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extra.md
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---
--
## Early 1800’s Franz Joseph Gall
* all behavior emanates from the brain
* particular regions of the cerebral cortex controlled specific functions, i.e. the brain does not act as a single organ.
* each function grew with use such as a muscle with exercise
* this growing causes the skull to budge creating a pattern of bumps “phrenology”
--
## Franz Joseph Gall– phrenology
<div style="font-size:0.7em">
<div></div>
>Standing at his lectern, the priest stared steadily upon one man in the congregation: Franz Joseph Gall. With his angry voice echoing off the church's hallowed walls, he pronounced,"There are those amongst us, who have lost their way from our Lord's divine path. With pomposity, they state the mind is situated in an organ as mushy and insubstantial as the brain. What ludicrousness is this, when all intelligent men know that God has imbued our thinking into our very soul, whereupon no one can put his finger precisely on the spot!"
</div>
[galls-phrenology.html](http://thevictoriantimes.blogspot.com/2011/10/galls-phrenology.html)
<div><img src="figs/image21_cc3a4ac.png" height="50px"><figcaption></figcaption></div>
--
## Phrenology
<div><img src="figs/image22_f181430.png" height="300px"><figcaption></figcaption></div>
## Pierre Flourens (French)
* Tested Gall’s ideas by removing different parts of the brain (dogs and rabbits) and asked if specific functions were compromised.
* Showed medulla important for respiration, cerebellum important for movements.
* Lesions in cortex affected either zero or many behaviors. Concluded that the cortex was one organ and not regionalized.

155
methods.md
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##Fluorescence Microscopy
## Brain lesion patients
* Lesions in brains or degenerative diseases help us understand brain function
* Phineas Gage– Railroad spike through frontal lobes changed his personality
<div><img src="figs/image7_0e1af20.png" height="200px"><figcaption></figcaption></div>
<div><img src="figs/image8_c3232ea.png" height="200px"><figcaption></figcaption></div>
Note:
Furthermore, studies of patients with brain lesions has historically been key to localizing parts of the brain that affect emotional states and learning and memory.
e.g. Phineas Gage in 1848 his whole personality changed after the spike went through his brain.
Harlow wrote: "the equilibrium... between his intellectual faculties and his animal propensities seems to have been destroyed"
---
## Model organisms— C. elegans
* The nematode worm *C. elegans* is great for genetic engineering and has a tiny nervous system (just 302 neurons)
<div><img src="figs/Adult_Caenorhabditis_elegans_d76c553.jpg" height="150px" title="CC from wikipedia https://commons.wikimedia.org/w/index.php?curid=2680458"><figcaption>C. elegans– commons.wikimedia.org/w/index.php?curid=2680458</figcaption></div>
<div><img src="figs/c-elegans-connectome_2_9548c95.jpg" height="150px"><figcaption>C. elegans wiring diagram– [openworm.org](http://www.openworm.org), neuroconstruct.org</figcaption></div>
Note:
It is difficult to visualize and record neurons and manipulate genes in humans so neuroscientists study a number of different model organisms.
Now to do neuroscience research we have to use model organisms of course. Small number of neurons, can be labeled using green fluorescent protein or other means.
C. elegans is a nematode or roundworm. It is non-infectious and non-parasitic organism just 1 mm long and it can be easily genetically engineered. That means you can introduce mutations to genes or express fancy inert proteins that allow you to track the function of genes and cells in living animals making it a great model organism.
For neuroscientists it has only 302 total neurons making it a great way to dissect neural circuits underlying simple behaviors. Many mutant worms have been isolated that affect nervous system function allowing us to learn about the function of those genes. And you can engineer the worms to express fluorescent proteins so that the animal's neurons glow under a microscope. How many of you have heard of green fluorescent protein?
Having just 302 neurons is great for for some types of studies, however we have more than a million neurons in each of our eyes just alone
More than 1 million neurons that just form the optic nerve from each of our eyes!
---
## Model organisms— squid
Squids have unusually large axons (1 mm diameter)
<div style="width:250px; float:left;"><img src="figs/20000_squid_holding_sailor_f98a242.jpg" height="300px"><figcaption>20000 Lieues Sous les Mers, J. Verne</figcaption></div>
<div style="width:500px; float:left;"><img src="figs/Squid_Loligo_pealei_cbafe46.jpg" height="300px"><figcaption>Atlantic squid, *Loligo pealei*</figcaption></div>
<!-- <div><img src="figs/axon_large_9a8a930.jpg" height="300px"><figcaption>Squid giant axon, R. Hanlon MBL Woods Hole</figcaption></div> -->
Note:
Jules Verne provided inspiration for the space age but also neuroscientists in the 1940s.
Squids are arguably the most important model organism in the history of neuroscience. They are rarely studied anymore but their large axons which are 1mm in diameter-- 1000x bigger than our axons-- made their axons amenable to sticking electrodes inside them in the 1930s-50s and allowed neuroscientist to discover the biophysical and mathematical basis of neuronal signaling. We will discuss squid giant axons in much more detail soon.
Other important invertebrate organisms in neuroscience research include sea slugs and fruit flies and zebrafish. Some of these are very amenable to genetic engineering like C. elegans and have nervous systems more similar to our own.
Phylum: Mollusca
Class: Cephalopoda
Order: Teuthida
Family: Loliginidae
Genus: Loligo
Atlantic squid (Loligo pealei)
Phylum: Mollusca
Class: Cephalopoda
Order: Sepiida
Family: Sepiidae
Genus: Sepia
---
## Model organisms— *Mus. musculus*
The mouse is a common model in neuroscience research.
<div style="width:225px; float:left;"><img src="figs/adult_mouse_jax_ec76ad4.jpg" height="200px"><figcaption>Common house mouse *Mus. musculus*, jax.org</figcaption></div>
<div style="width:300px; float:left;"><img src="figs/abi_adult_mouse_brain_e79e400.jpg" height="200px"><figcaption>Mouse brain 3D rendering, [Brain Explorer 2](http://mouse.brain-map.org/static/brainexplorer)</figcaption></div>
<div style="width:430px; float:left;"><iframe src="https://www.youtube.com/embed/stPThgZ2Y5o" width="420" height="315"></iframe><figcaption>Green fluorescent protein (GFP) labeled neurons inside a mouse brain</figcaption></div>
Note:
But mammals are the only animals that have evolved a convoluted superficial part of the brain called the neocortex. And it is the cerebral neocortex is crucial for our highest cognitive functions, even if it sometimes seems that in election years that humans have lost their cerebral function.
Thus for research pertaining to the structure and function of the mammalian brain and human disease we turn to rodents like the common house mouse. Mice are small with a brain 2 cm in length, develop fairly quickly, and their genome has long been one of the most amenable to genetic engineering though this is quickly changing newer molecular biology techniques (like the CRISPR/Cas9 system).
* Mouse brain is about 2 cm in length
* genetically tractable
* [https://www.youtube.com/watch?v=stPThgZ2Y5o](https://www.youtube.com/watch?v=stPThgZ2Y5o)
---
## Model organisms– other mammals
Higher mammals are used to study more complex brain functions.
<div><img src="figs/1f412_3fc8278.svg" height="200px"><figcaption>Cats– visual system function, locomotion</figcaption></div>
<div><img src="figs/1f412_f738dec.svg" height="200px">
<figcaption>
Non-human primates– attention, decision
making, vision, brain machine interfaces
</figcaption></div>
<div><iframe src="https://www.youtube.com/embed/UJ_rFMYDbAE" width="420" height="315"></iframe><figcaption>Rhesus monkey mind controlled wheelchair</figcaption></div>
<!--
<div style="float:left;"><figure style="display:inline-table;"><img src="figs/1f412_3fc8278.svg" height="200px"><figcaption style="display:table-caption; caption-side:bottom;">Cats– visual system function, locomotion</figcaption></figure></div>
<div style="float:left;"><figure style="display:inline-table;"><img src="figs/1f412_f738dec.svg" height="200px"><figcaption style="display:table-caption; caption-side:bottom;">Non-human primates– attention, decision making, vision, brain machine interfaces</figcaption></figure></div>
<div style="width:430px; float:left;"><iframe src="https://www.youtube.com/embed/L2O58QfObus" width="420" height="315"></iframe><figcaption>Rhesus monkey mind controlled wheelchair</figcaption></div>
-->
Note:
put new 2018 duke study in here. [interbrain cortical synchronization and mirror neurons between monkeys](http://dx.doi.org/10.1038/s41598-018-22679-x)
Research with cats was critical for work from the 1950s to 1980s that allowed neuroscientist to learn how visual signals are processed in the highest circuits of the mammalian brain.
And research with rhesus monkeys has been essential for learning about perceptual, attentional, and decision making in the mammalian brain together with research into brain-machine interfaces that have direct clinical applications for human patients.
3rs: Replacement, Reduction, and Refinement
---
## Fluorescence Microscopy
* Fluorescent molecules absorb light at one wavelength and emit it at another-longer wavelength.
* Uses optical filters to allow only light of a given wavelength in and out.
@@ -76,7 +221,7 @@ Here expressed in fly peripheral neurons
Note:
Remember that GFP is a gene that encodes a protein. You can put it behind the promoter to detect which cells express a given gene.
Remember that GFP is a gene that encodes a protein. You can put it behind the promoter to detect which cells express a given gene.
---
@@ -133,8 +278,8 @@ Note:
## Tumor detection
MRI
CT-SCAN
MRI
CT-SCAN
<div><img src="figs/image29_a6736bb.png" height="100px"><figcaption></figcaption></div>
@@ -146,7 +291,7 @@ Note:
## Magnetic resonance imaging (MRI)
<div><video height=400px controls src="figs/Animation01-01MagneticResonanceImaging.mp4"></video><figcaption>Neuroscience 5e Animation 1.1</figcaption></div>
<div><video height=400px controls src="figs/Animation01-01MagneticResonanceImaging.mp4"></video><figcaption>Neuroscience 5e Animation 1.1</figcaption></div>
Note:

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neuroanatomy1.md
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## What is neuroscience?
# What is neuroscience?
Neuroscience is a field of scientific study that seeks to understand how the nervous system carries out its functions and what goes wrong when it doesn’t.
Neuroscience is a field of scientific study that seeks to understand how the nervous system carries out its functions and what goes wrong when it doesn’t.
While humankind has learned alot about nervous system structure and function, there is a great deal left to understand. It's up to you to figure it all out.
<img src="figs/human-brain.svg" height="300px">
http://courses.pbsci.ucsc.edu/mcdb/bio125/
https://courses.pbsci.ucsc.edu/mcdb/bio125/
Note:
Welcome. This class will be an Introduction to Neuroscience– Neuroscience is a field that by necessity integrates information and techniques from many other scientific disciplines— not just biological sciences like genetics, molecular biology, biochemistry, immunology, physiology. But also physics, engineering, computer science, psychology. And these days neuroscience is touching upon fields as varied as sociology, criminology, marketing, ethics, and the law. So what is Neuroscience? Neuroscience is fundamentally a field that...
