Neuroscience

1
Neuroscience

• Crystal Sigulinsky
• Neuroscience Graduate Program
• University of Utah
• crystal.cornett_at_utah.edu

2
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

3
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/FileGray722.png Gray
's Anatomy of the Human Body, 1918
4
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/ImageSagittal_brain_
MRI.JPG
5
Objectives

• Basic Anatomy of the Nervous System
• Organization
• Cells
• Neurons
• Structure
• Mechanism of function
• Modeling neurons
• Neurodegenerative Diseases

6
Nervous System

• Multicellular organisms
• Specialized cells
• Complex information processing system
• Innervates the entire body
• Substrate for thought and function
• Gathers information
• External Organisms environment
• Internal Organisms self
• Processing
• Response initiated
• Perception
• Muscle activity
• Hormonal change

7
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/FileNervous_system_d
iagram.png
8
http//en.wikipedia.org/wiki/FileNSdiagram.png
9
Nervous System Anatomy Cells

• Neurons (Nerve Cells)
• Receive, process, and transmit information
• Glia
• Not specialized for information transfer
• Primarily a supportive role for neurons

10
Neurons
Wei-Chung Allen Lee, Hayden Huang, Guoping Feng,
Joshua R. Sanes, Emery N. Brown, Peter T. So,
Elly Nedivi
http//en.wikipedia.org/wiki/FileSmi32neuron.jpg
http//en.wikipedia.org/wiki/Neuron
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Neurons

• Neuron Doctrine
• Santiago Ramon y Cajal, 1891
• The neuron is the functional unit of the nervous
  system
• Specialized cell type
• Very diverse in structure and function
• Sensory, interneurons, and motor neurons

Above sparrow optic tectum Below chick
cerebellum
http//en.wikipedia.org/wiki/Santiago_RamC3B3n_y
_Cajal
12
Neuron Structure
Axon
Axon hillock
http//en.wikipedia.org/wiki/FileNeuron-no_labels
2.png
13
Neuron Structure/Function

• Specially designed to receive, process, and
  transmit information
• Dendrites receive information from other neurons
• Soma cell body, contains necessary cellular
  machinery, signals integrated prior to axon
  hillock
• Axon transmits information to other cells
  (neurons, muscles, glands)
• Polarized
• Information travels in one direction
• Dendrite ? soma ? axon

Axon hillock
http//en.wikipedia.org/wiki/FileNeuron-no_labels
2.png
14
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

15
Glia Types

• Macroglia
• 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

http//en.wikipedia.org/wiki/FileNeuron-no_labels
2.png
16
How do neurons work?

• Function
• Receive, process, and transmit information
• Signals
• Chemical
• Electrical

17
Bioelectricity

• Electric current generated by living tissue
• History

Electric Rays (Torpedos)
Electric Eels
http//en.wikipedia.org/wiki/FileTorpedo_fuscomac
ulata2.jpg
http//en.wikipedia.org/wiki/FileElectric-eel2.jp
g
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Bioelectricity

• Electric current generated by living tissue
• History
• Electric fish
• "Animal electricity
• Luigi Galvani, 1786
• Role in muscle activity
• Inspiration behind Voltas
• development of the battery

http//en.wikipedia.org/wiki/FileGalvani-frog-leg
s.PNG
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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

20
How do neurons work?

• Function
• Receive, process, and transmit information
• Unidirectional information transfer
• Signals
• Chemical
• Electrical
• What is the electrical state of a cell?

21
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

22
Driving Forces

• Chemical driving force
• Ficks 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

23
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

24
Ion Distributions
Cell Membrane
Cytoplasm
Extracellular Fluid
- - - - - - - -

• Na 15 mM
• K 150 mM
• Cl- 9 mM
• A- 156 mM

• Na 145 mM
• K 5 mM
• A 5 mM
• Cl- 125 mM
• A- 30 mM

25
Driving Forces

• Chemical driving force
• Ficks 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

26
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
  ionin/ionout 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

27
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

28
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

29
Synapse

• Functional connections between neurons
• Mediates transfer of information
• Allows for information processing
• Axon terminal talks to dendrite of another
  neuron
• Neurotransmitters activate ligand-gated ion
  channels

http//en.wikipedia.org/wiki/FileSynapse_Illustra
tion2_tweaked.svg
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Electric Signals

• Deviation in the membrane potential of the cell
• Spread according to different mechanisms
• Electrotonic conduction
• Dendrites
• Action Potential
• Axons

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Neuron Structure
Axon
Axon hillock
http//en.wikipedia.org/wiki/FileNeuron-no_labels
2.png
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Electrotonic Conduction

