NESC 2570 Lecture Notes - Lecture 1: Molecular Motor, Santiago Ramón Y Cajal, Amyotrophic Lateral Sclerosis
27 Jun 2018
School
Department
Course
Professor
Monday, September 14th 2015
Levels of Analysis in Neuroscience
Atoms
○
Molecules (protein, DNA, etc.)
○
Individual Cells
○
Pairs of cells connected by synapses
○
Networks of interacting cells
○
Systems in the brain that regulate behavior
○
Behaving Animal
○
Groups of animals
○
Alzheimer's Disease
Neurodegenerative
Loss of short term memory, cognitive functions
○
Loss of neurons in specific brain areas (ex. Hippocampus, important for
memory formation)
○
○
More than 15,000 Nova Scotians are now living with Alzheimer's
○
50% of people over 85 develop Alzheimer's
○
Cost will increase 10 fold
○
Why do cells die?
Why are some cells not affected?
○
Prevention?
○
Cure?
○
○
Neurons
Functional unit of the nervous system
○
Most anatomically diverse cell in the body
Yet most neurons have a number of common features
○
○
Dendrites, Cell Body and Axons
All these different neurons from different areas of the nervous system still have
the three common features
○
Neuronal Diversity
Good understanding of neuronal diversity established by the early 20th century
○
Pioneering cell-staining method by introduced by Camillo Golgi and utilized by
S. Ramon Y Cajal
Gogi Stain: tissue washed with silver salts, a few neurons take up the silver
and are stained black (A and B)
○
Only one neuron out of every thousand or so will pick up the stain while
the others won't
Cajal thought that they were individual cell like other cells in the
body but Golgi didn't agree
○
○
More recently developed fluorescent dyes C can be injected into individual
neurons using specialized equipment
○
○
Dendrites and axons and synapses allow neurons to perform their principle
function
The structure is dictated by the function
○
The essence of nervous function is signaling (AKA information
transmission)
Intracellular Signaling: From one part of the cell to another
○
Intercellular Signaling: communication between cells
○
○
○
The Axon
Job is to take impulses from one area of your body to another
○
Tube like process exiting from the axon hillock on the soma
○
Transmits electrical signals rapidly along its length
○
Usually does no branch until it terminates at synaptic terminals
○
Axon's cytoskeleton is highly plastic during development (axonal path- finding)
and acts as a highway for molecular motors
○
The Synapse
Where pre-synaptic axon terminals (synaptic boutons) meet post synaptic
dendrites
○
The site of intercellular information transfer
○
Term "synapse" comes from the Greek word "connect"
Coined by Sir Charles Sherrington ~ 100 years ago
○
Hypothesized it's existence from spinal cord reflexes years before any
anatomical correlate
○
○
The Dendrites
Some dendritic trees can be highly branched
○
Usually acts as synaptic input site
Integrates information from other cells
○
○
Some dendrites have numerous finger-like projections called dendritic spines
Highly plastic structures
○
○
The source of neuronal diversity is not well understood
Thought to be at least partially under genetic control
○
○
Genes and the Brain
Genes, the nervous system and behaviour
Genes influence behaviour, but
Large gaps in our understanding of:
How genes influence nervous system
○
How neurons produce behaviour
○
How environment and genes interact to alter neuronal function
○
○
○
Brian gene interactions are difficult to understand because of the complexity of
the brain
1015 synapses in the neocortex
○
A typical neuron has ~5,000 -200,000 synapses
○
Thousands of different neuronal types
○
20,000-25,000 protein coding genes in human genome
○
Not all involved in brain function
○
○
○
Genes, the nervous system, and behaviour
Genetic control of neuronal structure/function is not straight forward
○
Ex. Complexity of the human brain probably results from extra genes unique to
humans, right?
