biol125-lectures/2016-09-17-lecture01.md

## 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. 

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.

http://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...

And ultimately it is a field of science that seeks to understand how a lump of biological tissue siting inside our heads has evolved the capability of asking questions about its own nature.

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 or save us from the cylons on battlestar galactica, whichever comes first. And hopefully recent funding initiatives will help in this cause.

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## Site keyboard bindings

* Navigate: *arrow keys* and *spacebar*
* Fullscreen: *f*
* Overview: *o* or *esc*
* Zoom object: *alt/option–click*



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## 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

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. 

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## Neuroscience and the future of humankind

<figure><img src="figs/From_the_Earth_to_the_Moon_Jules_Verne_695f816.jpg" height="100px"><figcaption></figcaption></figure>
<figure><img src="figs/ScreenShot2016-01-04at12.58.17PM_e1dcf52.png" height="100px"><figcaption>['Star Trek' Wars](http://on.cc.com/1r4rOE1)</figcaption></figure>

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

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.



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## We will focus on a few basic features of the nervous system

* The mechanisms by which neurons produce signals
* 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>

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## The nervous system and its function is the product of both our genes and our environment

<div style="font-size:0.9em">
<div></div>

* We are now in a gene-centric “post-genomic” phase of neuroscience
* Human genome sequenced- approximately 20,000 genes.
* Most genes are expressed in the brain, either during development or in the adult.  It is the spatial and temporal regulation of these genes that builds a nervous system.
* Mice, flies, and worms have nervous systems and even express many of the same genes as humans. Genetics allows us to correlate gene activity with nervous system function.
* Neuroscience therefore encompasses many fields, including genetics, cell biology, physiology, and development biology.

</div>

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## Genome size does not predict nervous system complexity

<div style="font-size:0.7em">
<div></div>

organism   | # of genes | # of base pairs | # of neurons | development time (young adult)
---------- | ---------- | --- | ------------ | -------------------------  
*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 

</div>

<!-- <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. 

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.

* Drosophila 7-11 days (28-34degs C)
* zebrafish 3-4 days juvenile swimming and visual behavior. young adult at 3 mo. full adult at 6 mo.
* genome sizes at http://www.biology-pages.info/G/GenomeSizes.html

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## 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>


Note:

Out of those 20000 genes, there are many expressed genes that are common between the nervous system and other tissues, however there is also a substantial fraction that are expressed specifically in the nervous system

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## A single mutation can lead to dramatic brain size defects

Mutation in a spindle pole gene call ASPM1

<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. 

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.


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## 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:

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 302 total neurons making it a great model organism.

Now to do neuroscience research we have to use model organisms of course. Small number of neurons, can be labeled using GFP or other means.  Many mutant worms have been isolated that affect nervous system function.

However, we have more than a million neurons that just form the optic nerve from each of our eyes!


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## 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

Phylum: Mollusca
Class:  Cephalopoda
Order:  Teuthida
Family: Loliginidae
Genus:  Loligo

Atlantic squid (Loligo pealei)

Phylum: Mollusca
Class:  Cephalopoda
Order:  Sepiida
Family: Sepiidae
Genus:  Sepia


Other important invertebrate organisms in neuroscience research include sea slugs and fruit flies.

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## 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 labeled neurons inside a mouse brain</figcaption></div>

Note:

* Mouse brain is about 2 cm in length
* genetically tractable
* [https://www.youtube.com/watch?v=stPThgZ2Y5o](https://www.youtube.com/watch?v=stPThgZ2Y5o)


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## Model organisms– other mammals

Higher mammals are used to study more complicated brain functions

<div><figure style="float:left; display: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><figure style="float:left; display: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


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## 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”


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## What are brains made of?

So what are brains made of? A glob of squishy jello?

<figure><img src="figs/image9_e303503.png" height="100px"><figcaption></figcaption></figure>

Wikimedia Commons
<figure><img src="figs/image10_c067a0a.png" height="100px"><figcaption></figcaption></figure>

<figure><img src="figs/image11_fbb6fc7.png" height="100px"><figcaption></figcaption></figure>

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Yes— but this tissue is some pretty complicated soft tissue. The answer is the brain is made of cells.