Welcome. This class will be an Introduction to Neuroscience–
Neuroscience is a field that by necessity integrates information and techniques from many other scientific disciplines— not just biological sciences like genetics, molecular biology, biochemistry, immunology, physiology. But also physics, engineering, computer science, psychology. And these days neuroscience is touching upon fields as varied as sociology, criminology, marketing, ethics, and the law. So what is Neuroscience? Neuroscience is fundamentally a field that...
And ultimately it is a field of science that seeks to understand how this lump of biological tissue siting inside our heads has evolved the capability of asking questions about its own nature and existence.
While humankind has learned alot about nervous system structure and function, there is a great deal left to understand. It's up to you to figure it all out.
Thus it will be you, and your children, and your children’s children that will figure it all out and literally allow human beings to reach the stars.
--
## Syllabus and text book
<div style="width:700px; padding:25px 0; float:left;"><a href="https://courses.pbsci.ucsc.edu/mcdb/bio125/">https://courses.pbsci.ucsc.edu/mcdb/bio125/</a></div>
<div style="width:250px; float:left;"><img src="figs/ScreenShot2016-01-04at3.59.29PM_dea1077.png" height="200px"><figcaption></figcaption></div>
--
## Permission code requests
Just send me an email with the following subject line and body:
Just send me an email.
**subject line:**
```txt
permission code request biol 125
permission code request: #biol125
```
**body:**
```txt
ID#:
NAME: *First Middle Last*
EMAIL:
REASON YOU CANNOT ENROLL:
Id: 1234567
Name: First Last
Email: cruzid@ucsc.edu
Reason you cannot enroll: Brief description (one line).
```
--
@@ -39,9 +54,12 @@ REASON YOU CANNOT ENROLL:
* Menu: `m`
* Fullscreen: `f`
* Overview: `o` or `esc`
* Notes: `s`
* Zoom: `alt-click` or two-finger multi-touch (touch screens/trackpads)
* Zoom-scroll: two-finger drag (touch screens/trackpads while zoomed in)
* Print: `...lecture.html?print-pdf`
<!-- * Print: `...neuroanatomy1.html?print-pdf` -->
Recommend browser is Chrome on a laptop/PC. Some features that only have keyboard bindings (e.g. fullscreen, overview) may not work or be disabled on tablet/touch screen devices.
@@ -49,14 +67,14 @@ Recommend browser is Chrome on a laptop/PC. Some features that only have keyboar
## What are the nervous system’s functions?
* The nervous system organizes and controls an individual’s appropriate interactions with the environment
* Thus, it’s functions are dynamic, vast and wide-ranging – extending to include all thoughts, perceptions, bodily actions, behaviors, and even the very essence of one’s being: consciousness and the mind
* The nervous system organizes and controls an individual’s appropriate interactions with the environment <!-- .element: class="fragment fade-in" data-fragment-index="1"-->
* Its functions are dynamic, vast and wide-ranging – extending to include all thoughts, perceptions, bodily actions, behaviors, and even the very essence of one’s being: consciousness and the mind <!-- .element: class="fragment fade-in" data-fragment-index="2"-->
Note:
What does the nervous system do? It organizes and controls an individuals interactions with the environment. It does this by processing current or past experiential information and making and executing behavioral decisions.
Therefore the brain’s functions are dynamic, vast and wide ranging, and extends to include all thoughts, perceptions, and actions and the very core of what it means for each of one us to be us–– consciousness and the mind. It is this complex lump of biological tissue, this emergent computational system that allows us humans to not only imagine the future, but to create it as well.
Therefore the brain’s functions are dynamic, vast and wide ranging, and extends to include all thoughts, perceptions, and actions and the very core of what it means for each of one us to be us–– consciousness and the mind. It is this complex lump of biological tissue, this emergent computational system that allows us humans to not only imagine the future, but to create it as well.
--
@@ -64,7 +82,7 @@ Therefore the brain’s functions are dynamic, vast and wide ranging, and extend
<div><img src="figs/From_the_Earth_to_the_Moon_Jules_Verne_695f816.jpg" height="200px"><figcaption>J. Verne, 1865</figcaption></div>
<!--
<!--
<div><img src="figs/2015-06-22_15.39.40_7af33ea.png" height="200px"><figcaption>Edgar Rice Burroughs, 1912</figcaption></div>
<div><img src="figs/Do_androids_dream_of_electric_sheep_1968_2a4fe82.jpg" height="200px"><figcaption>Philip K. Dick, 1968</figcaption></div>
<div><img src="figs/The_forever_war_1974_1be2645.png" height="200px"><figcaption>Joe Haldeman, 1974</figcaption></div>
@@ -74,9 +92,9 @@ Therefore the brain’s functions are dynamic, vast and wide ranging, and extend
Note:
Ever since the dawn of the industrial age in the mid 19th century and Jules Verne's 1865 novel 'From the Earth to the Moon' humans have been dreaming of the future, not just here but among the stars. And those futures can become reality like when the Apollo astronauts landed on the moon and acknowledged the inspiration that Verne's orig sci-fi novel had on many.
Ever since the dawn of the industrial age in the mid 19th century and Jules Verne's 1865 novel 'From the Earth to the Moon' humans have been dreaming of the future, not just here but among the stars. And those futures can become reality like when the Apollo astronauts landed on the moon and acknowledged the inspiration that Verne's orig sci-fi novel had on many.
Neuroscience and its role for proper physiological function is going to play a role in many advances in health and technology for humankind now and far into the future--
Neuroscience and its role for proper physiological function is going to play a role in many advances in health and technology for humankind now and far into the future--
To reach the stars we will need:
@@ -102,7 +120,6 @@ The human brain and its limitless creativity has packed a bunch of computational
Since that time we've dreamed up fantastical futures in shows like Star Trek and the Jetsons and dystopian ones in Blade Runner and the Terminator or even ones past (for example think "long time ago in a galaxy far far away...")
Many of things dreamed of are already presentImagine some of things thought of and now already present flying aeroplanes, personal landspeeders, rocket ships to distant planets
\
- Edgar Rice Burroughs John Carter thought waves example.
@@ -118,25 +135,23 @@ Penfield mood organ
* The patterns of connections between nerve cells
* The relationship of different patterns of interconnections to different types of behavior
<div style="width:700px; padding:25px 0; float:left;"><a href="http://courses.pbsci.ucsc.edu/mcdb/bio125/">http://courses.pbsci.ucsc.edu/mcdb/bio125/</a></div>
<div style="width:250px; float:left;"><img src="figs/ScreenShot2016-01-04at3.59.29PM_dea1077.png" height="100px"><figcaption></figcaption></div>
Note:
Nervous
: relating to or affecting the nerves
Nervous
: relating to or affecting the nerves
nervosus
: latin
: sinewy, vigorous
nervosus
: latin
: sinewy, vigorous
nervus
: latin
: sinew
nervus
: latin
: sinew
sinew
: fibrous tissue linking bone or muscle to bone
: the parts of a structure, system, or thing that give it strength or bind it together
sinew
: fibrous tissue linking bone or muscle to bone
: the parts of a structure, system, or thing that give it strength or bind it together
@@ -147,14 +162,15 @@ sinew
<div style="font-size:0.9em">
<div></div>
* We are now in a gene-centric “post-genomic” phase of neuroscience
* Many genes are expressed in the brain, either during development or in the adult. It is the spatial and temporal regulation of these genes and an organisms interaction with the environment that builds a nervous system.
* Neuroscience therefore encompasses many fields, including genetics, cell biology, physiology, and development biology.
* Many genes are expressed in the brain, either during development or in the adult. It is the spatial and temporal regulation of these genes together with an organism's interaction with the environment that builds a nervous system.
* "nature <del style="color:red">OR</del> **AND** nurture"
</div>
Note:
* Neuroscience encompasses many fields: genetics, molecular and cell biology, developmental biology, physiology.
- not nature or nurture, nature and nurture
- language, learning to ride a bike
- clones, identical twins
@@ -167,23 +183,24 @@ Note:
<div></div>
organism | # of genes | # of base pairs | # of neurons | development time (young adult)
---------- | ---------- | --- | ------------ | -------------------------
*Caenorhabditis elegans* (nematode) | ~19,000 | ~97 million | 302 | 8 hrs
---------- | ---------- | --- | ------------ | -------------------------
*Caenorhabditis elegans* (nematode) | ~19,000 | ~97 million | 302 | 8 hrs
*Drosophila melanogaster* (fruit fly) | ~15,000 | ~120 million | ~250,000 | 7–11 days
*Danio rerio* (zebrafish) | ~24,000 | ~1.5 billion | ~10,000,000 | 30 days
Mouse | ~25,000 | ~3.5 billion | ~71,000,000 | 2-3 months
Human | ~20,000 | ~3.5 billion | ~100,000,000,000 | 18 years
African elephant | ~20,000 | ~3.1 billion | ~267,000,000,000 | 18 years
Mouse | ~25,000 | ~3.5 billion | ~71,000,000 | 2-3 months
Human | ~20,000 | ~3.5 billion | ~100,000,000,000 | 18 years
African elephant | ~20,000 | ~3.1 billion | ~267,000,000,000 | 18 years
</div>
<figcaption>see also Neuroscience 5e Box 01A</figcaption>
<!-- <figure><img src="figs/Neurscience5e-Box-01A-0_0eadd2b.jpg" height="100px"><figcaption></figcaption></figure> -->
Note:
Number of genes is not related to nervous system complexity or size. The nematode c. elegans has just 302 neurons, and yet its genome contains virtually as many genes as a humans. An african elephant brain weighs 3 times more than a human brain and has 3 times the number of neurons.
Number of genes is not related to nervous system complexity or size. The nematode c. elegans has just 302 neurons, and yet its genome contains virtually as many genes as a humans. An african elephant brain weighs 3 times more than a human brain and has 3 times the number of neurons.
Even number of base pairs: Paris japonica has 150 billion base pairs of DNA (50x larger than that of a human haploid genome)
Even number of base pairs: Paris japonica (white, star like flower) has 150 billion base pairs of DNA (50x larger than that of a human haploid genome)
The largest brains are those of sperm whales, weighing about 8 kg (18 lb). An elephant's brain weighs just over 5 kg (11 lb), a bottlenose dolphin's 1.5 to 1.7 kg (3.3 to 3.7 lb), whereas a human brain is around 1.3 to 1.5 kg (2.9 to 3.3 lb). Brain size tends to vary according to body size.
