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61
neuroanatomy1.md
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@@ -4,7 +4,7 @@ Neuroscience is a field of scientific study that seeks to understand how the ner
<img src="figs/human-brain.svg" height="300px">
https://courses.pbsci.ucsc.edu/mcdb/bio125/
https://canvas.ucsc.edu/courses/16047/assignments/syllabus
Note:
@@ -22,34 +22,19 @@ Thus it will be you, and your children, and your children’s children that will
## 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>
<div><a href="https://canvas.ucsc.edu/courses/16047/assignments/syllabus">https://canvas.ucsc.edu/courses/16047/assignments/syllabus</a></div>
--
<div style="width:200px;"><img src="figs/ScreenShot2016-01-04at3.59.29PM_dea1077.png" height="200px"><figcaption>5e 2011</figcaption></div>
## Permission code requests
Just send me an email.
**subject line:**
```txt
permission code request: #biol125
```
**body:**
```txt
Id: 1234567
Name: First Last
Email: cruzid@ucsc.edu
Reason you cannot enroll: Brief description (one line).
```
<div style="width:250px;"><img src="figs/neuroscience6e.jpg" height="200px"><figcaption>6e 2017</figcaption></div>
--
## Site keyboard bindings
<div style="font-size:0.8em">
<div></div>
* Navigate: arrow keys and `spacebar`
* Menu: `m`
* Fullscreen: `f`
@@ -61,7 +46,9 @@ Reason you cannot enroll: Brief description (one line).
<!-- * 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.
Recommend browser is Firefox or 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.
</div>
---
@@ -340,12 +327,8 @@ 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:
>(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 :
**The communication between neurons is only established by casual contact.
There is scarcely any nervous tissue apart from the neurons; the neurons are
also trophic units.**
>(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 : **The communication between neurons is only established by casual contact. There is scarcely any nervous tissue apart from the neurons; the neurons are also trophic units.**
---
@@ -437,10 +420,21 @@ afrotheria
</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> -->
<div style="width:300px; margin:0 25px; float:left;">
<figure><img src="figs/glia-astrocyte.svg" width="300px"><figcaption>[JA, CC0](https://creativecommons.org/share-your-work/public-domain/cc0/)</figcaption></figure>
<div style="float:left;"><img src="figs/glia-oligodendrocyte.svg" width="150px"><figcaption>JA, CC0</figcaption></div>
<div><img src="figs/glia-schwann.svg" width="100px"><figcaption>JA, CC0</figcaption></div>
</div>
Note:
@@ -484,13 +478,13 @@ 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
- gases and volatile anesthetics diffuse rapidly into the brain
blood—brain barrier permeability of CO2 greatly exceeds that of H+ thus pH of brain interstitial fluid reflect pCO2 rather than blood pH. Therefore a patient with metabolic acidosis may be brain alkalotic at teh same time.
blood—brain barrier permeability of CO2 greatly exceeds that of H+ thus pH of brain interstitial fluid reflect pCO2 rather than blood pH. Therefore a patient with metabolic acidosis may be brain alkalotic at the same time.
glucose is primary energy substrate of the brain. Nearly all oxygen consumption for the brain. GLUT-1 glucose transporters highly enriched in brain capillary endothelial cells. Since glucose is a polar substrate, this transporter facilitates its transport across the BBB.
@@ -500,6 +494,11 @@ water enters rapidly through diffusion.
<figure><img src="figs/Neurochemistry-fig32-1-BBB_5961e8a.jpg" height="100px"><figcaption></figcaption></figure>
See also review by [^Belanger:2011a] for info on energy dynamics between astrocytes-neurons.
[^Belanger:2011a]: Bélanger, M., Allaman, I., and Magistretti, P. J. (2011). Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation, Cell Metab, 14(6), 724-38
--

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neuroanatomy2.md
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@@ -5,7 +5,7 @@
Note:
Last time we learned some of the basic cellular anatomy of the nervous system. Today we will put the system in nervous system–– because nervous systems really are greater than the sum of its parts… in other words our brain is not just a blob of cells but it is the interconnections between cells, groups of cells, and brain regions that allow our fantastic feats of emergent biological computation. So lets discuss the overall the structure of the nervous system.
Last time we learned some of the basic cellular anatomy of the nervous system. Today we will put the system in nervous system–– because nervous systems really are greater than the sum of its parts… in other words our brain is not just a blob of cells but it is the interconnections between cells, groups of cells, and brain regions that allow our fantastic feats of emergent biological computation. So lets discuss the overall the structure of the nervous system.