Shown here is a section through a human brain.  If we zoom in on a tiny part of it


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## How many neurons in a human brain?

* 100 thousand
* 10 million
* 100 million
* 1 billion
* 10 billion
* 100 billion <!-- .element: class="fragment highlight-green" -->
* 1 trillion

Note:

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## Brains are made of cells

* Camillo Golgi (Italy)– believed that cells in the brain were connected forming a continuous network (reticular theory).
* Santiago Ramon y Cajal (Spain)– Brains made up of single cells-communicate at specialized areas called synapses.
* Shared Nobel prize in 1906

Note:

Cells widely accepted everywhere else in the 1830’s.  Neuroscientists last to accept this. 

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## The Nobel Prize in Physiology or Medicine 1906

>"in recognition of their work on the structure of the nervous system"

<div style="width:300px; float:left;"><img src="figs/CamilloGolgi_5c05797.jpg" height="200px"><figcaption class="big">

Camillo Golgi  
Pavia University  
Pavia, Italy  

</figcaption></div>

<div style="width:600px; float:left;"><img src="figs/SantiagoRamónyCajal_dd682a4.jpg" height="200px"><figcaption class="big">

Santiago Ramón y Cajal  
Madrid University  
Madrid, Spain  

</figcaption></div>


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## Golgi staining

Golgi staining: potassium chromate and silver nitrate (1873)

Golgi's drawing of the hippocampus impregnated by his stain (from Golgi's Opera Omnia). 

Nobel e-museum

<figure><img src="figs/golgi1_7ba8753.jpg" height="100px"><figcaption></figcaption></figure>

<figure><img src="figs/image12_666d3e4.png" height="100px"><figcaption></figcaption></figure>

Note:

Top golgi stain of a cortex at different magnifications, bottom is a drawing of Golgi’s in the hippocampus

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## Is the nervous system a syncytium?

* syncytium: a mass of cytoplasm with many nuclei but no internal cell boundries
* Answer: NO!

* Camillo Golgi
* Nobel Lecture December 11, 1906
* The Neuron Doctrine- theory and facts
* "...Far from being able to accept the idea of the individuality and independence of each nerve element, I have never had reason, up to now, to give up the concept which I have always stressed, that nerve cells, instead of working individually, act together, so that we must think that several groups of elements exercise a cumulative effect on the peripheral organs through whole bundles of fibers."

<figure><img src="figs/Figure1copy_dc1b35e.jpg" height="100px"><figcaption></figcaption></figure>

Note:

Golgi drew the structure of the hippocampos as being all fused together into a reticulum, no free axon endings

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## The Neuron Doctrine

* Santiago Ramon y Cajal
* Neurons are cells. Each is an individual entity anatomically, embryologically, and functionally.
* Neurons have a functional polarity

<figure><img src="figs/02f17_4b77a87.jpg" height="100px"><figcaption></figcaption></figure>

Note:

Neurons in culture have specific endings. EM methods, dye filling experiments. 

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## Two basic cell types in the nervous system

* Neurons and Glia

Note:



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## Glia

* Outnumber neurons by 10-50 fold
* myelin sheath
* blood-brain barrier 
* removing debris and excess neurochemicals
* structural support for neurons 
* critical role in brain development

Note:

greek for ‘glue’

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## Types of glial cells

<div style="width:600px; float:left;">
<div></div>

* Astrocytes– Support cells of the CNS, most numerous type of glia and contain star shaped long processes
* Microglia- CNS macrophages. Act as phagocytes, mobilized after infection, injury, or disease
* Oligodendrocytes–  Myelin producing cells of the CNS
* Schwann cells– Myelin producing cells of the PNS
* Satellite cells– Support cells of the PNS

</div>

<div style="width:300px; margin:0 25px; float:left;"><img src="figs/Fig_6852903.png" height="500px"><figcaption></figcaption></div>

<!-- <figure><img src="figs/10-01_GlialCells_1_bddb845.jpg" height="100px"><figcaption></figcaption></figure> -->


Note:

Satellite glial cells are glial cells that cover the surface of nerve cell bodies in sensory, sympathetic and parasympathetic ganglia.


