Neuroscience

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

Housekeeping Notes

Posting lectures online Writing Assignment

as #4 due Monday July 7th July 6th = Monday
Listed

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

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 = Organisms environment Internal = Organisms 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
Unconscious control

Autonomic NS

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, 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

Neurons

Neuron Doctrine
Santiago

Ramon y Cajal,
Above: sparrow optic tectum Below: chick cerebellum

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

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, signals integrated prior to axon hillock Axon: transmits information to other cells (neurons, muscles, glands) Information travels in one direction

Axon hillock

Polarized

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

Dendrite soma axon

Glia

Major cell type of the Nervous System

~10X Do

as many glia as neurons

Not designed to receive and transmit information

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
Astrocytes

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

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

Bioelectricity

Electric current generated by living tissues

Motion Storage

of positive and negative ions in the body

Essential for cellular and bodily functions

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

Impermeable barrier

Cell membrane

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

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

Nernst Equation

Calculates the equilibrium potential for each ion

= 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 [K+] = 150 mM [Cl-] = 9 mM [A-] = 156 mM

+
+ +

[Na+] = 145 mM [K+] = 5 mM [A+] = 5 mM [Cl-] = 125 mM [A-] = 30 mM

Driving Forces

Chemical driving force

Ficks First Law of Diffusion Species move from region of high concentration to low concentration until equilibrium Passive mechanism Charged species in an electric field move according to charge Passive mechanism Active transport pump

Electrical driving force

Na+/K+ 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 Cl- typically not pumped, so at equilibrium K+ dominates because greatest conductance Resting membrane potential usually very negative -70 mV

Permeability: PK: PNa: PCl = 1 : 0.04 : 0.45

Electric Signals

Deviation in the membrane potential of the cell

Depolarization

Reduction of charge separation across membrane Less negative membrane potential Increase in charge separation across membrane More negative membrane potential

Hyperpolarization

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

Neurotransmitters activate ligandgated 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 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 Induced point increase in ion concentration

Na+

Na+ channels opened

Na+ flows into cell Membrane potential shifts toward Na+ equilibrium potential (positive)

Depolarization Change in Potential

Diffusion of ions

Chemical gradient Charge (electrical) gradient

x=0

Potential dissipates as distance from source increases

Distance (x)

Electrotonic Conduction

Potential dissipates as distance from source increases

Graded

Potentials Summation
Spatially

Multiple sources of ion flux at different locations Repeated instances of ion flux at same location

Temporally

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 voltagegated Na+ channels Na+ influx further increases membrane potential, opening more Na+ channels Establishes a positive feedback loop

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

Ensures that all action potentials are the SAME size

Also, complete potential is regenerated each time, so does not fade out

Figure: Ion channel openings during action potential

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 potential causes a change in membrane polarization at the axon terminals Votage-modulated Ca2+ channels open Neurotransmitter is released

The Synapse

Activates ligandgated 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

+ Battery
+ + + +

Resistor Capacitor

+ Resistor

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 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

Ionic battery

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 Linear conductance relationship, gL Non-linear conductance relationship, gn(t,V)

Leak channels

Voltage-gated channels

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 ()

Capacitor takes time to rearrange charges Spread of voltage change inhibited by resistance of the cytoplasm (axial resistance) Spread of voltage limited by membrane resistance (leak channels)

Length constant ()

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

Increase

neuron 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

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 ()

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

Ohms Law: V = I x ra = resistance of cytoplasm, a = cross-sectional area of process

ra

= /a2

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

Ohms Law: V = I x Rin

Rin

= Rm/4a2
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 Intense depolarization Regenerates full depolarization of amplitude Prevents action potential from dying out

High density of Na+ channels

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 bodys 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 Alexanders Disease Transverse myelitis Chronic inflammatory demyelinating neuropathy Central pontine myelinosis Guillain-Barre Syndrome Impaired or lost conduction Neuronal death Symptoms vary widely and depend on the collection of neurons affected

Result:

Multiple Sclerosis

multiple scars Autoimmune condition

Symptoms vary greatly

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

Changes in sensation Neuropathic pain Muscle weakness, spasms, or difficulty moving Difficulty with coordination and balance Speech, swallowing or visual problems Fatigue 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

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

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

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

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/File:Sir_William_Richard_Gowers_Parkinson_Disease_sketch_1886.jpg