@@ -195,7 +212,20 @@ The largest brains are those of sperm whales, weighing about 8 kg (18 lb). An el
## There are many brain-specific and non-brain specific genes expressed in the nervous system
<figure><img src="figs/Neuroscience5e-Fig-01.01-1R_7806e74.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 1.1</figcaption></figure>
<!-- <figure><img src="figs/Neuroscience5e-Fig-01.01-1R_7806e74.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 1.1</figcaption></figure> -->
<div>
<div></div>
| tissue | Number of expressed genes |
| --- | --- |
| brain only | ~6000 |
| brain & all other tissues | ~8000 |
| other tissues only | ~6000 |
| | total: 20000 |
<figcaption>see also Neuroscience 5e Fig. 1.1</figcaption>
</div>
Note:
@@ -206,158 +236,23 @@ Out of those 20000 genes, there are many expressed genes that are common between
## A single mutation can lead to dramatic brain size defects
Mutation in a spindle pole gene call ASPM1
Mutation in a spindle pole gene call ASPM1 (altered mitosis during brain development)
<!-- <figure><img src="figs/Neuroscience5e-Fig-01.01-3R_562abf7.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 1.1</figcaption></figure> -->
<figure><img src="figs/Bond-natgenet2002-fig1.jpg" height="350px"><figcaption>[Bond:2002](https://dx.doi.org/10.1038/ng995), see also Neuroscience 5e Fig. 1.1</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-01.01-3R_562abf7.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 1.1</figcaption></figure>
Note:
Now mutations in single genes in the right place in our genome can cause drastic effects on the formation of our brain’s wiring.
Now mutations in single genes in the right place in our genome can cause drastic effects on the formation of our brain’s wiring.
For example, shown here is a person with a mutation in ASPM1 a protein used to make spindle poles for mitotic stem cells during embryonic development.
But most single gene mutations do not cause such drastic effects, with a more subtle and complex set of genetic and environmental risk factors causing neurological disease, similar to and probably exceeding the complex etiology of cancer.
---
## Model organisms— C. elegans
* It is hard to visualize and monitor neurons and manipulate genes in humans so neuroscientists study a number of different organisms
* The nematode worm *C. elegans* is great for genetic engineering and has a tiny nervous system (just 302 neurons)
<div><img src="figs/Adult_Caenorhabditis_elegans_d76c553.jpg" height="150px" title="CC from wikipedia https://commons.wikimedia.org/w/index.php?curid=2680458"><figcaption>C. elegans– commons.wikimedia.org/w/index.php?curid=2680458</figcaption></div>
<div><img src="figs/c-elegans-connectome_2_9548c95.jpg" height="150px"><figcaption>C. elegans wiring diagram– [openworm.org](http://www.openworm.org), neuroconstruct.org</figcaption></div>
Note:
Now to do neuroscience research we have to use model organisms of course. Small number of neurons, can be labeled using green fluorescent protein or other means.
C. elegans is a nematode or roundworm. It is non-infectious and non-parasitic organism just 1 mm long and it can be easily genetically engineered. That means you can introduce mutations to genes or express fancy inert proteins that allow you to track the function of genes and cells in living animals making it a great model organism.
For neuroscientists it has only 302 total neurons making it a great way to dissect neural circuits underlying simple behaviors. Many mutant worms have been isolated that affect nervous system function allowing us to learn about the function of those genes. And you can engineer the worms to express fluorescent proteins so that the animal's neurons glow under a microscope. How many of you have heard of green fluorescent protein?
Having just 302 neurons is great for for some types of studies, however we have more than a million neurons in each of our eyes just alone
More than 1 million neurons that just form the optic nerve from each of our eyes!
---
## Model organisms— squid
Squids have unusually large axons (1 mm diameter)
<div style="width:250px; float:left;"><img src="figs/20000_squid_holding_sailor_f98a242.jpg" height="300px"><figcaption>20000 Lieues Sous les Mers, J. Verne</figcaption></div>
<div style="width:500px; float:left;"><img src="figs/Squid_Loligo_pealei_cbafe46.jpg" height="300px"><figcaption>Atlantic squid, *Loligo pealei*</figcaption></div>
<!-- <div><img src="figs/axon_large_9a8a930.jpg" height="300px"><figcaption>Squid giant axon, R. Hanlon MBL Woods Hole</figcaption></div> -->
Note:
Jules Verne provided inspiration for the space age but also neuroscientists in the 1940s.
Squids are arguably the most important model organism in the history of neuroscience. They are rarely studied anymore but their large axons which are 1mm in diameter-- 1000x bigger than our axons-- made their axons amenable to sticking electrodes inside them in the 1930s-50s and allowed neuroscientist to discover the biophysical and mathematical basis of neuronal signaling. We will discuss squid giant axons in much more detail soon.
Other important invertebrate organisms in neuroscience research include sea slugs and fruit flies and zebrafish. Some of these are very amenable to genetic engineering like C. elegans and have nervous systems more similar to our own.
Phylum: Mollusca
Class: Cephalopoda
Order: Teuthida
Family: Loliginidae
Genus: Loligo
Atlantic squid (Loligo pealei)
Phylum: Mollusca
Class: Cephalopoda
Order: Sepiida
Family: Sepiidae
Genus: Sepia
---
## Model organisms— Mus. musculus
The mouse is a common model in neuroscience research.
<div style="width:225px; float:left;"><img src="figs/adult_mouse_jax_ec76ad4.jpg" height="200px"><figcaption>Common house mouse *Mus. musculus*, jax.org</figcaption></div>
<div style="width:300px; float:left;"><img src="figs/abi_adult_mouse_brain_e79e400.jpg" height="200px"><figcaption>Mouse brain 3D rendering, [Brain Explorer 2](http://mouse.brain-map.org/static/brainexplorer)</figcaption></div>
<div style="width:430px; float:left;"><iframe src="https://www.youtube.com/embed/stPThgZ2Y5o" width="420" height="315"></iframe><figcaption>Green fluorescent protein (GFP) labeled neurons inside a mouse brain</figcaption></div>
Note:
But mammals are the only animals that have evolved a convoluted superficial part of the brain called the neocortex. And it is the cerebral neocortex is crucial for our highest cognitive functions, even if it sometimes seems that in election years that humans have lost their cerebral function.
Thus for research pertaining to the structure and function of the mammalian brain and human disease we turn to rodents like the common house mouse. Mice are small with a brain 2 cm in length, develop fairly quickly, and their genome has long been one of the most amenable to genetic engineering though this is quickly changing newer molecular biology techniques (like the CRISPR/Cas9 system).
* Mouse brain is about 2 cm in length
* genetically tractable
* [https://www.youtube.com/watch?v=stPThgZ2Y5o](https://www.youtube.com/watch?v=stPThgZ2Y5o)
---
## Model organisms– other mammals
Higher mammals are used to study more complex brain functions.
<div><img src="figs/1f412_3fc8278.svg" height="200px"><figcaption>Cats– visual system function, locomotion</figcaption></div>
<div><img src="figs/1f412_f738dec.svg" height="200px">
<figcaption>
Non-human primates– attention, decision
making, vision, brain machine interfaces
</figcaption></div>
<div><iframe src="https://www.youtube.com/embed/UJ_rFMYDbAE" width="420" height="315"></iframe><figcaption>Rhesus monkey mind controlled wheelchair</figcaption></div>
<!--
<div style="float:left;"><figure style="display:inline-table;"><img src="figs/1f412_3fc8278.svg" height="200px"><figcaption style="display:table-caption; caption-side:bottom;">Cats– visual system function, locomotion</figcaption></figure></div>
<div style="float:left;"><figure style="display:inline-table;"><img src="figs/1f412_f738dec.svg" height="200px"><figcaption style="display:table-caption; caption-side:bottom;">Non-human primates– attention, decision making, vision, brain machine interfaces</figcaption></figure></div>
<div style="width:430px; float:left;"><iframe src="https://www.youtube.com/embed/L2O58QfObus" width="420" height="315"></iframe><figcaption>Rhesus monkey mind controlled wheelchair</figcaption></div>
-->
Note:
Research with cats was critical for work from the 1950s to 1980s that allowed neuroscientist to learn how visual signals are processed in the highest circuits of the mammalian brain.
And research with rhesus monkeys has been essential for learning about perceptual, attentional, and decision making in the mammalian brain together with research into brain-machine interfaces that have direct clinical applications for human patients.
3rs: Replacement, Reduction, and Refinement
---
## Brain lesion patients
* Lesions in brains or degenerative diseases help us understand brain function
* Phineas Gage– Railroad spike through frontal lobes changed his personality
<div><img src="figs/image7_0e1af20.png" height="200px"><figcaption></figcaption></div>
<div><img src="figs/image8_c3232ea.png" height="200px"><figcaption></figcaption></div>
Note:
Furthermore, studies of patients with brain lesions has historically been key to localizing parts of the brain that affect emotional states and learning and memory.
e.g. Phineas Gage in 1848 his whole personality changed after the spike went through his brain.
Harlow wrote: "the equilibrium... between his intellectual faculties and his animal propensities seems to have been destroyed"
2cm scale bar. left 13yr old female patient. right 11 yr old control.
---
@@ -371,7 +266,7 @@ A glob of squishy jello? <!-- .element: class="fragment strike" data-fragment-in
<figure class="fragment fade-in" data-fragment-index="1"><img src="figs/image11_fbb6fc7.png" height="100px"><figcaption>Wikimedia Commons</figcaption></figure>
Cells. <!-- .element: class="fragment fade-in" data-fragment-index="1"-->
Cells. (though jello is made of collagen...) <!-- .element: class="fragment fade-in" data-fragment-index="1"-->
Note:
@@ -399,9 +294,9 @@ Only after fundamental and rigorous work by these two scientists, C. Golgi and S
Golgi staining: potassium chromate and silver nitrate (1873)
<div><img src="figs/camillo_golgi_hippocampus_40b7a67.jpg" height="300px"><figcaption>Golgi's drawing of the hippocampus impregnated by his stain (from Golgi's Opera Omnia).</figcaption></div>
<div><figcaption class="big">Golgi's drawing of the hippocampus impregnated by his stain</figcaption><img src="figs/camillo_golgi_hippocampus_40b7a67.jpg" height="300px"><figcaption>from Golgi's Opera Omnia.</figcaption></div>
<div><img src="figs/golgi_nobel_lecture_fig9_eb014b5.png" height="300px"><figcaption>Golgi's drawing of hippocampal dentate gyrus, fig. 9 from Nobel lecture</figcaption></div>
<div><figcaption class="big">Golgi's drawing of hippocampal dentate gyrus</figcaption><img src="figs/golgi_nobel_lecture_fig9_eb014b5.png" height="300px"><figcaption>fig. 9 from Golgi's Nobel lecture</figcaption></div>
Note:
@@ -414,7 +309,7 @@ Golgi's drawing of hippocampus after performing his black potassum chromate and
* syncytium: a mass of cytoplasm with many nuclei but no internal cell boundries
* reticulum: a fine network or netlike structure
* Camillo Golgi, Nobel Lecture December 11, 1906, *The Neuron Doctrine- theory and facts*:
* Camillo Golgi, Nobel Lecture December 11, 1906, *The Neuron Doctrine- theory and facts*:
<div style="width:960px; font-size:0.6em">
<div></div>
@@ -440,11 +335,11 @@ Golgi drew the structure of the hippocampus as being all fused together into a r
Note:
Neurons in culture have specific endings. EM methods, dye filling experiments.