First of all it is a system of systems. In other words…
@@ -13,7 +13,7 @@ First of all it is a system of systems. In other words…
## Major components of the nervous system and their functional relationships
<div><figcaption class="big">central nervous system (CNS)</figcaption><video height=200px controls loop src="figs/cns_overview.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">central nervous system (CNS)</figcaption><video height=200px controls loop src="figs/cns_overview.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><img src="figs/Neuroscience5e-Fig-01.10-1R_cfe2e3e.png" height="400px"><figcaption>Neuroscience 5e Fig. 1.10</figcaption></div>
@@ -21,15 +21,14 @@ First of all it is a system of systems. In other words…
Note:
This illustrates the two top level systems of the nervous system, the CNS containing the brain and spinal cord and the PNS containing nerves and ganglia exiting the spinal cord.
Middle: illustrates the two top level systems of the nervous system, the CNS containing the brain and spinal cord and the PNS containing nerves and ganglia exiting the spinal cord.
This diagram outlines the functional hierarchy of different components or systems within the whole nervous system including relations between internal and external environment and sensory receptors in the PNS as well as skeletal muscle and smooth, cardiac muscles that the nervous system controls.
Right: outlines the functional hierarchy of different components or systems within the whole nervous system including relations between internal and external environment and sensory receptors in the PNS as well as skeletal muscle and smooth, cardiac muscles that the nervous system controls.
*Don't worry too much about memorizing the exact details of diagrams such as this, focus on the major concepts and their relations*
right vagus nerve primarily innervates the SA node, whereas the left vagus innervates the AV node
pns supplies smooth muscles, cardiac muscles, and glands. functions to maintain homeostasis, and is concerned with involunary functions.
* right vagus nerve primarily innervates the SA node, whereas the left vagus innervates the AV node
* pns supplies smooth muscles, cardiac muscles, and glands. functions to maintain homeostasis, and is concerned with involunary functions.
---
@@ -38,13 +37,17 @@ pns supplies smooth muscles, cardiac muscles, and glands. functions to maintain
* Nerves– bundles of axons, enveloped by glial cells that myelinate them
* White matter– areas of axon tracts
* Grey matter– areas of cell bodies
* Grey matter– areas of cell bodies
<div><img src="figs/coronal7b_21f2276.jpg" height="300px"><figcaption>B. Crawford and K. McBurney, Univ. of Victoria</figcaption></div>
Note:
* white matter: so named because of the bright shiny appearance to the naked eye
* gray matter: so named because it is less bright, a little more dull looking. But nothing dull about it.
--
## Common techniques to visualize brain structure
@@ -103,7 +106,7 @@ Heidenhahn
<div><img src="figs/2240_cut_aaaa4be.jpg" height="200px"><figcaption>[Brain Biodiversity Bank MSU, NSF](https://msu.edu/~brains/brains/human/coronal/montage.html)</figcaption></div>
<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:
@@ -146,7 +149,7 @@ Cortex
## Cell groupings: cortex vs nuclei
<figure><figcaption class="big">Cerebral cortex and thalamic nuclei</figcaption><img src="figs/2060_cell_abf6617.jpg" height="300px"><figcaption>[Brain Biodiversity Bank MSU, NSF](https://msu.edu/~brains/brains/human/coronal/2060_cell_labelled.html)</figcaption></figure>
<figure><figcaption class="big">Cerebral cortex and thalamic nuclei</figcaption><img src="figs/2060_cell_abf6617.jpg" height="400px"><figcaption>[Brain Biodiversity Bank MSU, NSF](https://msu.edu/~brains/brains/human/coronal/2060_cell_labelled.html)</figcaption></figure>
Note:
@@ -180,21 +183,14 @@ Note:
These are the basic parts of the CNS
Forebrain
Forebrain (prosencephalon): telencephalon (cerebral hemispheres) + diencephalon (thalamus)
Brain stem includes the midbrain, pons, medulla, and a portion of the spinal cord
Brain stem: Mesencephalon (midbrain) + rhombencephalon (pons + medulla). Brain stem includes the midbrain, pons, medulla, and a portion of the spinal cord
Think about how the nerves represent incoming and outgoing info from a specific location on the body.
Spinal cord
cervical enlargement
Note the order of nerves representing incoming and outgoing info from a specific location on the body.
lumbar enlargement
: nerves which supply the lower limbs
cauda equina
: nerves that innervate the pelvic organs and lower limbs. Includes motor innervation of the hips, knees, ankles, feet, internal anal sphincter and external anal sphincter.
Spinal nerves: cervical, thoracic, lumbar, sacral, coccygeal
---
@@ -234,13 +230,22 @@ It extends…
It receives sensory…
So it carries both afferent and efferent information.
So it carries both afferent and efferent information.
Nerve fibers…
Is thicker…
Cervical enlargement, lumbar enlargement
cervical enlargement
: refers to thickening where nerves supplying forelimbs attach. Between 5th cervical vertebrae and 1st thoracic vertebrae (C5 to T1)
lumbar enlargement
: nerves which supply the lower limbs. 11th thoracic vertebrae to second sacral vertebrae (T11 to S2)
cauda equina
: nerves that innervate the pelvic organs and lower limbs. Includes motor innervation of the hips, knees, ankles, feet, internal anal sphincter and external anal sphincter.