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## Astrocytes

* Restricted to CNS
* Maintain a proper chemical environment

<figure><img src="figs/image13_f34a1d6.png" height="100px"><figcaption></figcaption></figure>

<figure><img src="figs/image14_a95004a.png" height="100px"><figcaption></figcaption></figure>

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## Oligodendrocytes

Myelinate axons in CNS

Each cell can myelinate multiple axons

<figure><img src="figs/image15_3f99acf.png" height="100px"><figcaption></figcaption></figure>

<figure><img src="figs/image16_d6dfaa7.png" height="100px"><figcaption></figcaption></figure>

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## Schwann cells

* Myelinate axons in PNS
* One axon per cell

<figure><figcaption>Cross section through PNS nerve</figcaption><img src="figs/48_08SchwannMyelin_902bf3b.jpg" height="200px"><figcaption>[neuralcloud.it](http://neuralcloud.it)</figcaption></figure>

Note:

Discovered by German scientist Theodore Schwann. In 1839 he actually stated that all animal tissues are made of cells.


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## Neurons

* Main signaling unit of the nervous system
* Polarized– have axons and dendrites
* Communicate by electricity– usually using action potentials.
* Tremendous range of different cell types– categorized by morphology, molecular identity and physiological activity.

Note:

Now let’s think about the cell type most responsible for the brain’s business of biological computation— the neuron.

It is the...

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## Which of the following cell structures are found in neurons?

* DNA
* RNA
* Nucleus
* ER
* Mitochondria
* Microtubules
* Golgi
* Cell division machinery <!-- .element: class="fragment strike" -->

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## Neurons have a functional polarity.

 

Incoming information arrives

Information is assimilated

Information is sent to next neuron

synapses

<figure><img src="figs/neurons_9b62aa4.jpg" height="100px"><figcaption></figcaption></figure>

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## 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

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## Cell Body Structure


Figure 12.4

Structures of a neuron

<figure><img src="figs/image_7f746fe.jpg" height="100px"><figcaption></figcaption></figure>

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## Neuronal Processes: Dendrites

* Dendrites 
* Extensively branching from the cell body
* Transmit electrical signals (graded potentials) toward the cell body
* Function as receptive sites for other neurons

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## Dendritic spines

Purkinje cell

hippocampal dendrite

<figure><img src="figs/image17_7b9d67f.png" height="100px"><figcaption></figcaption></figure>

<figure><img src="figs/image18_5c73b35.png" height="100px"><figcaption></figcaption></figure>

Note:

* 2 billion transistors in an iphone6.
* 100 billion neurons,  each receiving up to 10000 synaptic connections
* quadrillion synapses, 10^15 in our nervous system

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## Dendritic Spines

spine

dendrite

axon

astrocyte


<figure><img src="figs/ImageDescriptionHere_7859c7e.jpg" height="100px"><figcaption></figcaption></figure>

Note:

False color of the dendrite of one neuron near an axon from another neuron from an EM image

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## Neuron Processes: Axons

* Axons (nerve fibers)
* Neuron has only one, but it can branch
* Impulse generator and conductor
* Transmits action potentials away from the cell body


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## Neuron Processes: Axons

* Axons
* Neurofilaments, actin microfilaments, and microtubules
* Provide strength along length of axon
* Aid in the transport of substances to and from the cell body
* Axonal transport

<figure><img src="figs/2-16_042d7c5.jpg" height="100px"><figcaption></figcaption></figure>

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## Neuron Processes

* Axons
* Branches along length are infrequent
* Axon collaterals
* Multiple branches at end of axon
* Terminal branches 
* End in knobs called axon terminals (also called end bulbs or boutons) 

Neuron Structure



Note:



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## Neuron Processes: Action Potentials

* Nerve impulse (action potential)
* 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:



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## Neurons are classified in different ways

* Morphology: unipolar, bipolar, and multipolar
* Function: sensory neurons, motor neurons, and interneurons
* Neurotransmitter expression: excitatory, inhibitory, dopaminergic, etc.