Neurons in culture have specific endings. EM methods, dye filling experiments.
Heinrich Wilhelm Gottfried von Waldeyer-Hartz (6 October 1836 – 23 January 1921) was a German anatomist and conceived the word 'neuron'.
Golgi in his nobel lecture:
Golgi in his nobel lecture:
>(3) The neuron is a physiological unit. This fundamental idea which Waldeyer
expressed with perfect precision has been enlarged upon both from
anatomical and functional sides with additional propositions, for example :
@@ -460,17 +355,17 @@ also trophic units.**
<div style="width:300px; float:left;"><img src="figs/CamilloGolgi_5c05797.jpg" height="200px"><figcaption class="big">
Camillo Golgi
Pavia University
Pavia, Italy
Camillo Golgi
Pavia University
Pavia, Italy
</figcaption></div>
<div style="width:600px; float:left;"><img src="figs/SantiagoRamonyCajal_dd682a4.jpg" height="200px"><figcaption class="big">
Santiago Ramón y Cajal
Madrid University
Madrid, Spain
Santiago Ramón y Cajal
Madrid University
Madrid, Spain
</figcaption></div>
@@ -509,7 +404,7 @@ Now there are two basic cell types in the nervous system, neurons and glia. We w
Up to 90% of brain cells in mammals.
During evolution the glia/neuron ratio basically follows a power relation ship [^Herculano-Houzel-2014] y(x) = kx^n where on a log-log plot k is the intercept and n is the slope. Some of this original comparative estimates of glia/neuron ratios among animals was performed by Friede (1954)
During evolution the glia/neuron ratio basically follows a power relation ship [^Herculano-Houzel-2014] y(x) = kx^n where on a log-log plot k is the intercept and n is the slope. Some of this original comparative estimates of glia/neuron ratios among animals was performed by Friede (1954)
Perhaps only 10% of cells in invertebrates like drosophila.
@@ -573,13 +468,13 @@ Astrocytes are star shaped, hence their name.
Astrocytes are your pizza delivery persons for neurons. They are also like your mom, constantly upkeeping your room or synapses as is the case for neurons.
They are the direct decendents of the mother stem cells that give rise to the neurons and glia of the nervous system.
They are the direct decendents of the mother stem cells that give rise to the neurons and glia of the nervous system.
Devasting diseases of astrocyte function include brain cancer with gliomas like glioblastomas typicaly being comprised of astrocytes gone wild. It is also thought that some childhoold epilepsies may originate from altered astrocyte function.
blood brain barrier-- control entry of neurotransmitters and hormones into the brain
areas of the brain without a blood-brain barrier (from Table 32-2 Basic Neurochemistry 6e):
areas of the brain without a blood-brain barrier (from Table 32-2 Basic Neurochemistry 6e):
Pituitary gland
Median eminence
@@ -589,7 +484,7 @@ Paraphysis
Pineal gland
Endothelium of the choroid plexus
There is a positive relationship between lipid solubility and brain uptake of chemical compounds
There is a positive relationship between lipid solubility and brain uptake of chemical compounds
- permeability of lipid soluble compounds is rapid (ethanol, nicotine, diazepam, THC)
- polar molecules (e.g. glycine and catecholamines) enter slowly across BBB
@@ -617,7 +512,7 @@ water enters rapidly through diffusion.
<div style="width:300px; float:left;"><figcaption class="big">young oligodendrocyte</figcaption><img src="figs/Fig2d-oligodendrocyte_82ab0a3.png" height="150px"><figcaption>Ackman et al., 2006</figcaption></div>
<div style="width:450px; float:left;"><figcaption class="big">mature oligodendrocyte</figcaption><img src="figs/olig_9390c05.png" height="400px"><figcaption>J. Ackman 2005</figcaption></div>
<div style="width:350px; float:left;"><figcaption class="big">mature oligodendrocyte</figcaption><img src="figs/olig_9390c05.png" height="300px"><figcaption>J. Ackman 2005</figcaption></div>
Note:
@@ -673,7 +568,9 @@ Note:
## Cell body (soma) of a neuron
<figure><img src="figs/Neuroscience5e-Fig-01.03-1R_444117f.jpg" height="500px"><figcaption></figcaption></figure>
<!-- <figure><img src="figs/Neuroscience5e-Fig-01.03-1R_444117f.jpg" height="500px"><figcaption></figcaption></figure> -->
<figure><img src="figs/neuron-soma.svg" height="350px"><figcaption>[JA, CC0](https://creativecommons.org/share-your-work/public-domain/cc0/)</figcaption></figure>
Note:
@@ -691,23 +588,42 @@ Note:
<!-- <figure><img src="figs/neurons_9b62aa4.jpg" height="100px"><figcaption></figcaption></figure> -->
<figure><img src="figs/Neuroscience5e-Fig-01.02-1R-pyr-neuron_aa8d83c.jpg" height="300px"><figcaption></figcaption></figure>
<!-- <figure><img src="figs/Neuroscience5e-Fig-01.02-1R-pyr-neuron_aa8d83c.jpg" height="300px"><figcaption></figcaption></figure> -->
Note:
Polarity is everywhere in physics... and biology!
* electric dipole moments of molecules
* earth's magnetic poles
* electromagnetic waves
* DNA (5'-->3')
* mitotic cells
* apical-basal orientation of cells within tissues
* animal embryos and neural tube
from oxford dict,
polar
: directly opposite in character or tendency
polarity
: the relative orientation of poles; the direction of a magnetic or electric field
: the tendency of organisms or parts to develop with distinct anterior or posterior ends, or to grow or orient in a particular direction
---
## Structures of a neuron
* cell body (soma)– metabolic center of the cell, contains the nucleus.
* dendrites– receive incoming signals from other nerve cells
* axon– carries signals to other neurons
* axon hillock– initiates action potentials
* synapse– site at which two neurons communicate
* synaptic cleft– area between pre and post-synaptic cell
* Cell body (soma)– metabolic center of the cell, contains the nucleus.
* Dendrites– receive incoming signals from other nerve cells
* Axon– carries signals to other neurons
* Axon hillock– initiates action potentials
* Synapse– site at which two neurons communicate
* Synaptic cleft– area between pre and post-synaptic cell
Note:
@@ -716,7 +632,7 @@ Note:
## Neuron processes: dendrites
* Dendrites
* Dendrites
* Extensively branching from the cell body
* Transmit electrical signals (graded potentials) toward the cell body
* Function as receptive sites for other neurons
@@ -729,15 +645,15 @@ Note:
## Dendritic spines
<div style="width:400px; float:left;"><figcaption class="big">Purkinje neuron</figcaption><img src="figs/denk_1995-purkinje_neuron_5316809.jpg" width="350px"><figcaption>Denk et al., 1995</figcaption></div>
<div style="width:400px; float:left;"><figcaption class="big">Purkinje neuron dendritic tree</figcaption><img src="figs/denk_1995-purkinje_neuron_5316809.jpg" width="350px"><figcaption>Denk et al., 1995</figcaption></div>
<div style="width:550px; float:left;"><figcaption class="big">CA1 pyramidal neuron</figcaption><img src="figs/Tonnesen2014_nn.3682-SF1_56795be.jpg" height="500px"><figcaption>Tønnesen et al., 2014. 500 nm scale</figcaption></div>
<div style="width:550px; float:left;"><figcaption class="big">CA1 pyramidal neuron dendrite and spines</figcaption><img src="figs/Tonnesen2014_nn.3682-SF1_56795be.jpg" height="400px"><figcaption>Tønnesen et al., 2014. 500 nm scale</figcaption></div>
Note:
* 2 billion transistors in an iphone6.
* 100 billion neurons, each receiving up to 10000 synaptic connections
* 100 billion neurons, each receiving up to 10000 synaptic connections
* quadrillion synapses, 10^15 in our nervous system
False color of the dendrite of one neuron near an axon from another neuron from an EM image
@@ -780,24 +696,8 @@ Note:
* Axon collaterals
* Multiple branches at end of axon
* Terminal branches
* End in knobs called axon terminals (also called end bulbs or boutons)
---
## Neuron signals: action potentials
* Nerve impulse (action potential or 'spike')
* Neuron receives and sends signals
* Generated at the initial segment of the axon
* Conducted along the axon
* Releases neurotransmitters at axon terminals
* Neurotransmitters – excite or inhibit neurons
Note:
We will be discussing the nature of basic unit of nervous conduction, the action potential or impulse in great detail in ensuing lectures.
* Terminal branches
* End in knobs called axon terminals (also called terminal boutons)
---
@@ -815,7 +715,7 @@ Note:
## Example morphologies– cerebellar neurons
<figure><figcaption class="big">Purkinje cell, cerebellum</figcaption><img src="figs/Neuroscience5e-Fig-01.02-3R-purkinje-neuron_688ca6e.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 1.2</figcaption></figure>
<figure><figcaption class="big">Purkinje cell, cerebellum</figcaption><img src="figs/Neuroscience5e-Fig-01.02-3R-purkinje-neuron_688ca6e.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 1.2</figcaption></figure>
Note:
@@ -824,14 +724,17 @@ Note:
## Example morphologies– cortical neurons
* Pyramidal neurons– multipolar neurons that contain both apical and basal dendrite. Also contain one axon.