Spinal nerves: cervical, thoracic, lumbar, sacral, coccygeal
---
@@ -252,6 +257,10 @@ Note:
This illustrates the overall structure of the spinal cord.
sympathetic chain ganglia
: stress, flight or flight response, epinephrine
: 20–30K cell bodies
---
## Internal anatomy of the spinal cord
@@ -277,9 +286,9 @@ Note:
Note:
sympathetic chain ganglia
: stress, flight or flight response, epinephrine
: 20–30K cell bodies
ventral nerve cord: the nervous system of bilaterians like nematodes, annelids and the arthropods (insects)
neural tube/dorsal nerve cord: chordates (fish, amphibians, reptiles, birds, and mammals)
---
@@ -306,7 +315,7 @@ Ventral columns (sometimes called anterolateral column)- carry pain info up and
*Cervical enlargement: Gray matter expanded to incorporate more sensory input from limbs and more cell bodies for motor control of limbs*
*Rexed's laminae are cytoarchitectonic divisions of spinal cord gray matter, see Table A1*
*Rexed's laminae are cytoarchitectonic divisions of spinal cord gray matter, see Table A1* ...don't worry about knowing the lamina
---
@@ -340,7 +349,7 @@ And all information from higher order or more rostral brain structures that goes
</div>
<div style="margin:0 50px;"><img src="figs/Neuroscience5e-Fig-A07-2R_debbe82.png" height="300px"><figcaption>Neuroscience 5e Fig. A7</figcaption></div>
<div style="margin:0 50px;"><figcaption class="big">Ventral surface of brain stem</figcaption><img src="figs/Neuroscience5e-Fig-A07-2R_debbe82.png" height="300px"><figcaption>Neuroscience 5e Fig. A7</figcaption></div>
Note:
@@ -388,7 +397,10 @@ XII | Hypoglossal Nerve | Controls muscles of tongue
Note:
This lists these 12 cranial nerves and their relevant sensory and/or motor function they carry. Notice that many of the nerves carry mixtures of sensory and motor information, which you could see with the color coding on the previous slide. Also notice that 4 of the 12 nerves concern sensory and motor information from the eyes. In fact the cranial nerve containing the most fibers is the optic nerve which contains 1.2 million axons that carries all the information necessary to perceive the visual world around you (compare with 130 million photoreceptors and 0.7 to 1.5 million RGCs)
This lists these 12 cranial nerves and their relevant sensory and/or motor function they carry.
Notice that many of the nerves carry mixtures of sensory and motor information, which you could see with the color coding on the previous slide.
Also notice that 4 of the 12 nerves concern sensory and motor information from the eyes. In fact the cranial nerve containing the most fibers is the optic nerve which contains 1.2 million axons that carries all the information necessary to perceive the visual world around you (compare with 130 million photoreceptors and 0.7 to 1.5 million RGCs)
---
@@ -399,7 +411,7 @@ This lists these 12 cranial nerves and their relevant sensory and/or motor funct
Note:
The tectum of the midbrain, which is latin for ‘roof’ contains the superior and inferior colliculi and is important for processing visual and auditory information as well as shaping motor commands for orienting the head and body.
The tectum of the midbrain, which is latin for ‘roof’ contains the superior and inferior colliculi and is important for processing visual and auditory information as well as shaping motor commands for orienting the head and body.
Ventral to the cerebral aqueduct through which cerebral spinal fluid circulates, you will find the tegmentum of the midbrain which contains the —>
@@ -427,17 +439,18 @@ 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…
* survived an axe beheading by Colorado farmer in 1945,
* survived an axe beheading by Colorado farmer in 1945,
* lived for 18 months with only a brain stem
* Fed corn dropped directly into his gullet
* Fed corn dropped directly into his gullet
* Mike choked to death during a sideshow tour in 1947, when the farmer was unable to clear Mike's esophagus
[dailymail 2018, headless chicken in thailand](http://www.dailymail.co.uk/news/article-5556351/Headless-chicken-survives-WEEK-decapitated.html)
---
## Cerebellum
@@ -461,6 +474,7 @@ It has two…
Neurons are form cortical sheets.
Receives…
---
@@ -511,13 +525,13 @@ Note:
The diencephalon contains the…
The thalamus can be generally thought of as the relay station to the cortex.
The thalamus can be generally thought of as the relay station to the cortex.
The hypothalamus lies ventral to the thalamus and controls an array of important physiological functions such as feeding, fluid balance, and hormonal secretions of the endocrine system.
