Neuroscience

Neuroscience

Crystal SigulinskyNeuroscience Graduate Program

University of [email protected]

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

Processinghttp://en.wikipedia.org/wiki/File:Gray722.pngGray'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 SystemOrganizationCells

NeuronsStructureMechanism 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

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: Gross Organization

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

Nervous System Anatomy: Cells

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

GliaNot specialized for information transferPrimarily a supportive role for neurons

Neurons

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

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

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 neuronshttp://en.wikipedia.org/wiki/Santiago_Ram%C3%B3n_y_Cajal

Above: sparrow optic tectum

Below: chick cerebellum

Neuron: Structure

Axon hillock

Axon

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, 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


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

MacrogliaAstrocytes

Regulate microenvironment in CNS Form Blood-Brain Barrier

Oligodendrocytes Myelinate axons of the CNS

Schwann Cells Myelinate axons of the PNS

MicrogliaClean up in the CNS


How do neurons work?

Function Receive, process, and transmit information

SignalsChemical Electrical

Bioelectricity

Electric current generated by living tissue History

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

Electric Rays (Torpedos) Electric Eels

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 informationUnidirectional information transfer

SignalsChemical 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 forceFick’s First Law of Diffusion Species move from region of high concentration to

low concentration until equilibriumPassive mechanism

Electrical driving forceCharged species in an electric field move

according to chargePassive 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

[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

Cytoplasm Extracellular Fluid

Cell Membrane

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-

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-

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+

+

+

+

+

+

+

+

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 eventsSensory 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 Neurotransmitters

activate ligand-gated ion channels

http://en.wikipedia.org/wiki/File:Synapse_Illustration2_tweaked.svg

Electric Signals

Deviation in the membrane potential of the cell

Spread according to different mechanismsElectrotonic conduction

Dendrites

Action Potential Axons

Neuron: Structure

Axon hillock

Axon


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+

Cha

nge

in P

oten

tial

Distance (x)

x = 0

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

A single neuron receives inputs from many other neuronsInput 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:Action_potential_vert.png


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

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

Figure: Ion channel openings during action potential

Action Potential Propagation

VelocityAction 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 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

The Synapse

Modeling Neurons

Neurons are electrically active Model as an electrical circuit

Battery Current (i) generator

ResistorCapacitor

+

-

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+Battery

Capacitor

Resistori

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+ + + +

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.wikipediahttp://en.wikipedia.org/wiki/File:MembraneCircuit.jpg

Neuron Design Objectives

Maximize computing powerIncrease neuron densityRequires neurons be small

Maximize response abilityMinimize response time to changes in environmentRequires fast conduction velocities

Passive Electrical Properties

Limitations to the design objectives Action potential generated in one segment

provides depolarization current for adjacent segmentMembrane is a capacitor

Takes time to move charges

Rate of passive spread varies inversely with the product of axial resistance and capacitance

= raCm


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


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 radiusLarger axon = smaller axial resistance = larger

current flow = shorter time to discharge the capacitor around axon = faster conduction velocity


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

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” 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

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


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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