* Pyramidal neurons– multipolar neurons that contain both apical and basal dendrites. Also contain one axon eminating from cell body
* Most common excitatory neuron in the cerebral cortex
<div style="width:250px; float:left;"><figcaption class="big">pyramidal neuron</figcaption><img src="figs/Neuroscience5e-Fig-01.02-1R-pyr-neuron_aa8d83c.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 1.2</figcaption></div>
<!-- <div style="width:250px; float:left;"><figcaption class="big">pyramidal neuron</figcaption><img src="figs/Neuroscience5e-Fig-01.02-1R-pyr-neuron_aa8d83c.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 1.2</figcaption></div> -->
<div style="width:300px; float:left;"><figcaption class="big">pyramidal neurons</figcaption><img src="figs/golgi-pyr-neurons-fig19-nobel-lecture_b94e6d1.png" height="400px"><figcaption>C. Golgi, Fig. 19 Nobel lecture</figcaption></div>
<div style="width:250px; float:left;"><figcaption class="big">pyramidal neuron</figcaption><img src="figs/pyramidal-neuron.svg" height="300px"><figcaption>[JA, CC0](https://creativecommons.org/share-your-work/public-domain/cc0/). see also Neuroscience 5e Fig. 1.2</figcaption></div>
<div style="width:400px; float:left;"><figcaption class="big">rat pyramidal neuron</figcaption><img src="figs/071030_03_vc0110-2_lay2_biocy_zproj-merge_66b7de1.png" height="400px"><figcaption>Ackman et al., 2009</figcaption></div>
<div style="width:300px; float:left;"><figcaption class="big">pyramidal neurons</figcaption><img src="figs/golgi-pyr-neurons-fig19-nobel-lecture_b94e6d1.png" height="300px"><figcaption>C. Golgi, Fig. 19 Nobel lecture</figcaption></div>
<div style="width:400px; float:left;"><figcaption class="big">rat pyramidal neuron</figcaption><img src="figs/071030_03_vc0110-2_lay2_biocy_zproj-merge_66b7de1.png" height="300px"><figcaption>Ackman et al., 2009</figcaption></div>
Note:
@@ -856,9 +759,12 @@ Note:
## Structure of a sensory neuron (afferent)
Function of an **afferent** neuron is to carry information from the sensory periphery towards the CNS or brain.
Function of an **afferent** neuron is to carry information from the sensory periphery towards the central nervous system.
<!-- <figure><figcaption class="big">nociceptive (pain) neuron</figcaption><img src="figs/image28_d35899e.png" height="400px"><figcaption></figcaption></figure> -->
<figure><figcaption class="big">sensory neuron</figcaption><img src="figs/sensory-neuron.svg"><figcaption>[JA, CC0](https://creativecommons.org/share-your-work/public-domain/cc0/)</figcaption></figure>
<figure><figcaption class="big">nociceptive (pain) neuron</figcaption><img src="figs/image28_d35899e.png" height="400px"><figcaption></figcaption></figure>
Note:
@@ -868,9 +774,12 @@ Afferent- term meaning to send information from periphery to the CNS or to brain
## Structure of a motor neuron (efferent)
Function of an **efferent** neuron is to carry information towards the muscles for effecting behavior.
Function of an **efferent** neuron is to carry information towards the muscles for bringing about behavior.
<!-- <figure><figcaption class="big">alpha motor neuron</figcaption><img src="figs/image29_df57dca.png" height="400px"><figcaption></figcaption></figure> -->
<figure><figcaption class="big">motor neuron</figcaption><img src="figs/motor-neuron.svg"><figcaption>[JA, CC0](https://creativecommons.org/share-your-work/public-domain/cc0/)</figcaption></figure>
<figure><figcaption class="big">alpha motor neuron</figcaption><img src="figs/image29_df57dca.png" height="400px"><figcaption></figcaption></figure>
Note:
@@ -895,12 +804,31 @@ Note:
## Inter-neuronal signaling occurs at synapses
<figure><img src="figs/image30_268faa4.png" height="400px"><figcaption></figcaption></figure>
<!-- <figure><img src="figs/image30_268faa4.png" height="400px"><figcaption></figcaption></figure> -->
<figure><img src="figs/synapse-model.svg" height="350px"><figcaption>JA, CC0</figcaption></figure>
Note:
We will be going into synapse structure and function in much detail later in the class, but just to complete our introduction to basic anatomical details of neurons this figure illustrates...
We will be going into synapse structure and function in much detail later in the class, but just to complete our introduction to basic anatomical details of neurons this figure illustrates...
---
## Neuron signals: action potentials
* Nerve impulse (action potential or 'spike')
* Neuron receives and sends signals
* Generated at the initial segment of the axon
* Conducted along the axon
* Releases neurotransmitters at axon terminals
* Neurotransmitters – excite or inhibit neurons
Note:
We will be discussing the nature of basic unit of nervous conduction, the action potential or impulse in great detail in ensuing lectures.
---
@@ -936,11 +864,14 @@ Note:
---
## Example of a simple circuit: stretch reflex (myotatic reflex)
## Example of a simple circuit: stretch (myotatic) reflex
The "knee-jerk response" is a simple reflex circuit.
<div style="width:100%; float:left;"><img src="figs/Neuroscience5e-Fig-01.07-1R-stretch-reflex-edit_c4d4d1a.jpg" width="700px"><figcaption>Neuroscience 5e Fig. 1.7</figcaption></div>
<!-- <div style="width:100%; float:left;"><img src="figs/Neuroscience5e-Fig-01.07-1R-stretch-reflex-edit_c4d4d1a.jpg" width="700px"><figcaption>Neuroscience 5e Fig. 1.7</figcaption></div> -->
<div style="width:100%; float:left;"><img src="figs/spinal-motor-reflex-arc.svg" height="350px"><figcaption>JA, CC0. see also Neuroscience 5e Fig. 1.7</figcaption></div>
<!-- <div style="width:250px; float:left;"><iframe src="https://www.youtube.com/embed/Ll8r5i0eaT8" height="150"></iframe><figcaption>Stretch reflex</figcaption></div> -->
@@ -960,7 +891,7 @@ Muscle lengthens, stretching muscle spindle (sensory ending), leading to incr al
## Ways to measure neural activity
* Extracellular recording– an electrode is placed near a neuron. Measures action potentials. Useful for detecting patterns of activity.
* Extracellular recording– an electrode is placed near a neuron. Measures action potentials. Useful for detecting patterns of activity.
* Intracellular recording– an electrode is placed inside a neuron-can measure smaller graded potential changes. Useful for isolating responses to single inputs.
Note:
@@ -970,9 +901,11 @@ You might have the anatomy skills of Cajal or Golgi and you know there is this r
---
## Extracellularly recorded responses underlying the myotatic reflex
## Extracellularly recorded responses underlying the stretch reflex
<figure><figcaption class="big">Extracellular recordings showing action potential firing frequencies</figcaption><img src="figs/Neuroscience5e-Fig-01.08-0_080fe2c.png" width="700px"><figcaption>Neuroscience 5e Fig. 1.8</figcaption></figure>
<!-- <figure><figcaption class="big">Extracellular recordings showing action potential firing frequencies</figcaption><img src="figs/Neuroscience5e-Fig-01.08-0_080fe2c.png" width="700px"><figcaption>Neuroscience 5e Fig. 1.8</figcaption></figure> -->
<figure><figcaption class="big">Extracellular electrode recordings showing action potential firing frequencies</figcaption><img src="figs/spinal-motor-reflex-extracellular.svg" height="350px"><figcaption>CC0, see also Neuroscience 5e Fig. 1.8, 1.9</figcaption></figure>
Note:
@@ -980,17 +913,17 @@ Note:
These ticks are spikes or action potentials recorded extracelluarly. Since the electrode tip is placed close to the neurons cell membrane, the electrode can pick up signals as they pass by. A little bit like someone wiretapping your phone line.
---
We will come back to this reflex circuit in greater detail time and again as we go through this course.
And really, the basic logic of this circuit and variants of it is replicated all over the brain and teasing apart all the types of cells, their response properties, and their functional interactions or connections with one another for all types of different sensory and motor behavior is the grand challenge, beauty, and fun of modern and future neuroscience.
<!-- ---
## Intracellularly recorded reponses underlying the myotatic reflex
<figure><figcaption class="big">Intracellular recordings of neuronal responses in the reflex circuit</figcaption><img src="figs/Neuroscience5e-Fig-01.09-0_3d0b7b5.jpg" height="500px"><figcaption>Neuroscience 5e Fig. 1.9</figcaption></figure>
Note:
We will come back to this reflex circuit in greater detail time and again as we go through this course.
And really, the basic logic of this circuit and variants of it is replicated all over the brain and teasing apart all the types of cells, their response properties, and their functional interactions or connections with one another for all types of different sensory and motor behavior is the grand challenge, beauty, and fun of modern and future neuroscience.
---
And really, the basic logic of this circuit and variants of it is replicated all over the brain and teasing apart all the types of cells, their response properties, and their functional interactions or connections with one another for all types of different sensory and motor behavior is the grand challenge, beauty, and fun of modern and future neuroscience. -->

348
neuroanatomy2.md
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@@ -1,4 +1,4 @@
## Neural Systems
# Neural Systems
* Circuits that do the same kinds of things are grouped into 'systems', e.g. sensory systems and motor systems
* Many neurons function between these systems, called associational systems. Associational systems are the most complex and least well characterized systems.
@@ -9,8 +9,6 @@ Last time we learned some of the basic cellular anatomy of the nervous system. T
First of all it is a system of systems. In other words…
TODO: exchange pngs for jpgs in this document
---
## Major components of the nervous system and their functional relationships
@@ -368,7 +366,7 @@ From the brain stem there emerges 12 left-right pairs of cranial nerves that car
## Cranial nerves
<div style="font-size:0.6em">
<div style="font-size:0.5em">
<div></div>
number | name | function
@@ -429,6 +427,8 @@ Now you’ve all heard the phrase ‘running around like a chicken with its head
<div><iframe src="https://www.youtube.com/embed/ATz3AdbjyRI" width="420" height="315"></iframe><figcaption>Mike the headless chicken</figcaption></div>
[http://www.dailymail.co.uk/news/article-5556351/Headless-chicken-survives-WEEK-decapitated.html](http://www.dailymail.co.uk/news/article-5556351/Headless-chicken-survives-WEEK-decapitated.html)
Note:
Well here is a grotesque way of convincing you that all you need to live is your brainstem…
@@ -528,13 +528,15 @@ Note:
Thalamus is essentially the relay nuclei that routes sensory information into the cortex. This routing of information is highly organized with different subdivisions sending information in parallel pathways to different visual, auditory, and somatosensory regions of the cerebral cortex. But the connections are highly reciprocal with cortical areas, such that the thalamus is integral to many sensory, motor, and cognitive functions as well as the generation of different electrical rhythms that underly different sleep states.
Which connections gets through to neocortex without a thalamic relay? **neuromodulatory input**: cholinergic, serotonergic, histamatergic, adrengergic, dopaminergic signaling. Pathways manipulated by drugs that manipulate behavioral state and mood. More on this later in the course.