---
## Thalamus
## Thalamus
* Pair of ovoid structures
* Incoming sensory information relays in the thalamus before entering the cerebral cortex. Many sensory, motor, and cognitive functions
@@ -534,7 +548,7 @@ Which connections gets through to neocortex without a thalamic relay? **neurom
## Thalamus– gateway to the cerebral cortex
<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 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="250px"><figcaption>[Brain Biodiversity Bank MSU, NSF](https://msu.edu/~brains/brains/human/coronal/montage.html)</figcaption></div>
@@ -544,7 +558,7 @@ The thalamus is located in the middle of the brain…
*red nucleus is part of midbrain, without a corticospinal tract it controls gait. Baby crawling controlled by red nucleus. Arm swinging while walking*
---
--
## Thalamus subdivisions
@@ -645,7 +659,8 @@ anterior commisure
## Laminar organization of neocortex
* Cortex itself has a thickness of only about 2-4mm
* Gray matter of human neocortex has a thickness of only about 2-4 mm
* Similar thickness in other mammals-- cortical gray matter in rodents is 1-2mm!
* 6 layers (neocortex)
* Layer IV is the primary input layer
* Layers II and III are cortico-cortical output layers
@@ -677,7 +692,7 @@ Note:
---
--
## Defects in cortical development
<div style="width:500px">
@@ -791,7 +806,7 @@ Note areas 4 (primary motor cortex), 1,2,3 (primary somatosensory cortex), area
* 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
* 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)
@@ -802,7 +817,7 @@ Note areas 4 (primary motor cortex), 1,2,3 (primary somatosensory cortex), area
<div style="width: 400px; font-size:0.7em;">
<div></div>
* Non-primary cortex
* Non-primary cortex
* everything in between
* referred to collectively as association cortex
@@ -812,7 +827,7 @@ Note areas 4 (primary motor cortex), 1,2,3 (primary somatosensory cortex), area
Note:
---
--
## Mapping brain activity with human neuroimaging

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neurophysiology1.md
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@@ -27,7 +27,7 @@ as well as general molecular signaling within neurons as any living cell might h
<div style="font-size:0.7em; width:600px">
<div></div>
* For intracellular recordings, an electrode is placed inside a cell such that the inside of the pipette is contiguous with the inside of the cell. If this electrode is connected to a voltmeter, which records transmembrane voltage across the cell membrane, one can determine the difference in voltage between the inside and outside of the cell.
* For intracellular recordings, an electrode is placed inside a cell such that the inside of the pipette is contiguous with the inside of the cell. If this electrode is connected to a voltmeter, which records transmembrane voltage across the cell membrane, one can determine the difference in voltage between the inside and outside of the cell.
* When one does this in neurons, the microelectrode reports a negative potential called the resting potential. Always a fraction of a volt (-40 to -90 mV).
* Volts are a unit of electrochemical potential energy. 1 Volt will drive 1 coulomb of charge (6.24x10<sup>18</sup> electrons) through a resistance of 1 ohm in 1 second.
@@ -37,7 +37,7 @@ as well as general molecular signaling within neurons as any living cell might h
Note:
To understand the basis of electrical excitability in neurons, we first need to understand that neurons, like other excitable cells, have a difference in electrical potential across the cell membrane when it is at rest.
To understand the basis of electrical excitability in neurons, we first need to understand that neurons, like other excitable cells, have a difference in electrical potential across the cell membrane when it is at rest.
To learn this physiologists stick electrodes inside of cells, including neurons. This electrode is hooked up to a voltmeter and another electrode sits outside the cell as a ground or reference electrode to complete the circuit. The difference in voltage between the inside of the cell and the outside of the cell is monitored over time and displayed on an oscilloscope.
@@ -68,7 +68,7 @@ Flow rate ~ Current (amperes) = `I`
Note:
And recall from physics that voltage is related to the resistance and current in an electrical circuit as described by Ohm’s law. This analogy of a water pump/water wheel circuit helps us understand these relationships better.
And recall from physics that voltage is related to the resistance and current in an electrical circuit as described by Ohm’s law. This analogy of a water pump/water wheel circuit helps us understand these relationships better.
Voltage
: is the potential difference, or electromotive force measured across the conductor in units of volts.
@@ -124,17 +124,17 @@ Note:
Signals in neurons can be generated by changing the membrane potential.
This includes receptor potentials inside your body’s sensory neurons for touch, heat, light, and sound.
This includes receptor potentials inside your body’s sensory neurons for touch, heat, light, and sound.
And synaptic potentials are the changes in membrane potential at synapses that underly the transfer of information from neuron to neuron.
Action potentials are the large electrical spikes or impulses that allow neuronal signals to propagate over long distances, including nerves centimeters to meters long.
Action potentials are the large electrical spikes or impulses that allow neuronal signals to propagate over long distances, including nerves centimeters to meters long.
---
## Types of electrical signals in neurons
<figure><img src="figs/Neuroscience5e-Fig-02.01-0_63cc814.png" height="500px"><figcaption>Neuroscience 5e Fig. 2.1</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-02.01-0_63cc814.png" height="500px"><figcaption>Neuroscience 5e/6e Fig. 2.1</figcaption></figure>
Note:
@@ -145,7 +145,7 @@ This figure shows these 3 types of neuronal signals.
- Here is a synaptic potential recorded in a postsynaptic neuron.