Mice actually have a larger number of genes that humans
○
Only ~75 million neurons
○
Fewer synapses than in humans as well
○
○
Genes the nervous system, and behaviour
The number of genes in an organisms genome is not a good indicator of somatic
variability of the organisms nervous system
Various genetic mechanisms may increase diversity and complexity
○
Ex. Drosophila axon guidance receptor (DSCAM) undergoes alternate
spicing when the genes DNA is being transcribed to mRNA
Exons (expressed nucleotide sequences) can be retained, or spiced
out with introns c(intervening nucleotide sequences)
○
○
Creates receptor with 38,016 possible variants (double the number of
predicted genes in the entire genome)
○
○
Example: Fruitless Fruit Flies
Fruitless specifies sexually dimorphic neural circuitry in the Drosophila
brain
○
Brains of Drosophila are sexually dimorphic (different in males and
females)
○
Males: more neurons in optic lobe and more mAL neuron in the antennal
lobe
○
○
Fruitless gene produces protein called Fru
Fru is expressed in the mAL neurons of male, but not female fruit
flies
○
○
Adults
30 mAL neurons in males
○
5 mAL neurons in females
○
Male and female mAL neurons have different morphologies
○
○
Larva
About the same number of mAL cells
○
○
More mAL neurons die in females during prepupal development
○
Fru Function
Fru protein protects against cell death in males and directs neuronal
projection morphology
○
○
Mutate Fru gene
Changes conformation of the Fru protein- so the protien becomes
non functional
Fru mutant males now have ~5 mAL neurons
○
Neurons have female morphology
○
○
○
Male mAL neurons terminate in subesophageal ganglion
Thought to transmit pheromonal information from antennal lobe to
rest of the brain
○
○
Mutant males that lack funtioning Fru gene court both males and females,
suggesting an inability to recognize female pheromone due to loss of
proper mAL projections
○
Glia
Take up all the other matter that neurons don't
○
Glia outnumber neurons ~3-10:1
○
Three broad categories
Astroglia
○
Oligodendroglia
○
Microglia
○
○
Glial cells retain their ability to divide throughout life
○
Astrocytes
Star like structure
○
Maintain chemical homeostasis
○
Component of the blood brain barrier
Surround vascular endothelial cells
○
○
Provide structure/ scaffolding for other CNS components
○
Isolates and insulates neurons from each other
Ex. Astrocytes are involved in glutamate uptake
○
○
One astrocyte can interact with 2 million synapses and influence their function
○
○
Oligodendrocytes
Myelin produces cell in the CAN
A signal oligodendrocyte can provide 30-50 myelin internodes
○
○
Fewer cells processes than astrocytes
○
Poor regenerative capacity
○
Also supplies axons with fuel to support high metabolic activity
~20% of body's energy required to fuel the brain
○
ATP is generated by the breakdown of glucose to pyruvate then
lactate in process known as glycolysis
○
○
Oligodendrocytes release lactate too (astrocytes described 1st)
After myelin formation
○
Especially important for survival of motor neurons
○
○
○
Amyotrophic lateral sclerosis (ALS)
Degeneration off large motor neurons
Other brain neurons spared
○
Voluntary movement lost over 1-5 years
○
Walking, talking, swallowing, breathing
○
Death usually due to respiratory failure
○
No effect on sensation or cognition
○
Stephen Hawking
○
○
Exact cause unknown
○
Latest theory
Motor neurons cannot absorb lactate supplied by
oligodendrocytes
Die from lack of energy compounds
○
Motor neuron s may be especially sensitive because of
long axons
○
Energy supply from cell body may be less efficient
○
○
○
○
○
Microglia
The CNS is an "immunologically privileged" organ due to BBB
Fewer immunological defenses than other body areas
○
○
Microglia share properties with macrophage (immune) cells found in other
tissues
○
Microglia secrete signaling molecules such as cytokines
Modulate local inflammation
Can affect cell survival after damage
○
○
○
Inflammatory state may contribute to neuronal damage in ma
neurodegenerative diseases (ex. Alzheimer's)
○
○
Chapter 1 - Neurons and Glia
September 12, 2015
12:33 AM
Monday, September 14th 2015
Levels of Analysis in Neuroscience
Atoms
○
Molecules (protein, DNA, etc.)