---
## Thalamus– gateway to the cerebral cortex
<div><figcaption class="big">Thalamus (brown), ventricles (blue)</figcaption><video height=300px controls loop src="figs/thalamus.m4v"></video><figcaption>[C. Krebs CC BY-NC-SA, Univ. British Columbia](http://www.neuroanatomy.ca/3D_files/3D_index.html?id=1)</figcaption></div>
<div style="width:400px"><figcaption class="big">Thalamus (brown), ventricles (blue)</figcaption><video height="250px" controls loop src="figs/thalamus.m4v"></video><figcaption>[C. Krebs CC BY-NC-SA, Univ. British Columbia](http://www.neuroanatomy.ca/3D_files/3D_index.html?id=1)</figcaption></div>
<div><figcaption class="big">Fiber stain</figcaption><img src="figs/2060_fiber-thalamus_207b466.png" height="300px"><figcaption>[Brain Biodiversity Bank MSU, NSF](https://msu.edu/~brains/brains/human/coronal/montage.html)</figcaption></div>
<div><figcaption class="big">Fiber stain</figcaption><img src="figs/2060_fiber-thalamus_207b466.png" height="250px"><figcaption>[Brain Biodiversity Bank MSU, NSF](https://msu.edu/~brains/brains/human/coronal/montage.html)</figcaption></div>
Note:
@@ -602,23 +604,6 @@ Limbic system includes the amygdala, as well as the part of the basal ganglia, p
Note:
---
## Lobes of the cerebral cortex
* frontal– planning responses to stimuli, contains: motor cortex (precentral gyrus)
* parietal– somatic sensory cortex (postcentral gyrus)
* temporal– audition and insular cortex (taste)
* occipital– vision
<div><img src="figs/Neuroscience5e-Fig-A03-1R_3474298.png" height="250px"><figcaption>Neuroscience 5e Fig. A3</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-A03-2R_c3b128c.png" height="250px"><figcaption>Neuroscience 5e Fig. A3</figcaption></div>
Note:
---
## Cortico-cortical connection pathways
@@ -637,7 +622,7 @@ Note:
<div style="margin-bottom:50px"><figcaption class="big">Fiber stain</figcaption><img src="figs/2240_fiber_d16bc49.jpg" height="200px"><figcaption>[Brain Biodiversity Bank MSU, NSF](https://msu.edu/~brains/brains/human/coronal/montage.html)</figcaption></div>
<div><figcaption class="big">Dorsal view</figcaption><img src="figs/Neuroscience5e-Fig-A11-1R_a8973d9_copy_9c648a7.jpg" height="200px"><figcaption>Neuroscience 5e Fig. A11</figcaption></div>
<div><figcaption class="big">Dorsal view</figcaption><img src="figs/Neuroscience5e-Fig-A11-1R_a8973d9_copy_9c648a7.jpg" height="200px"><figcaption>Neuroscience 5e Fig. A11</figcaption></div> <!-- .element: class="fragment fade-in"-->
<div><figcaption class="big">Dorsal view cut away</figcaption><img src="figs/Neuroscience5e-Fig-A11-3R_17d31f5_copy_406b96a.jpg" height="200px"><figcaption>Neuroscience 5e Fig. A11</figcaption></div> <!-- .element: class="fragment fade-in"-->
@@ -646,63 +631,21 @@ Note:
Note:
corpus callosum
: connections the cerebral hemispheres
: only in placental mammals (the eutherians)
: absent in monotremes and marsupials and other vertebrates (e.g. birds, reptiles, amphibians and fish)
anterior commisure
: connects temporal lobes
: connects both amygdala
: crossed projects from olfactory tracts
---
## Primary versus non-primary cortex
<div style="font-size:0.7em;">
<div></div>
* Primary cortex
* Cortical areas that are the primary projection fields targeted by the sensory input pathways
* Cortical areas that are the principal fields which have neurons that project down into the spinal cord for effecting control
* Primary visual (calcarine sulcus)
* Primary auditory
* Primary somatosensory (post-central gyrus)
* Primary motor (pre-central gyrus)
</div>
<div style="width: 400px; font-size:0.7em;">
<div></div>
* Non-primary cortex
* everything in between
* referred to collectively as association cortex
</div>
<div style="padding:0 50px;"><img src="figs/Neuroscience5e-Fig-26.01-0_copy_c5817b1.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 26.1</figcaption></div>
Note:
---
## Brain organization summary
<div><img src="figs/Neuroscience5e-Fig-A12-1R_copy_020ed62.jpg" height="315px"><figcaption>Neuroscience 5e Fig. A12</figcaption></div>
<div><iframe src="https://www.youtube.com/embed/snO68aJTOpM" width="420" height="315"></iframe><figcaption>Pinky and the Brain</figcaption></div>
Note:
corpus callosum
: connections the cerebral hemispheres
: only in placental mammals (the eutherians)
: absent in monotremes and marsupials and other vertebrates (e.g. birds, reptiles, amphibians and fish)
anterior commisure
: connects temporal lobes
: connects both amygdala
: crossed projects from olfactory tracts
---
## Laminar organization of neocortex
* Cortex itself has a thickness of only about 2-4mm.
* Cortex itself has a thickness of only about 2-4mm
* 6 layers (neocortex)
* Layer IV is the primary input layer
* Layers II and III are cortico-cortical output layers
@@ -753,13 +696,19 @@ Note:
Note:
[Gyrification from constrained cortical expansion](http://www.pnas.org/content/111/35/12667)
[^Tallinen:2014] http://dx.doi.org/10.1038/nphys3632
[^Watts:1998]
---
## Which of the following is true?
1. Do specific regions of the brain control specific functions?
2. Does each part of the brain do all functions?
2. Does each part of the brain do all functions? <!-- .element: class="fragment strike" data-fragment-index="1"-->
3. Does a specific function come from many parts of the brain?
Note:
@@ -768,36 +717,26 @@ Now lets expand on how functions are organized in the brain. Which of the follow
it’s a bit of a trick question because both of these answers are partially right depending on how you define a part of the brain or what kind of function you’re talking about, but it is not the case that
<!--
## Early 1800’s Franz Joseph Gall
---
* all behavior emanates from the brain
* particular regions of the cerebral cortex controlled specific functions, i.e. the brain does not act as a single organ.
* each function grew with use such as a muscle with exercise
* this growing causes the skull to budge creating a pattern of bumps “phrenology”
## Lobes of the cerebral cortex
## Franz Joseph Gall– phrenology
* frontal– planning responses to stimuli, contains: motor cortex (precentral gyrus)
* parietal– somatic sensory cortex (postcentral gyrus)
* temporal– audition and insular cortex (taste)
* occipital– vision
Standing at his lectern, the priest stared steadily upon one man in the congregation: Franz Joseph Gall. With his angry voice echoing off the church's hallowed walls, he pronounced,"There are those amongst us, who have lost their way from our Lord's divine path. With pomposity, they state the mind is situated in an organ as mushy and insubstantial as the brain. What ludicrousness is this, when all intelligent men know that God has imbued our thinking into our very soul, whereupon no one can put his finger precisely on the spot!"
<div><img src="figs/Neuroscience5e-Fig-A03-1R_3474298.png" height="250px"><figcaption>Neuroscience 5e Fig. A3</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-A03-2R_c3b128c.png" height="250px"><figcaption>Neuroscience 5e Fig. A3</figcaption></div>
http://thevictoriantimes.blogspot.com/2011/10/galls-phrenology.html
<div><img src="figs/image21_cc3a4ac.png" height="300px"><figcaption></figcaption></div>
Note:
## Phrenology
<div><img src="figs/image22_f181430.png" height="300px"><figcaption></figcaption></div>
## Pierre Flourens (French)
* Tested Gall’s ideas by removing different parts of the brain (dogs and rabbits) and asked if specific functions were compromised.
* Showed medulla important for respiration, cerebellum important for movements.
* Lesions in cortex affected either zero or many behaviors. Concluded that the cortex was one organ and not regionalized.
-->
---
## Korbinian Brodmann (1909)
* Used subtle anatomical differences in the brain to divide it into discrete areas or regions
@@ -842,214 +781,42 @@ Note areas 4 (primary motor cortex), 1,2,3 (primary somatosensory cortex), area
*area 22 superior temporal gyrus*
---
## Paul Broca (1861)
* Believed that functions could be localized in the brain
* Studied patients with aphasia– language disorders found in patients who have had a stroke
* Had a patient that could understand language but could not speak, problems with the organizational aspects of language. Found lesion in posterior frontal lobe (Brodmann areas 44/45)
* This kind of aphasia is called a motor or expressive aphasia
* Eight patients with similar problems all had similar lesions, always on the left side
* "Nous parlons avec l’hemisphere gauche!" "We speak with the left hemisphere!"
Note:
We also define regions of the brain based on studies of brain lesions in patients. Recall the guy with the railroad spike from last lecture. Well the French physician Paul Broca in the 19th c.
--
## Broca and a patient’s brain
<div><img src="figs/image25_2d10fa8.png" height="300px"><figcaption></figcaption></div>
Note:
---
## Carl Wernicke (1874)
## Primary versus non-primary cortex
* Had a patient that could speak but not understand language. Called receptive aphasia
* Damage was to a different area– left side, posterior part of the left temporal lobe (Brodmann areas 22/39/40)
* Argued that simple perceptual and motor activities were localized to a specific area and that most functions result from interconnections between areas. Idea of "distributive processing"
Note:
---
## Major brain areas involved in the comprehension and production of language
<div><img src="figs/Neuroscience5e-Fig-27.01-0_eaf66c7_copy_1841ced.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 27.1</figcaption></div>
Note:
*Arcuate fasciculus: major association fiber tract in CNS that connects Broca’s and Wernicke’s areas*
---
## Characteristics of Broca's and Wernicke's aphasias
<div><img src="figs/Neuroscience5e-Tab-27.01-0_859de7f_copy_4abca30.jpg" height="300px"><figcaption>Neuroscience 5e Table 27.1</figcaption></div>
Note:
*Broca's aphasia patients have limited writing. Loss of the ability to produce language (spoken or written)*
Apraxia
: verbal apraxia is difficulty starting and making voluntary movements (motor plans) needed for speech (with no paralysis or weakness of speech muscles)
dysarthria
: inability to move the muscles of the tongue and mouth to produce speech
agraphia
: inability to write
Agnosia
: inability to process sensory information
: affects a single modality
syntax
:the arrangement of words and phrases to create well-formed sentences in a language
Grammar
:in linguistics it is set of structural rules governing the composition of clauses, phrases, and words in any given natural language. The term refers also to the study of such rules, and this field includes morphology, syntax, and phonology, often complemented by phonetics, semantics, and pragmatics
<!-- ## Conduction aphasia
* Inability to produce appropriate responses to heard communication, even though the communication is understood.
* Can speak fluently but bad at making the connection from what has been heard to how to reply.
* Often associated with damage in the Arcuate fasiculus –an axon tract that connects wernike and broca areas.
* Difficulty repeating words
* Fluent, but with many incorrect word substitutions
* Good comprehension
<div><img src="figs/image26_0d58d77.png" height="300px"><figcaption></figcaption></div>
## Arcuate fasciculus: major association fiber tract in CNS that connects Broca’s and Wernicke’s areas
<div><img src="figs/image27_5c764df.png" height="300px"><figcaption></figcaption></div>
<div><img src="figs/ArcuatefasciculusiinCortex_1c69f77.png" height="300px"><figcaption></figcaption></div>
-->
---
## Other evidence of brain regionalization
* Fritsch and Hitzig (1870)– discrete limb movements in dogs can be produced by electrical stimulation of the contra-lateral motor cortex. Thus the right hand is controlled by the left hemisphere. 'Dominant' hemisphere
* Wilder Penfield (1950)– neurosurgeon, localized motor functions by stimulating specific areas of the brain
* Roger Sperry (1960s)– split brain patient studies
Note:
And there is lots of other evidence for localization of brain function, especially for sensory and motor information for limbs and body. In fact Fritsch…
And the Canadian physician Wilder Penfield performed classical mapping of motor function in the cerebral cortex by localized electrical stimulation.
