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					Neuroscience
    Crystal Sigulinsky
 Neuroscience Graduate Program
       University of Utah
    crystal.cornett@utah.edu
Housekeeping Notes

   Posting lectures online
   Writing Assignment
     Listed as #4 due Monday July 7th
     July 6th = Monday

   Office hours
     Friday,July 3rd, 5-6 pm, Moran Eye Center 3rd floor lobby
     By appointment

   Test
     Friday,   July 10th
Physics in
Visual Processes

   Imaging in the eye
     Optics

   Absorption of light in
    the eye
     Quantum   mechanics
   Nerve conduction
   Visual Information
    Processing
                             http://en.wikipedia.org/wiki/File:Gray722.png
                             Gray's Anatomy of the Human Body, 1918
Neuroscience

   Scientific study of the
    nervous system
   Highly interdisciplinary
       Structure/function
       Development/Evolution
       Genetics
       Biochemistry
       Physics
       Physiology
       Pathology
       Informatics/Computational

                                    http://en.wikipedia.org/wiki/Image:Sagittal_brain_MRI.JPG
Objectives

   Basic Anatomy of the Nervous System
     Organization
     Cells

   Neurons
     Structure
     Mechanism     of function
          Modeling neurons
   Neurodegenerative Diseases
Nervous System

   Multicellular organisms
   Specialized cells
   Complex information processing system
       Innervates the entire body
       Substrate for thought and function
       Gathers information
            External = Organism’s environment
            Internal = Organism’s self
       Processing
       Response initiated
            Perception
            Muscle activity
            Hormonal change
Nervous System Anatomy:
Gross Organization
   Central Nervous System (CNS)
       Brain
       Spinal cord
   Peripheral Nervous System
    (PNS)
       Cranial and spinal nerves
       Motor and sensory
       Somatic NS
            “Conscious control”
       Autonomic NS
            “Unconscious control”


                                     http://en.wikipedia.org/wiki/File:Nervous_system_diagram.png
http://en.wikipedia.org/wiki/File:NSdiagram.png
Nervous System Anatomy:
Cells

   Neurons (Nerve Cells)
     Receive,   process, and transmit information


   Glia
     Not specialized for information transfer
     Primarily a supportive role for neurons
  Neurons




Wei-Chung Allen Lee, Hayden Huang, Guoping Feng,            http://en.wikipedia.org/wiki/File:Smi32neuron.jpg
Joshua R. Sanes, Emery N. Brown, Peter T. So, Elly Nedivi
                                                            http://en.wikipedia.org/wiki/Neuron
Neurons

   Neuron Doctrine
     Santiago Ramon    y Cajal,
      1891
     The neuron is the                   Above: sparrow optic tectum
      functional unit of the              Below: chick cerebellum
      nervous system
   Specialized cell type
     Very diverse in structure
      and function
     Sensory, interneurons,
      and motor neurons
                                   http://en.wikipedia.org/wiki/Santiago_Ram%C3%B3n_y_Cajal
Neuron: Structure




                  Axon




        Axon hillock

                       http://en.wikipedia.org/wiki/File:Neuron-no_labels2.png
Neuron: Structure/Function

   Specially designed to
    receive, process, and
    transmit information
       Dendrites: receive information
        from other neurons
       Soma: “cell body,” contains
        necessary cellular machinery,                     Axon hillock
        signals integrated prior to
        axon hillock
       Axon: transmits information
        to other cells (neurons,
        muscles, glands)
                                         http://en.wikipedia.org/wiki/File:Neuron-no_labels2.png
   Polarized
       Information travels in one
        direction
            Dendrite → soma → axon
Glia

   Major cell type of the Nervous System
     ~10X   as many glia as neurons
   Not designed to receive and transmit information
     Do   influence information transfer by neurons
   Glia = “Glue” (Greek)
   Support neurons
     Maintain a proper environment
        Supply oxygen and nutrients
        Clear debris and pathogens

     Guide development
     Modulate neurotransmission
        Myelination
Glia: Types

   Macroglia                       http://en.wikipedia.org/wiki/File:Neuron-no_labels2.png

     Astrocytes
        Regulate microenvironment in CNS
        Form Blood-Brain Barrier

     Oligodendrocytes
          Myelinate axons of the CNS
     Schwann     Cells
          Myelinate axons of the PNS
   Microglia
     Clean   up in the CNS
How do neurons work?