○
Individual Cells
○
Pairs of cells connected by synapses
○
Networks of interacting cells
○
Systems in the brain that regulate behavior
○
Behaving Animal
○
Groups of animals
○
Alzheimer's Disease
Neurodegenerative
Loss of short term memory, cognitive functions
○
Loss of neurons in specific brain areas (ex. Hippocampus, important for
memory formation)
○
○
More than 15,000 Nova Scotians are now living with Alzheimer's
○
50% of people over 85 develop Alzheimer's
○
Cost will increase 10 fold
○
Why do cells die?
Why are some cells not affected?
○
Prevention?
○
Cure?
○
○
Neurons
Functional unit of the nervous system
○
Most anatomically diverse cell in the body
Yet most neurons have a number of common features
○
○
Dendrites, Cell Body and Axons
All these different neurons from different areas of the nervous system still have
the three common features
○
Neuronal Diversity
Good understanding of neuronal diversity established by the early 20th century
○
Pioneering cell-staining method by introduced by Camillo Golgi and utilized by
S. Ramon Y Cajal
Gogi Stain: tissue washed with silver salts, a few neurons take up the silver
and are stained black (A and B)
○
Only one neuron out of every thousand or so will pick up the stain while
the others won't
Cajal thought that they were individual cell like other cells in the
body but Golgi didn't agree
○
○
More recently developed fluorescent dyes C can be injected into individual
neurons using specialized equipment
○
○
Dendrites and axons and synapses allow neurons to perform their principle
function
The structure is dictated by the function
○
The essence of nervous function is signaling (AKA information
transmission)
Intracellular Signaling: From one part of the cell to another
○
Intercellular Signaling: communication between cells
○
○
○
The Axon
Job is to take impulses from one area of your body to another
○
Tube like process exiting from the axon hillock on the soma
○
Transmits electrical signals rapidly along its length
○
Usually does no branch until it terminates at synaptic terminals
○
Axon's cytoskeleton is highly plastic during development (axonal path- finding)
and acts as a highway for molecular motors
○
The Synapse
Where pre-synaptic axon terminals (synaptic boutons) meet post synaptic
dendrites
○
The site of intercellular information transfer
○
Term "synapse" comes from the Greek word "connect"
Coined by Sir Charles Sherrington ~ 100 years ago
○
Hypothesized it's existence from spinal cord reflexes years before any
anatomical correlate
○
○
The Dendrites
Some dendritic trees can be highly branched
○
Usually acts as synaptic input site
Integrates information from other cells
○
○
Some dendrites have numerous finger-like projections called dendritic spines
Highly plastic structures
○
○
The source of neuronal diversity is not well understood
Thought to be at least partially under genetic control
○
○
Genes and the Brain
Genes, the nervous system and behaviour
Genes influence behaviour, but
Large gaps in our understanding of:
How genes influence nervous system
○
How neurons produce behaviour
○
How environment and genes interact to alter neuronal function
○
○
○
Brian gene interactions are difficult to understand because of the complexity of
the brain
1015 synapses in the neocortex
○
A typical neuron has ~5,000 -200,000 synapses
○
Thousands of different neuronal types
○
20,000-25,000 protein coding genes in human genome
○
Not all involved in brain function
○
○
○
Genes, the nervous system, and behaviour
Genetic control of neuronal structure/function is not straight forward
○
Ex. Complexity of the human brain probably results from extra genes unique to
humans, right?