And then there is the fascinating split brain studies of Sperry and Gazzaniga in the 1960s
---
## Penfield stimulation studies
<div><iframe src="https://www.youtube.com/embed/l1SAC1HcAzc" width="420" height="315"></iframe><figcaption>Stimululation based brain mapping</figcaption></div>
Note:
Epileptic patient. mapping the cortical tissue before resecting the site of tissue where the seizures are being generated.
*Start about minute 3*
---
## Split brain studies: Nobel prize 1981
<div style="font-size:0.9em; width:100%">
<div style="font-size:0.7em;">
<div></div>
* The corpus callosum and anterior commissure are the two axon tracts that connect the two sides of the brain. They are sometimes cut to prevent the spread of severe epilepsies
* Each side of the brain works independently from the other
* Roger Sperry showed that the left hemisphere dominates speech, writing, right hand stereognosis, analysis of right visual field
* Right hemisphere dominates, emotional coloring of language, spatial abilities, left hand stereognosis, analysis of left visual field
* Primary cortex
* Cortical areas that are the primary projection fields targeted by the sensory input pathways
* Cortical areas that are the principal fields which have neurons that project down into the spinal cord for effecting control
* Primary visual (calcarine sulcus)
* Primary auditory
* Primary somatosensory (post-central gyrus)
* Primary motor (pre-central gyrus)
</div>
<div><img src="figs/sperry_postcard_cf69954.jpg" height="200px"><figcaption>R. Sperry</figcaption></div>
<div style="font-size:0.7em; width:500px">
<div style="width: 400px; font-size:0.7em;">
<div></div>
>"for his discoveries concerning the functional specialization of the cerebral hemispheres"
* Non-primary cortex
* everything in between
* referred to collectively as association cortex
</div>
<div style="padding:0 50px;"><img src="figs/Neuroscience5e-Fig-26.01-0_copy_c5817b1.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 26.1</figcaption></div>
Note:
The classic split brain studies which Roger Sperry got the Nobel for in 1981 showed the lateralized localization of language that Broca and Wernicke anticipated as well as several other higher functions. They took advance of the fact that in patients with severe epilepsies, sometimes the commissures connecting the two hemispheres are cut to prevent the spread of seizures.
And since each side of the brain to some degree can work independently of the other
* Humans are 90% right handed as a population and the degree of lateralization among individuals is strong, regardless of left or right-handedness
* 96% of right handers having left hemisphere speech, compared with 70% of left handers
* Twin studies have demonstrated some genetic influence on handedness, but 75% of the variance is nongenetic and individually specific, with only 25% explained by genes [#Bishop:2013]. Even the segregation of of handedness and language laterality suggests a complex polygenic set of factors, with 96% of right handers having left hemisphere speech, compared with 70% of left handers [#Bishop:2013].
---
## Confirmation of hemispheric specialization for language
## Mapping brain activity with human neuroimaging
<div><img src="figs/Neuroscience5e-Fig-27_split-brain_copy_8719b7e.jpg" height="500px"><figcaption>Neuroscience 5e Fig. 27.3</figcaption></div>
Note:
Here is an illustration of the experiment performed by by Sperry and his colleagues for these split brain studies.
After the corpus callosum connecting the two hemisphere was cut to alleviate epileptic seizures, the patients were asked to fixate on a point and name objects presented in each visual field.
Now you haven’t learned about the visual system yet, but just as sensory information from your left hand goes to your right hemisphere, visual information from the lateral part of your left visual field goes to your right visual cortex.
Split brain patients could not correctly name objects presented in their left visual field, presumably because that info could not reach the left hemispheres because the callosal connections were severed. But split brain patients could correctly name an object when presented in their right visual field, because that information was received by the left visual cortex and could be passed onto the language centers.
In all Sperry and his colleagues showed that language, mathematical, and logical reasoning is dominant in the left hemisphere and that shape recognition, spatial attention, emotional processing, and creativity in more dominant in the right hemisphere.
*right hemisphere: 'coloring' language with emotive tonal variation, 'prosody'. Adds additional meaning to verbal communication. Mandarin chinese. Monotone professor lecture*. Evidence suggest similar areas of the right hemisphere associate with this emotive coloring of language.
Similar areas used in sign language thus this constellation of brain regions specializes in symbolic representation and communication, rather than just spoken language.
PET:
: positron emission tomography
: detects pairs of gamma rays emitted indirectly by a radioactive tracer injected into bloodstream (positron-emitting radionuclide)
CT:
: computerized tomography
: a series of X-ray images from different angles
: computer processing to create cross-sectional images
Babbling sounds from a baby shows that there is a pattern of sounds produced sequentially that are related to the phones necessary for producing spoken language. Language imitation follows other imitations (mirror neurons?) during developmental learning and behavioral acquistion. Brain is continuously simulating the future based on past experienced training patterns.
--
## Mapping brain activity with fMRI
<figure><img src="figs/Neuroscience5e-Fig-27.06-0_2687612_copy_718a9bc.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 27.6</figcaption></figure>
<figure><figcaption class="big">functional magnetic resonance imaging (fMRI)</figcaption><img src="figs/Neuroscience5e-Fig-27.06-0_2687612_copy_718a9bc.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 27.6</figcaption></figure>
Note:
@@ -1058,4 +825,15 @@ Note:
- different patterns of brain activity localization depending on what the task is
- Actually sitting inside a small space magnet
---
## Brain organization summary
<div><img src="figs/Neuroscience5e-Fig-A12-1R_copy_020ed62.jpg" height="315px"><figcaption>Neuroscience 5e Fig. A12</figcaption></div>
<div><iframe src="https://www.youtube.com/embed/snO68aJTOpM" width="420" height="315"></iframe><figcaption>Pinky and the Brain</figcaption></div>
Note:

165
neurophysiology1.md
View File

@@ -1,4 +1,4 @@
## Neuronal signaling
# Neuronal signaling
* Electrical signals of nerve cells
* Voltage-dependent membrane permeability
@@ -104,6 +104,13 @@ mole
: this number is expressed by the Avogadro constant
electricity
: movement of charged carriers through a medium in presence of electric field
: duality of electromagnetic waves as wave or particle
: AC (oscillation of electrons in place) vs DC (movment of electrons)
100 m/s == 360K m/hr == 223 mph
---
## Electrical signals
@@ -208,7 +215,7 @@ Now we already saw that we can stick an electrode into a cell, and hook it up to
Now what if do the same recordings, but also electrically stimulate the cell so that positive or negative charge is added—
---
--
## Recording passive and active electrical signals in a nerve cell
@@ -249,11 +256,24 @@ All electrical signals are the due to the flow of charge, positive or negative.
---
## Ionic movements across neuronal membranes
<figure><img src="figs/Neuroscience5e-Fig-02.04-0R_cf6b01f.png" height="400px"><figcaption>Neuroscience 5e Fig. 2.4</figcaption></figure>
Note:
there are active ion transporters like the Na-K ATPase and there are ion channels. For example you could pretend this is a Na channel that opens when the neuron is depolarized.
---
## Ion transporters and ion channels
* Ion transporters– actively move ions against their concentration gradients, therefore create ion concentration gradients
* Ion channels– proteins that allow only certain kinds of ions across the membrane
* Allow ions to diffuse across the membrane (e.g. due to concentration gradients).
* Allow ions to diffuse across the membrane (e.g. due to concentration gradients).
Note:
@@ -295,19 +315,6 @@ Ion channels span the membrane and act as pores. They can open and close, often
And they can be additionally regulated or ‘gated’ by different mechanisms including voltage or binding of ligands such as neurotransmitters. We will learn much more about the selectivity and function of ion channels a couple lectures from now.
---
## Ionic movements across neuronal membranes
<figure><img src="figs/Neuroscience5e-Fig-02.04-0R_cf6b01f.png" height="500px"><figcaption>Neuroscience 5e Fig. 2.4</figcaption></figure>
Note:
So again there are active ion transporters like the Na-K ATPase and there are ion channels. For example you could pretend this is a Na channel that opens when the neuron is depolarized.
---
## The resting potential
@@ -381,7 +388,7 @@ Note:
## Nernst equation
<div style="font-size:0.7em;">
<div style="font-size:0.6em;">
<div></div>
* Statement of the equilibrium condition for a single ion species across a membrane that is permeable only to that ionic species:
@@ -391,13 +398,13 @@ Note:
* *F* = faraday constant (9.6x10<sup>4</sup> J mol<sup>-1</sup> V<sup>-1</sup>)
* *z* = valence of the ion, including sign.
* ln = natural logarithm (base *e*)
* [*x*]<sub>out</sub> extracellular concentration of an ion extracellular; [*x*]<sub>in</sub> intracellular concentration
* [*x*]<sub>out</sub> extracellular concentration of an ion; [*x*]<sub>in</sub> intracellular concentration
* RT/F can be a constant at room temperature to give a simplified equation
</div>
<div><figcaption class="big">Nernst equation</figcaption><img src="figs/ScreenShot2016-01-12at12.35.02PM_cfc06b6.png" height="100px"><figcaption>For calculations for any temperature, E<sub>x</sub> in volts (V)</figcaption></div>
<div><figcaption class="big">Nernst equation</figcaption><img src="figs/ScreenShot2016-01-12at12.35.02PM_cfc06b6.png" height="100px"><figcaption>For calculations at any temperature, E<sub>x</sub> in volts (V)</figcaption></div>
<div><figcaption class="big">Simplified Nernst equation</figcaption><img src="figs/ScreenShot2016-01-12at12.35.07PM_dc81a98.png" height="100px"><figcaption>For calculations at room temperature (68ºF = 20ºC = 20+273 = 293ºK), E<sub>x</sub> in millivolts (mV)</figcaption></div>
@@ -426,7 +433,8 @@ z
: the valence of the ion in question
ln
: the natural logarithm which has the mathematical constant e or 2.718 as it’s base
: the natural logarithm which has the mathematical constant *e* =~2.718 as it’s base (Euler's number)
: ln(e) = 1, where e =~ 2.718
Now many of the classical experiments recording membrane potential in squid axon or other preparations were conducted at room temperature, which is 20ºC or about 68ºF.