   Function
     Receive,   process, and transmit information
   Signals
     Chemical
     Electrical
 Bioelectricity

  Electric current generated by living tissue
  History

       Electric Rays (Torpedos)                                             Electric Eels




http://en.wikipedia.org/wiki/File:Torpedo_fuscomaculata2.jpg   http://en.wikipedia.org/wiki/File:Electric-eel2.jpg
Bioelectricity

 Electric current generated by living tissue
 History
     Electric
             fish
     "Animal electricity”
        Luigi Galvani, 1786
        Role in muscle activity

        Inspiration behind Volta’s

         development of the battery
                                      http://en.wikipedia.org/wiki/File:Galvani-frog-legs.PNG
Bioelectricity

   Electric current generated by living tissues
     Motion   of positive and negative ions in the body
   Essential for cellular and bodily functions
     Storage of  metabolic energy
     Performing work
     Cell-cell signaling
     Sensation
     Muscle control
     Hormonal balance
     Cognition
   Important Diagnostic Tool
How do neurons work?

   Function
     Receive, process, and transmit information
     Unidirectional information transfer

   Signals
     Chemical
     Electrical



   What is the electrical state of a cell?
Membrane Potential

   Difference in electrical potential across cell membrane
   Generated in all cells
   Produced by separation of charges across cell membrane
       Ion solutions
            Extracellular fluid
            Cytoplasm
       Cell membrane
            Impermeable barrier
       Ion channels
            Permit passage of ions through cell membrane
            Passive (leaky channels) = with gradient
            Active = against gradient
   Resting membrane potential
       KCl Simple Model
Driving Forces

   Chemical driving force
     Fick’sFirst Law of Diffusion
     Species move from region of high concentration to
      low concentration until equilibrium
     Passive mechanism
   Electrical driving force
     Charged  species in an electric field move
      according to charge
     Passive mechanism
Nernst Equation

   Calculates the equilibrium potential for each
    ion



    R  = gas constant, T = temperature, F = Faraday
      constant, z = charge of the ion
     Assumptions:
        Membrane is permeable to ion
        Ion is present on both sides of membrane
Ion Distributions

              Cell Membrane
Cytoplasm           -   +       Extracellular Fluid
                    -   +
   [Na+] = 15 mM              [Na+] = 145 mM
                    -   +
   [K+] = 150 mM   -   +
                               [K+] = 5 mM
                    -   +      [A+] = 5 mM
   [Cl-] = 9 mM    -   +      [Cl-] = 125 mM
                    -   +
   [A-] = 156 mM              [A-] = 30 mM
                    -   +
Driving Forces

   Chemical driving force
       Fick’s First Law of Diffusion
       Species move from region of high concentration to low concentration
        until equilibrium
       Passive mechanism
   Electrical driving force
       Charged species in an electric field move according to charge
       Passive mechanism
   Na+/K+ pump
       Active transport pump
            3Na+ out of cell
            2 K+ into cell
       Aids to set up and maintain initial concentration gradients
Resting Membrane Potential

   Actually 4 ions (K+, Na+,Cl-, Ca2+) that strongly influence potential
   Goldman-Hodgkin-Katz Equation
        Takes into account all ionic species and calculates the membrane potential



             P = permeability
                   Proportional to number of ion channels allowing passage of the ion
             Not specific to the resting membrane potential
             Can replace p with conductance (G) and [ion]in/[ion]out with Eion
        Greater the membrane permeability = greater influence on membrane potential
   Permeability: PK: PNa: PCl = 1 : 0.04 : 0.45
        Cl- typically not pumped, so at equilibrium
        K+ dominates because greatest conductance
        Resting membrane potential usually very negative -70 mV
Electric Signals

   Deviation in the membrane potential of the cell
       Depolarization
            Reduction of charge separation across membrane
            Less negative membrane potential
       Hyperpolarization
            Increase in charge separation across membrane
            More negative membrane potential
   Cause: Ion channels open/close
       Large change in permeability of ions relative to each other
       Negligible change in bulk ion concentrations!
       Induce changes in net separation of charge across cell membrane

       Goldman equation only applies to steady state
Electric Signals

   Initiated by discrete events
     Sensory    neurons
          Examples:
             Vision: photoreceptors - absorb light triggering a chemical
              signaling cascade that opens voltage-gated ion channels
             Touch: mechanoreceptors - mechanical pressure or distortion
              opens stress-gated voltage channels
     Neuron-neuron,        neuron-muscle, neuron-gland
          Chemical signals open ligand-gated ion channels at the
           Synapse
Synapse