- Here is an action potential in a motor neuron. **Look as the y-axes here**— the action potential has a much larger amplitude change than receptor or synaptic potentials.
- Here is an action potential in a motor neuron. **Look as the y-axes here**— the action potential has a much larger amplitude change than receptor or synaptic potentials.
To understand the basis of these electrical signals we first need to learn about how this baseline membrane potential is generated, which is the neurons membrane potential while it is at rest. We will spend most of today's class learning about the neurons resting membrane potential and which will lead into how the action potential is generated that we'll continue with next class.
@@ -159,7 +159,7 @@ To understand the basis of these electrical signals we first need to learn about
* The membrane of a nerve cell maintains an electrical polarization
* The cell is polarized– at rest, an electrical gradient is maintained across the plasma membrane (negative charge is greater inside the cell)
* The cell has a resting potential– difference in voltage across the membrane of a cell (~ -70 mV)
* The cell has a concentration gradient– difference in distribution of ions between the inside and outside of a membrane
* The cell has a concentration gradient– difference in distribution of ions between the inside and outside of a membrane
</div>
@@ -206,14 +206,14 @@ Just remember that a neuron not eliciting any electrical signals is ‘resting
</div>
<div style="margin:0 15px"><img src="figs/Neuroscience5e-Fig-02.02-1R_f6f9bef_b7eea85.png" height="400px"><figcaption>Neuroscience 5e Fig. 2.2</figcaption></div>
<div style="margin:0 15px"><img src="figs/Neuroscience5e-Fig-02.02-1R_f6f9bef_b7eea85.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 2.2</figcaption></div>
Note:
Now we already saw that we can stick an electrode into a cell, and hook it up to an oscilloscope and passively record its resting membrane potential on the slide from earlier.
Now we already saw that we can stick an electrode into a cell, and hook it up to an oscilloscope and passively record its resting membrane potential on the slide from earlier.
Now what if do the same recordings, but also electrically stimulate the cell so that positive or negative charge is added—
Now what if do the same recordings, but also electrically stimulate the cell so that positive or negative charge is added—
--
@@ -226,20 +226,20 @@ Now what if do the same recordings, but also electrically stimulate the cell so
</div>
<div style="margin:0 15px"><img src="figs/Neuroscience5e-Fig-02.02-2R_3b5b1ef.png" width="500px"><figcaption>Neuroscience 5e Fig. 2.2</figcaption></div>
<div style="margin:0 15px"><img src="figs/Neuroscience5e-Fig-02.02-2R_3b5b1ef.png" width="500px"><figcaption>Neuroscience 5e/6e Fig. 2.2</figcaption></div>
Note:
So we insert the microelectrode into the cell and find that this neuron is resting at -65 mV.
So we insert the microelectrode into the cell and find that this neuron is resting at -65 mV.
Then we inject a small amount of negative current (less than 1 nA) so that we hyperpolarize the cell and we see that the membrane responds passively, meaning that the membrane potential changes and recovers with an exponential relationship.
* 1-(1/e) = 63% (rise) Vm and 1/e (37%) (decat) of Vm
If we depolarize the cell membrane from rest by injecting pulses of positive current we get corresponding passive responses with exponential rises and decays of membrane potential– **unless that cell is a neuron and we’ve exceeded the threshold potential (shown by the red dotted line) for generating an action potential in that neuron.
If we depolarize the cell membrane from rest by injecting pulses of positive current we get corresponding passive responses with exponential rises and decays of membrane potential– **unless that cell is a neuron and we’ve exceeded the threshold potential (shown by the red dotted line) for generating an action potential in that neuron.**
Notice if we inject stronger current pulses, we get more action potentials, also known as a higher spiking or firing rate, rather than different action potential amplitudes. If the depolarization is sufficient to generate an AP, that AP amplitude stays largely the same within each individual neuron.
Notice if we inject stronger current pulses, we get more action potentials, also known as a higher spiking or firing rate, rather than different action potential amplitudes. If the depolarization is sufficient to generate an AP, that AP amplitude stays largely the same within each individual neuron.
We will go over more detail each of these components later on...
@@ -252,18 +252,18 @@ We will go over more detail each of these components later on...
Note:
All electrical signals are the due to the flow of charge, positive or negative. In this case of neurons the charge is due to the movement cations such as Na and K and anions such as Cl and neuronal membranes are selectively permeable to some of these ions giving rise to the flow of charge or current across the cell membrane.
All electrical signals are the due to the flow of charge, positive or negative. In this case of neurons the charge is due to the movement cations such as Na and K and anions such as Cl and neuronal membranes are selectively permeable to some of these ions giving rise to the flow of charge or current across the cell membrane.
---
## 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>
<figure><img src="figs/Neuroscience5e-Fig-02.04-0R_cf6b01f.png" height="400px"><figcaption>Neuroscience 5e/6e 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.
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.
