain concentration gradients for sodium and potassium across nerve membrane (essential for nerve conduction).
     -helps preserve proper cell volume
     -action:
      pumps 3 Na+ out of cell
      pumps 2 K+ into cell
      (if you understand what the pump does it will help you  understand nerve physiology)

III. Membrane Potentials
 A.  What is membrane potential?
  1.  What cells possess a membrane potential?
   -all cells
  2.  What is a potential?
   -separation of opposite charges
    analagous to stretching a rubber band--these charges want to come together, but holding them  apart leads to energy which can be      released
   -cells have more positive charges outside and more negative charges inside
 

  3.  How is membrane potential measured?
   -placement of microelectrodes on inside and outside of cell to measure voltage.  Reported as charge inside cell (always negative).

B.  How is resting membrane potential established and  maintained?
  Concentration and permeability of ions in ICF and ECF
  -Main ions which contribute to membrane potential are:     Na+, K+, and large negatively charged anions.
  -Their relative concentrations and membrane permeability determine membrane potential.
   *Relative permeability is determined by the leak channels present and passage of ions through them

  ION  ECF        ICF               Relative Permeability
  Na+  150 mM 15 mM                          1
  K+  5 mM        150 mM                     50-75
  Anions- 0           65                                0

  -Concentration gradients of Na and K are maintained by activity of ATPase pump.

OUBAIN--rat poison, destroys the activity of the pump.     What would this do to RMP?

C.  Potentials in Excitable Cells
 Excitable cells
  muscle, neurons, heart

D.  Structure of a neuron

   dendrite
   cell body (soma)
   axon
   axon hillock
   synapse
   neuron 2
E.   Graded Potentials- one of 2 kinds of potentials found in excitable cells such as neurons
 1.  Characteristics of graded potentials
  a. Graded means that strength of response depends on stimulus intensity
  b.  Graded potentials are initiated in either the dendrites or cell body and are responses to such things as sensory receptor activation or may be     generated postsynpatically
  c. Summation of graded potentials at axon hillock may result in an action potential

F.  Action Potentials
 1.  Components
  a.  Resting membrane potential (polarization of charges with typical nerve at -70mV).
  b.  Depolarization--the membrane potential is reduced i.e. less separation of charges until the     separation of charge is reversed, with the inside of     the cell more positive than the outside of the cell.
  c.  Repolarization--the membrane potential returns     to resting potential
  d.  Hyperpolarization--the potential is even greater     than at rest.

 2.  Physiological events leading to components of action     potential
  a.  Triggering stimulus is a change in voltage at the axon    hillock.  Stimulus results from input to neuron such as    firing of synapses. If depolarization exceeds a “threshold”    potential, an action potential will be generated.
   -typical threshold is -55 to -50 mV
   -an AP is an all-or-none phenomenon.  Whether the     triggering depolarization is only a little greater than     threshold or a lot more than threshold, the same     action potential will be generated.

  b. Q: Why does a super-threshold depolarization generate    an action potential?
 
 
 

       A: Voltage-gated sodium channels open

   -At RMP, most Na+ channels are closed
   -Depolarization of the membrane changes the     conformation of the Na+ channel in such a way that     a gate opens, allowing Na+ to diffuse into the cell     (down concentration gradient)
   -As Na+ diffuses into cell, the membrane      depolarizes further, which causes more voltage-    gated sodium channels to open.
   -A positive feedback loop is quickly generated which    allows very rapid influx of sodium through open     channels.
  c.  What stops Na+ influx?
   Inactivation gate swings shut
   Eventaully Na+ channels will return to a state during    which they are closed, but capable of opening
  d.  Q:  What causes repolarization?
         A:  Voltage-gated potassium channels open
    The same initial depolarization causes K+      channels to open--it just takes longer
    When K+ channels open, get K+ efflux
  e.  Q:  What causes hyperpolarization
   --excess K+ efflux, drawing too much + charge out     of cell
  f.  Only a relatively small percentage of the total     concentration of either Na+ or K+ ions diffuses during an    AP.  Initial concentrations are restored by the Na+/K+-   ATPase pump.
 

 
 Diagram AP and show events
 
 
 
 
 
 
 
 
 

 3.  Refractory Periods
  a.  Absolute refractory period
   -Period of time during which a patch of membrane     cannot be stimulated to undergo another action     potential
   -Why?  Occurs during action potential when Na+     channels cannot be opened.  i.e. Na+ channels must    be reset in order to undergo another A.P.
 