   Functional
    connections
    between neurons
       Mediates transfer of
        information
       Allows for
        information
        processing
   Axon terminal
    “talks to” dendrite
    of another neuron
                               http://en.wikipedia.org/wiki/File:Synapse_Illustration2_tweaked.svg
       Neurotransmitters
        activate ligand-
        gated ion channels
Electric Signals

 Deviation in the membrane potential of the cell
 Spread according to different mechanisms
     Electrotonic conduction
          Dendrites
     Action   Potential
          Axons
Neuron: Structure




                  Axon




        Axon hillock

                       http://en.wikipedia.org/wiki/File:Neuron-no_labels2.png
Electrotonic Conduction

   Passive spread of electrical potential
                                                                           Na+
   Induced point increase in ion concentration
        Na+ channels opened
             Na+ flows into cell
             Membrane potential shifts
              toward Na+ equilibrium
              potential (positive)
                   Depolarization
   Diffusion of ions




                                                   Change in Potential
        Chemical gradient
        Charge (electrical)                                                x=0
         gradient
   Potential dissipates as distance from source
    increases
                                                                         Distance (x)
Electrotonic Conduction

   Potential dissipates as distance from source
    increases
     “GradedPotentials”
     Summation
          Spatially
               Multiple sources of ion flux at different locations
          Temporally
               Repeated instances of ion flux at same location
          Allows for information processing
Processing

                                       http://en.wikipedia.org/wiki/File:Neuron-no_labels2.png


   A single neuron receives inputs from many
    other neurons
     Input   locations
        Dendrites – principle site
        Soma – low occurance

     Inputs   converge as they travel through the neuron
          Changes in membrane potential sum temporally and
           spatially
Transmitting Information

    Signal inputs do not always elicit an output signal
       Change in membrane potential must exceed the threshold potential for an action potential
        to be produced
       Mylenated axons
                Axon hillock = trigger zone for axon potential
          Unmyelenated axons
                Action potentials can be triggered anywhere along axon




                       Axon
                       hillock




http://en.wikipedia.org/wiki/File:Neuron-no_labels2.png
                                                                  http://en.wikipedia.org/wiki/File:Action_potential_vert.png
Action Potentials

   “All-or-none” principle
      Sufficient increase in
       membrane potential at the
       axon hillock opens voltage-           http://en.wikipedia.org/wiki/File:Action_potential_vert.png
       gated Na+ channels
      Na+ influx further increases
       membrane potential, opening
       more Na+ channels
      Establishes a positive
       feedback loop
             Ensures that all action
              potentials are the SAME size                Figure: Ion channel openings
        Also, complete potential is                      during action potential
         regenerated each time, so does
         not fade out
   Turned off by opening of
    voltage gated K+ channels

                                                       http://faculty.washington.edu/chudler/ap.html
Action Potential Propagation

   Velocity
     Action potential in one region of axon provides
      depolarization current for adjacent region
        Passive spread of depolarization is not instantaneous
        Electrotonic conduction is rate-limiting factor

   Unidirectional
     Voltage    gated channels take time to recover
          Cannot reopen for a set amount of time, ensuring signal
           travels in one direction
Transmitting Information

   Presynaptic action                          The Synapse
    potential causes a
    change in membrane
    polarization at the
    axon terminals
   Votage-modulated
    Ca2+ channels open
   Neurotransmitter is
    released
       Activates ligand-
        gated ion channels on
        dendrites of next cell   http://en.wikipedia.org/wiki/File:Synapse_Illustration2_tweaked.svg
Modeling Neurons

 Neurons are electrically active
 Model as an electrical circuit
     Battery
          Current (i) generator
     Resistor                          +
                                                           +
                                   Battery             i       Resistor
     Capacitor
                                               -   +
                                               -   +
                                               -   +
                                               -   +

                                             Capacitor
Membranes as Capacitors

   Capacitor
       Two conductors separated by
        an insulator
       Causes a separation of charge
            Positive charges accumulate
             on one side and negative
             charges on the other
   Plasma Membrane
       Lipid bilayer = insulator
       Separates electrolyte solutions
        = conductors

                                           http://en.wikipedia.org/wiki/File:NeuronCapacitanceRev.jpg
Ionic Gradients as Batteries