Mice actually have a larger number of genes that humans
○
Only ~75 million neurons
○
Fewer synapses than in humans as well
○
○
Genes the nervous system, and behaviour
The number of genes in an organisms genome is not a good indicator of somatic
variability of the organisms nervous system
Various genetic mechanisms may increase diversity and complexity
○
Ex. Drosophila axon guidance receptor (DSCAM) undergoes alternate
spicing when the genes DNA is being transcribed to mRNA
Exons (expressed nucleotide sequences) can be retained, or spiced
out with introns c(intervening nucleotide sequences)
○
○
Creates receptor with 38,016 possible variants (double the number of
predicted genes in the entire genome)
○
○
Example: Fruitless Fruit Flies
Fruitless specifies sexually dimorphic neural circuitry in the Drosophila
brain
○
Brains of Drosophila are sexually dimorphic (different in males and
females)
○
Males: more neurons in optic lobe and more mAL neuron in the antennal
lobe
○
○
Fruitless gene produces protein called Fru
Fru is expressed in the mAL neurons of male, but not female fruit
flies
○
○
Adults
30 mAL neurons in males
○
5 mAL neurons in females
○
Male and female mAL neurons have different morphologies
○
○
Larva
About the same number of mAL cells
○
○
More mAL neurons die in females during prepupal development
○
Fru Function
Fru protein protects against cell death in males and directs neuronal
projection morphology
○
○
Mutate Fru gene
Changes conformation of the Fru protein- so the protien becomes
non functional
Fru mutant males now have ~5 mAL neurons
○
Neurons have female morphology
○
○
○
Male mAL neurons terminate in subesophageal ganglion
Thought to transmit pheromonal information from antennal lobe to
rest of the brain
○
○
Mutant males that lack funtioning Fru gene court both males and females,
suggesting an inability to recognize female pheromone due to loss of
proper mAL projections
○
Glia
Take up all the other matter that neurons don't
○
Glia outnumber neurons ~3-10:1
○
Three broad categories
Astroglia
○
Oligodendroglia
○
Microglia
○
○
Glial cells retain their ability to divide throughout life
○
Astrocytes
Star like structure
○
Maintain chemical homeostasis
○
Component of the blood brain barrier
Surround vascular endothelial cells
○
○
Provide structure/ scaffolding for other CNS components
○
Isolates and insulates neurons from each other
Ex. Astrocytes are involved in glutamate uptake
○
○
One astrocyte can interact with 2 million synapses and influence their function
○
○
Oligodendrocytes
Myelin produces cell in the CAN
A signal oligodendrocyte can provide 30-50 myelin internodes
○
○
Fewer cells processes than astrocytes
○
Poor regenerative capacity
○
Also supplies axons with fuel to support high metabolic activity
~20% of body's energy required to fuel the brain
○
ATP is generated by the breakdown of glucose to pyruvate then
lactate in process known as glycolysis
○
○
Oligodendrocytes release lactate too (astrocytes described 1st)
After myelin formation
○
Especially important for survival of motor neurons
○
○
○
Amyotrophic lateral sclerosis (ALS)
Degeneration off large motor neurons
Other brain neurons spared
○
Voluntary movement lost over 1-5 years
○
Walking, talking, swallowing, breathing
○
Death usually due to respiratory failure
○
No effect on sensation or cognition
○
Stephen Hawking
○
○
Exact cause unknown
○
Latest theory
Motor neurons cannot absorb lactate supplied by
oligodendrocytes
Die from lack of energy compounds
○
Motor neuron s may be especially sensitive because of
long axons
○
Energy supply from cell body may be less efficient
○
○
○
○
○
Microglia
The CNS is an "immunologically privileged" organ due to BBB
Fewer immunological defenses than other body areas
○
○
Microglia share properties with macrophage (immune) cells found in other
tissues
○
Microglia secrete signaling molecules such as cytokines
Modulate local inflammation
Can affect cell survival after damage
○
○
○
Inflammatory state may contribute to neuronal damage in ma
neurodegenerative diseases (ex. Alzheimer's)
○
○
Chapter 1 - Neurons and Glia
September 12, 2015 12:33 AM
Monday, September 14th 2015
Levels of Analysis in Neuroscience
Atoms
○
Molecules (protein, DNA, etc.)
○
Individual Cells
○
Pairs of cells connected by synapses
○
Networks of interacting cells
○
Systems in the brain that regulate behavior
○
Behaving Animal
○
Groups of animals
○
Alzheimer's Disease
Neurodegenerative
Loss of short term memory, cognitive functions
○
Loss of neurons in specific brain areas (ex. Hippocampus, important for
memory formation)
○
○
More than 15,000 Nova Scotians are now living with Alzheimer's
○
50% of people over 85 develop Alzheimer's
○
Cost will increase 10 fold
○
Why do cells die?