---
@@ -277,7 +277,7 @@ there are active ion transporters like the Na-K ATPase and there are ion channel
Note:
So how do ions get across the lipid cell membrane bilayer? Remember there are proteins in the cell membrane. Some of these are selective ion transporters, remember the Na-K ATPase from cell biology. These work to create concentration gradients.
So how do ions get across the lipid cell membrane bilayer? Remember there are proteins in the cell membrane. Some of these are selective ion transporters, remember the Na-K ATPase from cell biology. These work to create concentration gradients.
There are also ion channels that form pores in the cell membrane that are selectively permeable for certain kinds of ions to cross the membrane. These allow ions move across the membrane
@@ -311,7 +311,7 @@ Here is one these ion transporters— the Na-K pump that moves 3 Na out of the c
Note:
Ion channels span the membrane and act as pores. They can open and close, often in a voltage-dependent fashion as we will learn thursday. And ion channels even show selectively such that there are different types of Na, K channels as well as others.
Ion channels span the membrane and act as pores. They can open and close, often in a voltage-dependent fashion as we will learn thursday. And ion channels even show selectively such that there are different types of Na, K channels as well as others.
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.
@@ -327,11 +327,11 @@ Note:
We actually can predict what the resting membrane potential is by knowing the concentrations of ions inside and outside the cell and knowing the relative permeability of these ions to move across the cell membrane.
If a cell membrane is largely permeable to just one ion species, we can use the Nernst equation to predict the membrane potential for all kinds of cells.
If a cell membrane is largely permeable to just one ion species, we can use the Nernst equation to predict the membrane potential for all kinds of cells.
If a cell membrane is permeable to more than one ion, we can use the Goldman equation.
We will come back to these in a minute.
We will come back to these in a minute.
*Walther Nernst (1864-1941), West Prussia, 1920 Nobel Prize in chemistry*
@@ -341,15 +341,15 @@ We will come back to these in a minute.
## Electrochemical equilibrium
<figure><figcaption class="big">orange dots K⁺, green dots Cl⁻. This simulated membrane is only permeable to K⁺</figcaption><img src="figs/Neuroscience5e-Fig-02.05-1R-2_163131c.png" height="500px"><figcaption>Neuroscience 5e Fig. 2.5</figcaption></figure>
<figure><figcaption class="big">orange dots K⁺, green dots Cl⁻. This simulated membrane is **only permeable to K⁺**</figcaption><img src="figs/Neuroscience5e-Fig-02.05-1R-2_163131c.png" height="500px"><figcaption>Neuroscience 5e/6e Fig. 2.5</figcaption></figure>
Note:
First let’s discuss **electrochemical** equilibrium, which is the balance of two driving forces— electrical AND chemical diffusion– across a cell membrane.
First let’s discuss **electrochemical** equilibrium, which is the balance of two driving forces— electrical AND chemical diffusion– across a cell membrane.
Imagine the following experiment. We have a cell and record intracellular membrane potential with electrodes and a voltmeter.
Imagine the following experiment. We have a cell and record intracellular membrane potential with electrodes and a voltmeter.
If this membrane is only permeable to K⁺, and KCl concentration is the same inside and outside the cell, there is no net flux of K⁺
@@ -378,7 +378,7 @@ Note:
## Resting membrane potential video
<div><video height=400px controls src="figs/Animation02-01TheRestingMembranePotential.mp4"></video><figcaption>Neuroscience 5e Animation 2.1</figcaption></div>
<div><video height=400px controls src="figs/Animation02-01TheRestingMembranePotential.mp4"></video><figcaption>Neuroscience 5e Animation 2.1</figcaption></div>
Note:
@@ -410,7 +410,7 @@ Note:
Note:
So I stated that the Nernst equation is how we can calculate the equilibrium potential for a cell membrane permeable to one type of ion.
So I stated that the Nernst equation is how we can calculate the equilibrium potential for a cell membrane permeable to one type of ion.
And here is the Nernst equation is:
@@ -437,7 +437,7 @@ ln
: 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.
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.
Thus to make calculations simpler in the classic scientific papers (often from the 1930s and 1940s before computers) this equation for experiments carried out at room temperature (20ºC = 68ºF = 20ºC+273ºK = 293ºK) is often simplified to the following of:
@@ -450,14 +450,14 @@ 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
E =
E =
@@ -474,15 +474,15 @@ log(7) / log10(7)
<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:
Open up your browser's web developer javascript console (shift-ctrl-k (Firefox) or cmd-alt-j (Chrome)). Copy/paste the following lines:
```javascript
R = 8.3 //Gas constant
F = 9.6 * Math.pow(10,4) //Faraday constant
F = 9.6 * 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:
Relation of the natural logarithm (base *e* 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 javascript. Copy/paste the following lines. Try varying *x* a few times and re-calculate:
```javascript
x = 5
@@ -539,14 +539,14 @@ For CaCl₂: (58/2)log10(10/1) = +29 mV
Since the Nernst equation is really just a linear equation of the form y = mx, you can think of this first term at the slope and the equilibrium potential for an ion varies linearly with the log of the concentration gradient. In other words there is 58 mV per tenfold change in the concentration gradient when we are talking about our potassium examples above, which is depicted here -->
<!--
<!--
## Electrochemical equilibrium
<div><img src="figs/Neuroscience5e-Fig-02.05-2R_c30075c.png" height="500px"><figcaption>Neuroscience 5e Fig. 2.5</figcaption></div>
This plot depicts this equilibrium relationship for a hypothetical cell permeable only to potassium.