   Concentration of ions differ between inside the neuron and outside the
    neuron
        Additionally, Na+/K+ pump keeps these ions out of equilibrium
   Ion channels permeate the membrane
      Selective for passage of certain ions
      Vary in their permeability
      Always open to some degree = “leaky”
   Net Result: each ionic gradient acts as a battery
        Battery
             Source of electric potential
             An electromotive force generated by differences in chemical potentials
        Ionic battery
             Voltage created is essentially the electrical potential needed (equal and opposite) to
              cancel the diffusion potential of the ions so equal number of ions enter and leave the
              neuron
             Establish the resting membrane potential of the neuron
Ion Channels as Resistors

   Resistor
       Device that impedes current flow
            Generates resistance (R)
   Ion channels vary in their permeability
       “Leaky”
            Always permeable to some degree
       Permeability is proportional to conductivity
       Conductance (g) = 1/R
       Ion channels modeled as a battery plus a resistor
   Leak channels
       Linear conductance relationship, gL
   Voltage-gated channels
       Non-linear conductance relationship, gn(t,V)
Neuron modeled as an
Electrical Circuit




                                                               Ion pump




                     Created by Behrang Amini
        http://en.wikipedia.org/wiki/File:Hodgkin-Huxley.jpg
Cable Equation

   Describes the passive spread
    of voltage change in the
    membrane of dendrites and
    axons


       Time constant (τ)
            Capacitor takes time to
             rearrange charges
       Length constant (λ)
            Spread of voltage change
             inhibited by resistance of the
             cytoplasm (axial resistance)
            Spread of voltage limited by
             membrane resistance (leak
             channels)
                                          http://en.wikipedia.org/wiki/File:NeuronResistanceCapacitanceRev.jpg
Hodgkin-Huxley Model

   Describes how action potentials in neurons are
    initiated and propagated




                                           Nrets at en.wikipedia
                           http://en.wikipedia.org/wiki/File:MembraneCircuit.jpg
Neuron Design Objectives

   Maximize computing power
     Increaseneuron density
     Requires neurons be small

   Maximize response ability
     Minimize  response time to changes in environment
     Requires fast conduction velocities
Passive Electrical Properties

 Limitations to the design objectives
 Action potential generated in one segment
  provides depolarization current for adjacent
  segment
     Membrane     is a capacitor
         Takes time to move charges
     Rate
         of passive spread varies inversely with the
     product of axial resistance and capacitance
         = raCm
Passive Electrical Properties

   Membrane Capacitance (C)
       Limits the conduction velocity
            ΔV = Ic x Δt / C, where Ic = current flow across capacitor, t = time, and C
             = capacitance
            Takes time to unload the charge on a capacitor when changing potential.
       Function of surface area of plates (A), distance between plates (d) and
        insulator properties (ε)


       Lipid bilayer = great insulator properties and very thin = high
        capacitance
       Smaller neuron = smaller area = shorter time to change membrane
        potential = faster conduction velocity
Passive Electrical Properties

   Axial resistance (ra)
     Limits    conduction velocity
          Ohm’s Law: ΔV = I x ra
     ra   = ρ/πa2
          ρ = resistance of cytoplasm, a = cross-sectional area of
           process
     Increases  with decreasing axonal radius
     Larger axon = smaller axial resistance = larger
      current flow = shorter time to discharge the
      capacitor around axon = faster conduction velocity
Passive Electrical Properties

   Input resistance (Rin)
     Limits      the change in membrane potential
           Ohm’s Law: ΔV = I x Rin
     Rin   = Rm/4πa2
           Rm = specific membrane resistance
                 Function of ion channel density and their conductance
           Rin = function of Rm and cross sectional area of process
     Smaller  axon = fewer channels and smaller area = greater
      resistance = smaller current for a given membrane potential
      = longer time to discharge capacitor = slower conduction
      velocities
Increasing Conduction
Velocity

   Increase axon diameter
     Axial resistance decreases in proportion to square of axon
      diameter
     Capacitance increases in direct proportion to diameter
     Net effect
           Increased diameter reduces raCm
                 Increases rate of passive spread
     Giant axon of squid
        Axon diameter = 1 mm

     Limitations:
        Need to keep neurons small so can increase their numbers

        Energy cost also increases with larger axon diameter
Increasing Conduction
Velocity

   Myelination of axons
     Wrapping   of glial membranes around axons
     Increases the functional thickness of the axonal membrane
          100x thickness increase
          Decreases capacitance of the membrane