   Show on AP diagram when this is occurring

  b. Relative Refractory period
   -A second action potential can be produced but it     requires a stronger stimulus
   -Occurs during hyperpolarization.  Potential is      further from theshold, so greater stimulation is     required to exceed threshold potential
 

 3.  Effects of hyperkalemia/hypokalemia on generation of action   potentials

   -What is hyperkalemia?
    *elevated K+ in blood
   -What effect would it have on RMP?
    *would result in a less negative RMP
   -What effect would this have on generation of an     AP?
    *less stimulus required to exceed threshold,      leading to hyperexcitability of neurons

   -Hypokalemia example  (reason for Gatorade)

 D.  Conduction of action potential throughout cell
  1.   Origin of AP=axon hillock
   Direction of flow=down the axon to the axon      terminals where synapse is located

  2.  How does the A.P. travel?
   a. Flow of current
    -attraction of + and - charges causes       movement of + charges within neuron to      adjacent area
    -each adjacent area undergoes an A.P. as      depolarization of new patch of membrane      exceeds threshold and results in a new A.P.
   b. Fiber Types
    Myelinated vs. unmyelinated
    -what does saltatory mean?  jumping
    -myelin is a lipid sheath secreted by Schwann      cells and oligodendrocyte cells which insulates     the membrane.  Myelin prevents diffusion of      ions across neuron membrane.
    -Between areas of myelination        are unmyelinated areas known as the Nodes      of Ranvier.  Nodes of Ranvier contain many      voltage-gated Na+ and K+ channels.
    -Nodes of Ranvier are located close enough to     each other that the + charges can actually      jump from one Node to another and induce an     A.P. at each Node
    -much quicker than having to induce an AP      every step of the way

IV.  Synaptic Transmission
 A.   Synaptic structure
 Presynaptic axon terminal
 Postsynaptic neuron
 Synaptic knob--contains neurotransmitter vesicles
 Synaptic cleft
 Subsynaptic membrane -- contains neurotransmitter receptors
  (chemical gated ion channels, or ion channels opened by    NT’s)

 B.  Events in Synaptic Conduction
 1.   Propagation of AP to axon terminal
 2.  Opening of voltage-gated Ca++ channels in synaptic    knob, with Ca++ influx
 3. Ca++ influx causes exocytosis of vesicles containing    neurotransmitters with release of neurotransmitters into    the synaptic cleft
 4. Binding of NT to receptors on subsynaptic membrane
 5. Opening of chemical-gated ion channels
 6. Removal of neurotransmitter
  1.  Inactivation by enzymes  in subsynaptic membrane    (e.g. acetylcholinesterase)
  2.  Re-uptake into axon terminal where it can be: stored &    recycled or degraded in axon terminal

C.  Types of Synapses
 1.  Excitatory
  -NT binding results in opening of both Na+ and K+     channels.
  - More Na+ will enter cells because both       concentration and electrical gradient favor the movement.    Less K+ will rush out because it moves only because of    concentration gradient.
  -Results in slight depolarization of neuron known as     excitatory post synaptic potential or EPSP
  -More than one EPSP must usually sum to exceed     threshold for the postsynaptic neuron to undergo an AP
 2.  Inhibitory
  -NT binding results in opening of either K+ or Cl-     channels, leading to slight hyperpolarization
  -hyperpolarization is IPSP
  -neuron is further away from threshold, so an AP is less
   likely

D.  Neuronal Integration
 1.  Convergence
  a.  Many axons converging on a single postsynaptic     neuron
  b.  All EPSP’s and IPSP’s occurring on the same neuron    during a window of time must be sufficient to generate a    greater than threshold depolarization to induce an action    potential in the postsynaptic neuron.  Multiple EPSP’s can    add (summation) while IPSP’s and EPSP’s can cancel    each other out
   -Draw diagram

 2.  Divergence
 
 
 
 

 E.  Summation
 -possible because postsynaptic potentials are graded  potentials
 -Grand post-synaptic
  1  Temporal summation
   -occurs when a neuron fires with several EPSP’s in     rapid succession, so that each EPSP adds on to     further depolarize membrane.  More NT released by    a single neuron in a time period due to successive     AP’s arriving at presynaptic knob.  More NT leads to     more open channels, leading to greater       depolarization.
  2.  Spatial summation
   -occurs when different neurons converging on the     postsynaptic neuron fire simulataneously