• Passive spread of electrical potential
• 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
• Chemical gradient
• Charge (electrical)
• gradient
• Potential dissipates as distance from source
  increases

Na
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Electrotonic Conduction

• Potential dissipates as distance from source
  increases
• Graded Potentials
• Summation
• Spatially
• Multiple sources of ion flux at different
  locations
• Temporally
• Repeated instances of ion flux at same location
• Allows for information processing

34
Processing
http//en.wikipedia.org/wiki/FileNeuron-no_labels
2.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

35
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

http//en.wikipedia.org/wiki/FileNeuron-no_labels
2.png
http//en.wikipedia.org/wiki/FileAction_potential
_vert.png
36
Action Potentials

• All-or-none principle
• Sufficient increase in membrane potential at the
  axon hillock opens voltage-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
• Also, complete potential is regenerated each
  time, so does not fade out
• Turned off by opening of voltage gated K channels

http//en.wikipedia.org/wiki/FileAction_potential
_vert.png
Figure Ion channel openings during action
potential
http//faculty.washington.edu/chudler/ap.html
37
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

38
Transmitting Information
The Synapse

• Presynaptic action 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/FileSynapse_Illustra
tion2_tweaked.svg
39
Modeling Neurons

• Neurons are electrically active
• Model as an electrical circuit
• Battery
• Current (i) generator
• Resistor
• Capacitor

40
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/FileNeuronCapacitanc
eRev.jpg
41
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

42
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)

43
Neuron modeled as an Electrical Circuit
Ion pump
Created by Behrang Amini http//en.wikipedia.org/
wiki/FileHodgkin-Huxley.jpg
44
Cable Equation

• Describes the passive spread of voltage change in
  the membrane of dendrites and axons
• Time constant (t)
• Capacitor takes time to rearrange charges
• Length constant (?)
• 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/FileNeuronResistance
CapacitanceRev.jpg
45
Hodgkin-Huxley Model

• Describes how action potentials in neurons are
  initiated and propagated

Nrets at en.wikipedia http//en.wikipedia.org/wiki
/FileMembraneCircuit.jpg
46
Neuron Design Objectives

• Maximize computing power
• Increase neuron density
• Requires neurons be small
• Maximize response ability
• Minimize response time to changes in environment
• Requires fast conduction velocities

47
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

48
Passive Electrical Properties

• Membrane Capacitance (C)
• Limits the conduction velocity
• ?V Ic x ?t / 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 (e)
• Lipid bilayer great insulator properties and
  very thin high capacitance
• Smaller neuron smaller area shorter time to
  change membrane potential faster conduction
  velocity

49
Passive Electrical Properties

• Axial resistance (ra)
• Limits conduction velocity
• Ohms Law ?V I x ra
• ra ?/pa2
• ? 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

50
Passive Electrical Properties

• Input resistance (Rin)
• Limits the change in membrane potential
• Ohms Law ?V I x Rin
• Rin Rm/4pa2
• 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

51
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

52
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

53
Myelin
http//en.wikipedia.org/wiki/FileNeuron-no_labels
2.png

• Lipid-rich substance
• Produced by Schwann cells and Oligodendrocytes
  that wrap around axons
• Gaps between Nodes of Ranvier

54
Action Potential Propagation

• Myelin decreases capacitance
• Depolarization current moves quickly
• Current flow not sufficient to discharge
  capacitance along entire length of axon
• Length gt 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

55
Demyelination

• Loss of the myelin sheath that insulates axons
• Examples
• Multiple sclerosis
• Acute disseminated encephalomyelitis
• Alexanders 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

56
Multiple Sclerosis

• multiple scars
• Autoimmune condition
• Immune system attacks CNS
• Kills oligodendrocytes
• 2-150 affected in 100,000 people
• More prevalent in women
• Onset in young adults
• Physical and cognitive symptoms
• Arise from loss of myelination impairing axon
  conduction
• Start as discrete attacks
• Progress to chronic problems

• Symptoms vary greatly
• Changes in sensation
• Neuropathic pain
• Muscle weakness, spasms, or difficulty moving
• Difficulty with coordination and balance
• Speech, swallowing or visual problems
• Fatigue
• Cognitive impairment

57
Nervous System Anatomy Gross Organization

• Innervates every part of the body
• Hierarchical organization

http//en.wikipedia.org/wiki/FileNervous_system_d
iagram.png
58
http//en.wikipedia.org/wiki/FileNSdiagram.png
59
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

60
Neuronal Death

• One of few non-regenerating cell populations
• Axons can re-grow if cell body survives
• Targetderived 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

61
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

62
Alzheimers 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

63
Parkinsons 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/FileSir_William_Rich
ard_Gowers_Parkinson_Disease_sketch_1886.jpg