     Same   increase in axonal diameter by myelination produces
      larger decrease in raCm
          More effective increase of conduction velocity
Myelin


                       http://en.wikipedia.org/wiki/File:Neuron-no_labels2.png


 Lipid-rich substance
 Produced by Schwann cells and
  Oligodendrocytes that wrap around axons
 Gaps between = Nodes of Ranvier
    Action Potential Propagation

   Myelin decreases capacitance
        Depolarization current moves quickly
        Current flow not sufficient to discharge capacitance along entire length of axon
              Length > 1 m
   Myelin sheath interrupted every 1-2 mm
        Nodes of Ranvier
              Exposed bare membrane (~2 um)
                     Increases capacitance
                     Depolarization current slows
              High density of Na+ channels
                     Intense depolarization
                     Regenerates full depolarization of amplitude
                     Prevents action potential from dying out
   Saltatory Conduction
        Action potential “hops” from one node of Ranvier to the next, down the axon
              Fast in myelinated regions
              Slow in bare membrane regions
   Ion flow restricted to nodes of Ranvier
        Improves energy efficiency
              NS uses >20% of body’s metabolic energy!!
              High resistance of myelinated membrane reduces current leak
              Less work by Na+/K+ pump
Demyelination

   Loss of the myelin sheath that insulates axons
   Examples:
       Multiple sclerosis
       Acute disseminated encephalomyelitis
       Alexander’s Disease
       Transverse myelitis
       Chronic inflammatory demyelinating neuropathy
       Central pontine myelinosis
       Guillain-Barre Syndrome
   Result:
       Impaired or lost conduction
       Neuronal death
       Symptoms vary widely and depend on the collection of neurons
        affected
Multiple Sclerosis

   “multiple scars”                        Symptoms vary greatly
   Autoimmune condition                        Changes in sensation
       Immune system attacks CNS               Neuropathic pain
       Kills oligodendrocytes                  Muscle weakness, spasms, or
                                                 difficulty moving
   2-150 affected in 100,000                   Difficulty with coordination
    people                                       and balance
       More prevalent in women                 Speech, swallowing or visual
   Onset in young adults                        problems
   Physical and cognitive                      Fatigue
    symptoms                                    Cognitive impairment
       Arise from loss of myelination
        impairing axon conduction
       Start as discrete attacks
       Progress to chronic problems
Nervous System Anatomy:
Gross Organization
   Innervates every part of the
    body
   Hierarchical organization




                                   http://en.wikipedia.org/wiki/File:Nervous_system_diagram.png
http://en.wikipedia.org/wiki/File:NSdiagram.png
Nervous System Anatomy:
Gross Organization

   Information processing in the brain is highly parallel
   Localization of function
     Parallel streams   of information in separate tracts and nuclei
   Hierarchical processing scheme
     Information is relayed serially from one nucleus to the next
     Each nucleus performs a specific processing step
     More and more abstract information is extracted from the
      sensory inputs
Neuronal Death

 One of few non-regenerating cell populations
 Axons can re-grow if cell body survives
     Target–derived       neurotrophic signals
          Necessary for survival
     Barriers   to re-growth
        Scar tissue
        Absence of appropriate developmental guidance signals
             Loss of signal
             Switch in response to signal
Neurodegenerative Diseases

   Ataxia
     Conditions causing problems with movements
     Cerebellar ataxia
        Cerebellum affected – coordination of movements

     Sensory ataxia
        Dorsal columns affected – diminished sensitivity to joint and body
         part position
     Vestibular ataxia
        Vestibular system affected – disequilibrium and vertigo

   Dimentia
     Conditions affecting cognitive function
     Cortical or subcortical areas affected
Alzheimer’s Disease

   Most common type of dimentia
   Degenerative disease
   Terminal
   Symptoms vary
       Memory loss
            Particularly recent memories
       Confusion
       Anger
       Mood swings
       Language problems
       Long term memory loss
       Sufferer eventually withdraws as senses decline
   Associated with plaques and tangles in the brain
Parkinson’s Disease

   Common type of ataxia
   Degenerative, chronic and
    progressive
   Insufficient production of the
    neurotransmitter dopamine
        Reduced stimulation of the motor
         cortex by the basal ganglia
   Characteristic symptoms
      Muscle rigidity
      Tremor
      Slowing or loss of physical
       movement
      Eventually high level cognitive
       and language problems

                   http://en.wikipedia.org/wiki/File:Sir_William_Richard_Gowers_Parkinson_Disease_sketch_1886.jpg

				
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