This plot depicts this equilibrium relationship for a hypothetical cell permeable only to potassium.
-->
@@ -562,9 +562,9 @@ This plot depicts this equilibrium relationship for a hypothetical cell permeabl
Note:
Remember that electrochemical equilibrium is the:
Remember that electrochemical equilibrium is the:
I = g(Vm-Ex). g = conductance, no. of open channels. (Vm-Ex) = driving force causing either positive or negative current.
I = g(Vm-Ex). g = conductance, no. of open channels. (Vm-Ex) = driving force causing either positive or negative current.
@@ -572,7 +572,7 @@ I = g(Vm-Ex). g = conductance, no. of open channels. (Vm-Ex) = driving force ca
## Electrochemical equilibrium video summary
<div><video height=400px controls src="figs/Animation02-02ElectrochemicalEquilibrium.mp4"></video><figcaption>Neuroscience 5e Animation 2.2</figcaption></div>
<div><video height=400px controls src="figs/Animation02-02ElectrochemicalEquilibrium.mp4"></video><figcaption>Neuroscience 5e Animation 2.2</figcaption></div>
Note:
@@ -583,7 +583,7 @@ Note:
## 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="350px"><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/6e Fig. 2.6</figcaption></div>
Note:
@@ -597,7 +597,7 @@ If our hypothetical battery holds the membrane at -58 mV, the equilbrium potenti
At more negative membrane potentials than the nernst equilbrium potential we get net inward flow due to the stronger electrical driving force which in the case of potassium here is causing it to move against its chemical gradient.
<!--
<!--
## Membrane potential influences ion fluxes
<figure><img src="figs/Neuroscience5e-Fig-02.06-2R_1ec257b.png" height="400px"><figcaption>Neuroscience 5e Fig. 2.6</figcaption></figure>
@@ -622,7 +622,7 @@ The results of this thought experiment are displayed here, displaying the net mo
</div>
So to summarize, remember that both the direction (inward vs outward) and magnitude of charge flow or current depends on membrane potential.
So to summarize, remember that both the direction (inward vs outward) and magnitude of charge flow or current depends on membrane potential.
Just remember Ohm’s law, I = V/R and rewrite it as Ix = (Vm - Ex)/R
@@ -657,9 +657,9 @@ So imagine we have 10 mM KCl and 1mM NaCl inside the cell and 1 mM KCl and 10mM
If we have a simplified situation like earlier where the membrane is permeable to just K we can use Nernst eqn to show that the Veq will be -58mV at room temp. If just permeable to Na we can use Nernst to show the Veq will be +58mV
Now imagine the cell membrane is permeable to both K and Na and that these permeabilities or ability of ions to pass across the membrane are not equal for K and Na, then we have to use the Goldman eqn.
Now imagine the cell membrane is permeable to both K and Na and that these permeabilities or ability of ions to pass across the membrane are not equal for K and Na, then we have to use the Goldman eqn.
Which looks like a more complex version of the Nernst equation but with added terms that take into account the concentrations and relative membrane permeabilities of multiple ion species.
Which looks like a more complex version of the Nernst equation but with added terms that take into account the concentrations and relative membrane permeabilities of multiple ion species.
There is no valence term, thus since choride is an anion, its concentration terms are flipped.
@@ -690,7 +690,7 @@ For a typical neuron at rest, pK : pNa : pCl = 1 : 0.05 : 0.45. Note that becaus
Note:
Cells are a bit like a semipermeable bag of electrolytes with different concentrations of ionic species inside and outside.
Cells are a bit like a semipermeable bag of electrolytes with different concentrations of ionic species inside and outside.
---
@@ -769,7 +769,7 @@ 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="400px"><figcaption>Neuroscience 5e fig. 2.8</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-02.08-0_40bc007.png" height="400px"><figcaption>Neuroscience 5e/6e fig. 2.8; Hodgkin and Katz *J. Physiol* 1949</figcaption></figure>
Note:
@@ -823,14 +823,14 @@ 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="400px"><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 and Huxley *Nature* 1939</figcaption></figure>
Note:
Hodgkin and Huxley, Nature 1939 squid giant axon
Image adapted from Principles of Neurobiology, L. Luo Garland Fig 2-19 which in turn adapted from Nature 1939.
Image adapted from Principles of Neurobiology, L. Luo Garland Fig 2-19 which in turn adapted from Nature 1939.