 F.  Neurotransmitters
  1.  Classical Neurotransmitters
   a.  Characteristics
   -small, often a single amino acid
   -generate rapid brief response on membrane      potential by either directly opening chemical-gated     channels or by opening channel via a 2nd      messenger
   -act by binding receptor on subsynaptic membrane
    -Examples:
   -acetylcholine
   -epinephrine
   -norepinephrine
   -dopamine
   -serotonin
  2.  Neuropeptides
   a. Characteristics
   -larger (2-40 amino acids in length)
   -act mainly as neuromodulators to do things such as    increase/decrease neurotransmitter synthesis or     increase/decrease NT receptors
   -slow, prolonged responses
   -may act on presynaptic or postsynaptic cell
   -Examples: VIP, NPY
  3.  Effect of neurotransmitter binding to receptor is to    induce a graded potential which depends on amount of    NT and other characteristics of synapse such as number    of NT-R
 
 

 G.  Pathophysiology and Effect of Drugs on Synapses
  1.  Cocaine
   -re-uptake inhibitor for NT dopamine
   What does this mean?
   Dopamine responsive nerves involved in “pleasure”     pathways; thus sensation is extremely pleasureable

  2.  Prozac (antidepressant)
   -blocks re-uptake of serotonin

  3.  Parkinson’s Disease
   -loss of dopaminergic neurons which act on basal     nuclei neurons which in turn inhibit muscle tone
   -disinhibition of muscle tone--tremors

  4.  Strychnine
   -receptor antagonist for glycine receptors
   -normally glycine generates IPSP’s which inhibit     muscle tone--convulsions, death
 

  5.  Tetanus toxin
   -inhibits release mechanisms for GABA (gamma     amino butyric acid)
   -GABA also a muscle inhibitor-muscle rigidity, death
 
 

 V.  Organization of the Nervous System
  A.  Central Nervous System (brain, spinal cord)
  B.  Peripheral Nervous System
   1.  Afferent division--carries info to the CNS
   -sensory information
   -information about internal environment (e.g. BP     receptors)
   2.  Efferent division--carries info from CNS to      periphery
   a.  Somatic nervous system
    -motor neurons innervating skeletal muscle
   b.  Autonomic nervous system
    -neurons innervating smooth muscle, cardiac      muscle & glands
    i.  Sympathetic nervous system-predominates       in fight or flight situations
    ii.  Parasympathetic nervous system-      predominates in relaxed situations

  C.  Types of Neurons
   1.   Afferent-specialized structure with sensory     receptor located at one end and axon at other end.      No dendrites and no presynaptic inputs
   2.  Efferent neurons-many pre-synaptic inputs
   3.  Interneurons-lie completely within CNS
    -act to connect afferent and efferent neurons
    -function to increase complexity of such things     as thought, emotion, etc.

VI.  Afferent Division
 A.  Afferent Receptors
  1.  Receptor types:
   -photoreceptors
   -mechanoreceptors (stretch, pressure, bending)
   -thermoreceptors
   -osmoreceptors/chemoreceptors
   -nociceptors
  2.  Transduction of stimulus
   a.  stimulation of receptor leads either to:
    i.  direct opening of ion channels
    e.g. mechanical distortion of some        pressure receptors distorts channels in       a way which allows Na+ influx
    ii. activation of afferent receptor causes       release of chemical messenger which opens     chemical-gated channels

  Why do local anesthetics work?  e.g. procaine, novacaine,   lidocaine, etc.  They act on activation gates of sodium    channel, making them recalcitrant to opening

 B.  Example of an afferent pathway-the pain pathway
  1.  Types of pain receptors
   -mechanical (cutting, pinching, pressure)
   -thermal (extreme heat, cold)
   -polymodal (all types of damage, including      chemicals released during injury)
 
  2.  Types of afferent pain fibers
   a.  A Delta fibers
    -specific for mechanical and thermal       nociceptors
    -fast pain pathway
    -via myelinated fibers
   b.  C fibers
    -polymodal receptors
    -small, unmyelinated fibers
    -may be activated by chemicals released      during tissue injury such as bradykinin,       prostaglandins, etc.
    -prolonged presence of chemical leads to      longer duration of pain
    Many analgesics such as aspirin, are       prostaglandin synthesis inhibitors
  3.  Pathway
   a.  Stimulus acts on naked nerve endings of afferent      neuron
   b.  membrane depolarizes and A.P’s are propagated    to the terminals in the spinal cord
   c.  Substance P released from afferent axon      terminal (presynaptic fiber)
   d.  Interneurons carry A.P.’s to the somatosensory     area of cerebral cortex (pain is localized to specific     area of body) and to the thalamus and reticular     formation (where pain is perceived)
  4.  Endogenous Analgesic System
   a. modification of pain through release of natural     opiates (endorphins, enkephalins and dynorphin)
   b.  opiates bind to afferent fiber and inhibit release of    Substance P
 