Why are some cells not affected?
○
Prevention?
○
Cure?
○
○
Neurons
Functional unit of the nervous system
○
Most anatomically diverse cell in the body
Yet most neurons have a number of common features
○
○
Dendrites, Cell Body and Axons
All these different neurons from different areas of the nervous system still have
the three common features
○
Neuronal Diversity
Good understanding of neuronal diversity established by the early 20th century
○
Pioneering cell-staining method by introduced by Camillo Golgi and utilized by
S. Ramon Y Cajal
Gogi Stain: tissue washed with silver salts, a few neurons take up the silver
and are stained black (A and B)
○
Only one neuron out of every thousand or so will pick up the stain while
the others won't
Cajal thought that they were individual cell like other cells in the
body but Golgi didn't agree
○
○
More recently developed fluorescent dyes C can be injected into individual
neurons using specialized equipment
○
○
Dendrites and axons and synapses allow neurons to perform their principle
function
The structure is dictated by the function
○
The essence of nervous function is signaling (AKA information
transmission)
Intracellular Signaling: From one part of the cell to another
○
Intercellular Signaling: communication between cells
○
○
○
The Axon
Job is to take impulses from one area of your body to another
○
Tube like process exiting from the axon hillock on the soma
○
Transmits electrical signals rapidly along its length
○
Usually does no branch until it terminates at synaptic terminals
○
Axon's cytoskeleton is highly plastic during development (axonal path- finding)
and acts as a highway for molecular motors
○
The Synapse
Where pre-synaptic axon terminals (synaptic boutons) meet post synaptic
dendrites
○
The site of intercellular information transfer
○
Term "synapse" comes from the Greek word "connect"
Coined by Sir Charles Sherrington ~ 100 years ago
○
Hypothesized it's existence from spinal cord reflexes years before any
anatomical correlate
○
○
The Dendrites
Some dendritic trees can be highly branched
○
Usually acts as synaptic input site
Integrates information from other cells
○
○
Some dendrites have numerous finger-like projections called dendritic spines
Highly plastic structures
○
○
The source of neuronal diversity is not well understood
Thought to be at least partially under genetic control
○
○
Genes and the Brain
Genes, the nervous system and behaviour
Genes influence behaviour, but
Large gaps in our understanding of:
How genes influence nervous system
○
How neurons produce behaviour
○
How environment and genes interact to alter neuronal function
○
○
○
Brian gene interactions are difficult to understand because of the complexity of
the brain
1015 synapses in the neocortex
○
A typical neuron has ~5,000 -200,000 synapses
○
Thousands of different neuronal types
○
20,000-25,000 protein coding genes in human genome
○
Not all involved in brain function
○
○
○
Genes, the nervous system, and behaviour
Genetic control of neuronal structure/function is not straight forward
○
Ex. Complexity of the human brain probably results from extra genes unique to
humans, right?