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## Some nerve cell morphologies found in the human nervous system

<figure><img src="figs/Neurscience5e-Fig-3_a0c1df2.jpg" height="100px"><figcaption></figcaption></figure>

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## Some neuronal morphologies

Purkinje cell, cerebellum

Hippocampal neuron

<figure><img src="figs/image19_f5adbad.png" height="100px"><figcaption></figcaption></figure>

<figure><img src="figs/image20_124ad72.png" height="100px"><figcaption></figcaption></figure>

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## Some neuronal morphologies

* Pyramidal neurons:  multipolar neurons that contain both apical and basal dendrite.  Also contain one axon. 
* Most common excitatory neuron in the cerebral cortex.

<figure><img src="figs/image21_d8ed7c5.png" height="100px"><figcaption></figcaption></figure>

<figure><img src="figs/image22_3c8b8f9.png" height="100px"><figcaption></figcaption></figure>

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## Different morphologies of neurons in the retina.  

Coombs et al., 2006

<figure><img src="figs/image23_f065820.png" height="100px"><figcaption></figcaption></figure>

<figure><img src="figs/image24_a2e8d3e.png" height="100px"><figcaption></figcaption></figure>

Note:



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## Basic structure of a sensory neuron (afferent)

skin

spinal cord

<figure><img src="figs/image28_d35899e.png" height="100px"><figcaption></figcaption></figure>

Note:

Afferent- term meaning to send information from periphery to the CNS or to brain

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## Structure of a motor neuron (efferent)

<figure><img src="figs/image29_bfd15ce.png" height="100px"><figcaption></figcaption></figure>

Note:

Efferent sends info to muscles

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## Neurons communicate by electricity

* Axons project great distances
* Neurons do not touch each other directly.
* Come in close proximity at the synapse
* Use action potentials to transmit information
* Action potential causes release of neurotransmitter that is received by post-synaptic cells.

Note:



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## Title Text

<figure><img src="figs/image30_268faa4.png" height="100px"><figcaption></figcaption></figure>

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## Properties of the action potential

* rapid
* transient
* all or none
* self-regenerating
* can go long distances. 15 m in a giraffe
* highly stereotyped
* discrimination is based on patterns of firing

Note:



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## Neural Circuits

* Neurons don’t function in isolation, they are organized into circuits that process specific kinds of information
* Direction of information flow is important for understanding the function of a circuit
* Afferent neurons– carry information toward the brain
* Efferent– carry info from the brain

Note:



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## Example of a simple circuit:knee jerk response (myotatic reflex)

<figure><img src="figs/image31_999ac07.png" height="100px"><figcaption></figcaption></figure>

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## The “knee-jerk response,” a simple reflex circuit

[http://www.youtube.com/watch?v=RmKKeI9totE](http://www.youtube.com/watch?v=RmKKeI9totE)

<figure><img src="figs/Neurscience5e-Fig-4_4de973d.jpg" height="100px"><figcaption></figcaption></figure>

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## Ways to measure neural 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:



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## Relative Frequency of Action Potentials in Different Components of the Myotatic Reflex

extracellular recordings-action potentials

<figure><img src="figs/PN01060_d9ea863.jpg" height="100px"><figcaption></figcaption></figure>

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## Intracellularly Recorded Reponses Underlying the Myotatic Reflex

Neuroscience 4e, Sinauer

<figure><img src="figs/PN01072_ddd3e36.jpg" height="100px"><figcaption></figcaption></figure>

<figure><img src="figs/PN01071_02ebee2.jpg" height="100px"><figcaption></figcaption></figure>

Note:

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