@@ -442,9 +450,9 @@ ln(x) / log10(x) = 2.30
—> 2.30 * log10(x) = ln(x)
logarithm slope example:
x = seq(0,10,0.10)
plot(x,log(x), asp=1)
plot(x,log10(x), asp=1)
x = seq(0,10,0.10);
plot(x,log(x), asp=1);
plot(x,log10(x), asp=1);
R = 8.3 J/K*mol, T = 37ºC + 273ºC = 310 K, F = 9.6*10^4 J/mol*V
@@ -455,22 +463,60 @@ E =
log(7) / log10(7)
R = 8.3
F = 9.6 * 10^4
T = 20+273
(R*T / F) * 1000 * 2.3
==>58.26427
<figure><img src="figs/Screen_Shot_2016-09-29_at_5.15.39_AM_6d8392d.png" height="100px"><figcaption></figcaption></figure>
<figure><img src="figs/Screen_Shot_2016-09-29_at_5.15.43_AM_5c77e27.png" height="100px"><figcaption></figcaption></figure>
--
## Obtaining the simplified Nerst equation
<div style="font-size:0.7em">
<div></div>
Open up your browser's javascript console `cmd-alt-j (or View-->Developer-->). Copy/paste the following lines:
```javascript
R = 8.3 //Gas constant
F = 9.6 * Math.pow(10,4) //Faraday constant
T = 20+273 //Room temperature in Kelvins
```
Relation of the natural lograrithm (base ~2.718...) to the base 10 logarithm is always `ln(x) = 2.30 * log10(x)` or `ln(x) / log10(x) = 2.30`. ln() is `Math.log()` and log10() is `Math.log10()` in js. Copy/paste the following lines. Try varying *x* a few times and re-calculate:
```javascript
x = 5
Math.log(x) / Math.log10(x)
```
Now use our constants defined above, convert to base10 log, and adjust the voltage from V to mV. We get 58 mV for our answer:
```javascript
(R*T / F) * 2.3 * 1000
```
=>58.26427 mV
</div>
Note:
```
var a = [2,5,7,10,1000]
a.forEach(el => console.log( Math.log(el) / Math.log10(el) ))
```
---
## Examples
<div style="font-size:0.7em;">
<div></div>
* Calculate the following equilibrium potentials at room temperature:
* Outside 10 mM KCl, Inside 1 mM KCl membrane only permeable to K⁺ ?
* E<sub>K+</sub> = <span class= "fragment fade-in">(58/1)log10(10/1) ==> +58</span>
@@ -480,6 +526,8 @@ T = 20+273
* E<sub>Ca2+</sub> = <span class= "fragment fade-in">(58/2)log10(10/1) ==> +29 mV</span>
* Nernst predicts linear relationship with a slope of 58 mV (58/z) per 10 fold ion change in concentration gradient <!-- .element: class="fragment fade-in"-->
</div>
Note:
log10(10) = 1
@@ -532,9 +580,9 @@ Note:
---
## Membrane potential influences ion fluxes
## Membrane potential influences the flux of ions
<div><figcaption class="big">Simulated cell at room temperature</figcaption><img src="figs/Neuroscience5e-Fig-02.06-1R_5d1ff2f.png" height="400px"><figcaption>Neuroscience 5e Fig. 2.6</figcaption></div>
<div><figcaption class="big">Simulated cell at room temperature</figcaption><img src="figs/Neuroscience5e-Fig-02.06-1R_5d1ff2f.png" height="350px"><figcaption>Neuroscience 5e Fig. 2.6</figcaption></div>
Note:
@@ -552,7 +600,7 @@ At more negative membrane potentials than the nernst equilbrium potential we get
## Membrane potential influences ion fluxes
<figure><img src="figs/Neuroscience5e-Fig-02.06-2R_1ec257b.png" height="500px"><figcaption>Neuroscience 5e Fig. 2.6</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-02.06-2R_1ec257b.png" height="400px"><figcaption>Neuroscience 5e Fig. 2.6</figcaption></figure>
Note:
@@ -565,6 +613,9 @@ The results of this thought experiment are displayed here, displaying the net mo
## Both direction and magnitude of ion flux depend on the membrane potential
<div style="font-size:0.8em;">
<div></div>
* What would happen if we could add charge to one side without changing the ion distribution?
* Adding negative charge into one side (or positive charge to the other) creates a potential difference across the membrane
* This discourages K⁺ from wanting to flow down its concentration gradient
@@ -572,6 +623,8 @@ The results of this thought experiment are displayed here, displaying the net mo
* At more negative potentials K⁺ will want to flow against its concentration gradient
* Scientists can experimentally vary both ion concentrations and membrane potential
</div>
Note:
So to summarize, remember that both the direction (inward vs outward) and magnitude of charge flow or current depends on membrane potential.
@@ -585,7 +638,7 @@ And we as scientists can experimentally vary...
## Equilibrium with more than one permeant ion
<div style="font-size:0.8em;">
<div style="font-size:0.7em;">
<div></div>
* If inside solution contains 10 mM KCl and 1 mM NaCl and outside solution contains 1 mM KCl and 10 mM NaCl...
@@ -658,7 +711,24 @@ Cells are a bit like a semipermeable bag of electrolytes with different concentr
## Extracellular and intracellular ion concentrations
<figure><img src="figs/Neuroscience5e-Tab-02.01-0_88dd39c.png" height="500px"><figcaption>Neuroscience Table 2.1</figcaption></figure>
<!-- <figure><img src="figs/Neuroscience5e-Tab-02.01-0_88dd39c.png" height="350px"><figcaption>Neuroscience Table 2.1</figcaption></figure> -->
<div style="font-size:0.6em;">
<div></div>
| ion | intracellular conc. (mM) | extracellular conc. (mM) | ratio [x]<sub>out</sub>/[x]<sub>in</sub> |
| --- | --- | --- | --- |
| potassium (K<sup>+</sup>), squid | 400 | 20 | ~0.05 |
| potassium (K<sup>+</sup>), mammal | 140 | 5 | ~0.04 |
| sodium (Na<sup>+</sup>), squid | 50 | 440 | ~9 |
| sodium (Na<sup>+</sup>), mammal | 5–15 | 145 | ~9 |
| chloride (Cl<sup>-</sup>), squid | 40–150 | 560 | ~3.7 |
| chloride (Cl<sup>-</sup>), mammal | 4–30 | 110 | ~3.7 |
| calcium (Ca<sup>2+</sup>), squid | 0.0001 | 10 | 100000 |
| calcium (Ca<sup>2+</sup>), mammal | 0.0001 | 1–2 | 10000 |
<figcaption>see also Neuroscience Table 2.1</figcaption>
</div>
Note:
@@ -687,7 +757,7 @@ As I hinted at earlier today and in a previous lecture, the squid giant axon was
<div><img src="figs/Squid_Loligo_pealei_cbafe46.jpg" height="300px"><figcaption>Atlantic squid, *Loligo pealei*</figcaption></div>
<div><iframe src="https://www.youtube.com/embed/omXS1bjYLMI" width="420" height="315"></iframe><figcaption>Squid giant axon electrophysiology</figcaption></div>
<div><iframe src="https://www.youtube.com/embed/I6jxrxcLxiI" width="560" height="315"></iframe><figcaption>Squid giant axon electrophysiology</figcaption></div>
Note:
@@ -698,10 +768,9 @@ Note:
## Alan Hodgkin and Bernard Katz– 1949
* Hypothesis– if axon resting potential (-65 mV) is predominantly due to K⁺ permeability then changing the outside (K⁺) should change the resting potential in a manner predicted by the Nernst equation
* Experiment– stick an electrode inside axon, one outside axon (in bath). Change the concentration of K⁺ in the bath and measure new membrane potential
* Assumption– intracellular K⁺ is unchanged during experiment
* Nernst predicts– resting potential goes up with a slope of 58 mV per tenfold change in K⁺ gradient
* Hypothesis– if axon resting potential (-65 mV) is predominantly due to K⁺ permeability then changing [K⁺]<sub>out</sub> should change the resting potential in a manner predicted by the Nernst equation
* Experiment– stick an electrode inside axon, one outside axon (in bath). Change the concentration of K⁺ in the bath and measure new membrane potential. Assume intracellular K⁺ is unchanged during experiment.
* Nernst equation prediction– resting potential will depolarize with a slope of 58 mV per tenfold change in K⁺ gradient
Note:
@@ -711,7 +780,7 @@ Alan Hodgkin, Andrew Huxley, Bernard Katz
## K⁺ concentration gradient determines resting membrane potential
<figure><img src="figs/Neuroscience5e-Fig-02.08-0_40bc007.png" height="500px"><figcaption>Neuroscience 5e fig. 2.8</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-02.08-0_40bc007.png" height="400px"><figcaption>Neuroscience 5e fig. 2.8</figcaption></figure>
Note:
@@ -744,10 +813,10 @@ So they correctly concluded that…
## Hodgkin and Katz– 2
* Question– What causes the axon to depolarize during an action potential?
* Measured the membrane potential after initiating an action potential
* Found– Membrane potential during the action potential approached E<sub>Na</sub>
* Measured the membrane potential after initiating an action potential
* Found– Membrane potential during the action potential approached E<sub>Na</sub>
* Hypothesis– During an action potential the axon becomes predominantly permeable to Na⁺ and no longer to K⁺
* Experiment– What happens to the action potential when [Na⁺] is reduced in the external medium?
* Experiment– Measure action potentials after decreasing [Na⁺]<sub>out</sub>
Note:
@@ -766,7 +835,7 @@ Their experiment was to lower Na concentrations in the extracellular medium—
## The action potential as measured by Hodgkin, Huxley, and Katz
<figure><img src="figs/hodkin-huxley-nature-1939-AP_d30dfee.png" height="500px"><figcaption>Adapted from Hodgkin Huxley *Nature* 1939</figcaption></figure>
<figure><img src="figs/hodkin-huxley-nature-1939-AP_d30dfee.png" height="400px"><figcaption>Adapted from Hodgkin Huxley *Nature* 1939</figcaption></figure>
Note:
@@ -781,7 +850,7 @@ Capacitance (farads) is the ability of a body to store an electrical charge. Any
## Role of sodium in the generation of an action potential
<figure><figcaption class="big">Lowering Na⁺ decreases both the rate and the rise of an action potential</figcaption><img src="figs/Neuroscience5e-Fig-02.09-1R_2c02203.png" height="500px"><figcaption>Neuroscience 5e Fig. 2.9</figcaption></figure>
<figure><figcaption class="big">Lowering Na⁺ decreases both the rate and the rise of an action potential</figcaption><img src="figs/Neuroscience5e-Fig-02.09-1R_2c02203.png" height="400px"><figcaption>Neuroscience 5e Fig. 2.9</figcaption></figure>
Note:
@@ -862,5 +931,3 @@ Llinas Sugimori J Physiol 1980 Purkinje neurons
Note:
And this is just a overall summary of what we have been discussing
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