Mice actually have a larger number of genes that humans
○
Only ~75 million neurons
○
Fewer synapses than in humans as well
○
○
Genes the nervous system, and behaviour
The number of genes in an organisms genome is not a good indicator of somatic
variability of the organisms nervous system
Various genetic mechanisms may increase diversity and complexity
○
Ex. Drosophila axon guidance receptor (DSCAM) undergoes alternate
spicing when the genes DNA is being transcribed to mRNA
Exons (expressed nucleotide sequences) can be retained, or spiced
out with introns c(intervening nucleotide sequences)
○
○
Creates receptor with 38,016 possible variants (double the number of
predicted genes in the entire genome)
○
○
Example: Fruitless Fruit Flies
Fruitless specifies sexually dimorphic neural circuitry in the Drosophila
brain
○
Brains of Drosophila are sexually dimorphic (different in males and
females)
○
Males: more neurons in optic lobe and more mAL neuron in the antennal
lobe
○
○
Fruitless gene produces protein called Fru
Fru is expressed in the mAL neurons of male, but not female fruit
flies
○
○
Adults
30 mAL neurons in males
○
5 mAL neurons in females
○
Male and female mAL neurons have different morphologies
○
○
Larva
About the same number of mAL cells
○
○
More mAL neurons die in females during prepupal development
○
Fru Function
Fru protein protects against cell death in males and directs neuronal
projection morphology
○
○
Mutate Fru gene
Changes conformation of the Fru protein- so the protien becomes
non functional
Fru mutant males now have ~5 mAL neurons
○
Neurons have female morphology
○
○
○
Male mAL neurons terminate in subesophageal ganglion
Thought to transmit pheromonal information from antennal lobe to
rest of the brain
○
○
Mutant males that lack funtioning Fru gene court both males and females,
suggesting an inability to recognize female pheromone due to loss of
proper mAL projections
○
Glia
Take up all the other matter that neurons don't
○
Glia outnumber neurons ~3-10:1
○
Three broad categories
Astroglia
○
Oligodendroglia
○
Microglia
○
○
Glial cells retain their ability to divide throughout life
○
Astrocytes
Star like structure
○
Maintain chemical homeostasis
○
Component of the blood brain barrier
Surround vascular endothelial cells
○
○
Provide structure/ scaffolding for other CNS components
○
Isolates and insulates neurons from each other
Ex. Astrocytes are involved in glutamate uptake
○
○
One astrocyte can interact with 2 million synapses and influence their function
○
○
Oligodendrocytes
Myelin produces cell in the CAN
A signal oligodendrocyte can provide 30-50 myelin internodes
○
○
Fewer cells processes than astrocytes
○
Poor regenerative capacity
○
Also supplies axons with fuel to support high metabolic activity
~20% of body's energy required to fuel the brain
○
ATP is generated by the breakdown of glucose to pyruvate then
lactate in process known as glycolysis
○
○
Oligodendrocytes release lactate too (astrocytes described 1st)
After myelin formation
○
Especially important for survival of motor neurons
○
○
○
Amyotrophic lateral sclerosis (ALS)
Degeneration off large motor neurons
Other brain neurons spared
○
Voluntary movement lost over 1-5 years
○
Walking, talking, swallowing, breathing
○
Death usually due to respiratory failure
○
No effect on sensation or cognition
○
Stephen Hawking
○
○
Exact cause unknown
○
Latest theory
Motor neurons cannot absorb lactate supplied by
oligodendrocytes
Die from lack of energy compounds
○
Motor neuron s may be especially sensitive because of
long axons
○
Energy supply from cell body may be less efficient
○
○
○
○
○
Microglia
The CNS is an "immunologically privileged" organ due to BBB
Fewer immunological defenses than other body areas
○
○
Microglia share properties with macrophage (immune) cells found in other
tissues
○
Microglia secrete signaling molecules such as cytokines
Modulate local inflammation
Can affect cell survival after damage
○
○
○
Inflammatory state may contribute to neuronal damage in ma
neurodegenerative diseases (ex. Alzheimer's)
○
○
Chapter 1 - Neurons and Glia
September 12, 2015 12:33 AM
Document Summary
Loss of neurons in specific brain areas (ex. More than 15,000 nova scotians are now living with alzheimer"s. Yet most neurons have a number of common features. All these different neurons from different areas of the nervous system still have the three common features. Good understanding of neuronal diversity established by the early 20th century. Pioneering cell-staining method by introduced by camillo golgi and utilized by: ramon y cajal. Gogi stain: tissue washed with silver salts, a few neurons take up the silver and are stained black (a and b) Only one neuron out of every thousand or so will pick up the stain while the others won"t. Cajal thought that they were individual cell like other cells in the body but golgi didn"t agree. More recently developed fluorescent dyes c can be injected into individual neurons using specialized equipment. Dendrites and axons and synapses allow neurons to perform their principle function.
