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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 7 th July 6 th = Monday Office hours

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neuroscience

Neuroscience

Crystal Sigulinsky

Neuroscience Graduate Program

University of Utah

crystal.cornett@utah.edu

housekeeping notes
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
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

neuroscience4
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
Objectives
  • Basic Anatomy of the Nervous System
    • Organization
    • Cells
  • Neurons
    • Structure
    • Mechanism of function
      • Modeling neurons
  • Neurodegenerative Diseases
nervous system
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
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

nervous system anatomy cells
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
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/File:Smi32neuron.jpg

http://en.wikipedia.org/wiki/Neuron

neurons11
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_Ram%C3%B3n_y_Cajal

neuron structure
Neuron: Structure

Axon

Axon hillock

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

neuron structure function
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/File:Neuron-no_labels2.png

slide14
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
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/File:Neuron-no_labels2.png

how do neurons work
How do neurons work?
  • Function
    • Receive, process, and transmit information
  • Signals
    • Chemical
    • Electrical
bioelectricity
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

bioelectricity18
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

bioelectricity19
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 work20
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
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
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
nernst equation
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
[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

Ion Distributions

Cell Membrane

Cytoplasm

Extracellular Fluid

-

-

-

-

-

-

-

-

+

+

+

+

+

+

+

+

driving forces25
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
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
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 signals28
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
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/File:Synapse_Illustration2_tweaked.svg

electric signals30
Electric Signals
  • Deviation in the membrane potential of the cell
  • Spread according to different mechanisms
    • Electrotonic conduction
      • Dendrites
    • Action Potential
      • Axons
neuron structure31
Neuron: Structure

Axon

Axon hillock

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

electrotonic conduction

x = 0

Change in Potential

Distance (x)

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+

electrotonic conduction33
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
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

Axon hillock

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/File:Neuron-no_labels2.png

http://en.wikipedia.org/wiki/File:Action_potential_vert.png

action potentials
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/File:Action_potential_vert.png

Figure: Ion channel openings during action potential

http://faculty.washington.edu/chudler/ap.html

action potential propagation
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 information38
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/File:Synapse_Illustration2_tweaked.svg

modeling neurons

+

+

i

Battery

Resistor

-

+

-

+

-

+

-

+

Capacitor

Modeling Neurons
  • Neurons are electrically active
  • Model as an electrical circuit
    • Battery
      • Current (i) generator
    • Resistor
    • Capacitor
membranes as capacitors
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
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
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
Neuron modeled as an Electrical Circuit

Ion pump

Created by Behrang Amini

http://en.wikipedia.org/wiki/File:Hodgkin-Huxley.jpg

cable equation
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
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
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
passive electrical properties
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 properties48
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 properties49
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 properties50
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
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 velocity52
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
Myelin
  • Lipid-rich substance
  • Produced by Schwann cells and Oligodendrocytes that wrap around axons
  • Gaps between = Nodes of Ranvier

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

action potential propagation54
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
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”

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

Multiple Sclerosis
nervous system anatomy gross organization57
Nervous System Anatomy: Gross Organization
  • Innervates every part of the body
  • Hierarchical organization

http://en.wikipedia.org/wiki/File:Nervous_system_diagram.png

nervous system anatomy gross organization59
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
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
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
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
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