 
 

VII.  Efferent Division
 A. Autonomic Nervous System
  1.  General Pathway
   a.  2 neuron chains, first has cell body in CNS with its    axon forming the pre-ganglionic fiber
   b.  Synapse of pre-ganglionic fiber on 2nd neuron     occurs within the ganglion (a group of cell bodies of     neurons)
   c. Second neuron is the post-ganglionic fiber which     synapses on effector organ (smooth muscle, gland,     cardiac muscle)
  2.  Sympathetic Division
   -preganglionic fibers arise in thoracic and lumbar     regions of the spine
   -preganglionic fibers release the NT acetylcholine
   -ACh binds to nicotinic ACh receptors
   -special sympathetic path
    preganglionic fiber synapses on adrenal      medulla which releases neurotransmitters into     the blood in response
   -postganglionic fibers release epi/norepi at effector     organ
   -Epi/norepi bind to either alpha adrenergic or beta     adrenergic receptors
  3. Parasympathetic Division
   -preganglionic fibers arise in cranial and sacral     regionsof spine
   -preganglionic fibers release acetylcholine which     binds to nicotinic ACh receptors
   -postganglionic fibers also release acetylcholine     which binds to muscarinic receptors on target      organs
 
 
 
 
 
 
 
 
 
 

SUMMARY PICTURE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  4.  General Functions/Characteristics of the Autonomic    Nervous System
   a.  Governs involuntary, visceral organ activities
   b.  Most target organs are innervated by both      sympathetic and parasympathetic fibers which often    have opposing actions on a given gland
    e.g. lungs under sympathetic dominance have     bronchodilation and bronchoconstriction      under parasympathetic dominance
    e.g. Sympathetic increases HR;        parasympathetic decreases HR
   c.  Specific Organs and Effects of Sympathetic/      Parasympathetic Dominance
 
    -Heart Sympathetic increases HR, increases      force of contraction, increases dilation of      coronary blood vessels

    -Blood vessels, strictly have sympathetic      innervation and causes constriction of vessels     to skin, viscera

    -G.I. System
     Sympathetic decreases digestive activity      but increases motility of system
     Parasympathetic increases digestion

    -Sweat glands
     Sympathetic stimulates secretion of       sweat glands and apocrine glands

    -Eye
     Sympathetic--dilation of pupil
     Parasympathetic constricts pupil

VIII.  Neuromuscular Junction
 A.  Neuromuscular jxn synapse
  -releases acetylcholine
 

 B.  Types of muscle & characteristics
 
 C.  Structure of skeletal muscle
  1.  muscle>muscle fiber (cell)>myofibrils>thick and thin    filaments>proteins>subunits
  2.  Thick filament
   -myosin with globular head which contacts actin on     thin filament
  3.  Thin filament
   a.  actin, binds to myosin to form cross bridges for      contraction
   b.  tropomyosin, covers the myosin binding site on      actin
   c.  troponin, anchors tropomyosin in place covering      the myosin binding site (at rest)
 
 D.   Action on skeletal muscle
 
  1.  depolarization of muscle membrane causes release of     Ca++ from SR (specialized organelle in muscle     which stores calcium)
  2.  Calcium in cytoplasm can bind to troponin
  3.  Binding of calcium to troponin causes physical shift in    tropomyosin to uncover actin’s myosin binding site
  4.  Actin and myosin can form crossbridges and muscle    contracts

 E.  Smooth muscle contraction
  1.  Calcium influx results in a cascade of biochemical    events resulting in actin-myosin crossbridging

 F.  Some neuromuscular diseases:
  1.  Guillain Barre syndrome
   -demyelination of neurons causing muscular      weakness (slow conduction of action potentials)
   -immune destruction frequently following respiratory     infection

  2.  Myasthenia gravis
   -autoimmune antibodies against ACh-R
   -treatment with neostigmine
    an acetylcholinesterase inhibitor, why?