Capacitance (farads) is the ability of a body to store an electrical charge. Any object that can be electrically charged exhibits capacitance. Dielectric materials. Storage of electrical energy temporarily in an electric field. **Unlike a resistor, an ideal capacitor does not dissipate energy. Instead, a capacitor stores energy in the form of an electrostatic field between its plates.**
@@ -838,7 +838,7 @@ 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="400px"><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/6e Fig. 2.9; Hodgkin and Katz *J. Physiol* 1949</figcaption></figure>
Note:
@@ -849,7 +849,7 @@ When Hodgkin and Katz did this low extracellular Na experiment, the AP had a sma
## Role of sodium in the generation of an action potential
<figure><img src="figs/Neuroscience5e-Fig-02.09-2R_6ca6c4f.png" height="400px"><figcaption>Neuroscience 5e Fig. 2.9</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-02.09-2R_6ca6c4f.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 2.9; Hodgkin and Katz *J. Physiol* 1949</figcaption></figure>
Note:
@@ -875,7 +875,7 @@ So a summary of the Hodgkin and Katz experiment conclusions...
## Resting membrane and action potentials entail permeabilities to different ions
<figure><img src="figs/Neuroscience5e-Fig-02.07-0_caebcb8.png" height="400px"><figcaption>Neuroscience 5e Fig. 2.7</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-02.07-0_caebcb8.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 2.7</figcaption></figure>
Note:
@@ -894,10 +894,7 @@ Note:
And this is just a overall summary of what we have been discussing
<!--
<!--
## Action potential form and nomenclature
@@ -938,5 +935,3 @@ AHP due to voltage-gated K⁺ channels, including Ca²⁺ activated potassium ch
Llinas Sugimori J Physiol 1980 Purkinje neurons
-->
---

155
neurophysiology2.md
View File

@@ -1,12 +1,12 @@
## Voltage dependent membrane permeability
<div style="font-size:0.8em;">
<div style="font-size:0.7em;">
<div></div>
* Hodgkin and Huxley hypothesis– Action potential can be explained by **voltage-gated ion channels**
* Experiment– Measure ion permeability at varying membrane potentials
* Problem– Difficult to systematically vary the cell potential and also measure ion permeability
* Solution– Voltage clamping. Fix membrane potential in a cell without triggering an action potential while measuring ion permeability
* Solution– Voltage clamping. Fix membrane potential in a cell without triggering an action potential while measuring ion permeability (~conductance)
</div>
@@ -16,19 +16,17 @@ Note:
We learned last time that the experiments of Hodgkin, Huxley, and Katz showed that the Vm during an AP approaches ENa. And they thought that this might be due to changes in permeability for Na in the cell membrane that changes during the course of an action potential. Thus Hodgkin and Huxley hypothesized that APs can be explained by ion channels that change their permeability due to voltage— that these channels are voltage-gated.
Alan Hodgkin and Andrew Huxley began this work in the late 1930s, and quickly finished one paper before helping with the British war effort during WWII. Indeed Hodgkin said that he lost all interest in neurophysiology during those dark years as one might imagine. But as things calmed down after the war they renewed their collaboration and got back to the business of neuronal excitability.
Alan Hodgkin and Andrew Huxley began this work in the late 1930s, and quickly finished one paper before helping with the British war effort during WWII. Indeed Hodgkin said that he lost all interest in neurophysiology during those dark years as one might imagine. But as things calmed down after the war they renewed their collaboration and got back to the business of neuronal excitability.
So they needed to proved that ion permeability changes according to membrane potential but there was an issue— how to vary the membrane potential in a systematic way and also measure the ion permeabilities?
So they needed to proved that ion permeability changes according to membrane potential but there was an issue— how to vary the membrane potential in a systematic way and also measure the ion permeabilities?
The solution was to build an electrophysiological recording apparatus with feedback circuitry such that you can fix or clamp the voltage across the cell membrane.
[http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1469-7793/homepage/celebrating_the_work_of_alan_hodgkin_and_andrew_huxley.htm](http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1469-7793/homepage/celebrating_the_work_of_alan_hodgkin_and_andrew_huxley.htm)
--
---
## Action potential summary video
<div><video height=400px controls src="figs/Animation02-03TheActionPotential.mp4"></video><figcaption>Neuroscience 5e Animation 2.3</figcaption></div>
<div><video height=400px controls src="figs/Animation02-03TheActionPotential.mp4"></video><figcaption>Neuroscience 5e Animation 2.3</figcaption></div>
Note:
@@ -36,7 +34,7 @@ Summary of last time…
--
## More Vm examples
## More V<sub>m</sub> examples
<div style="font-size:0.7em;">
<div></div>
@@ -52,39 +50,38 @@ Summary of last time…
* <span class= "fragment fade-in">`Pk = 0.5; Pna = 0.5; Pcl = 0; kOut = 1; kIn = 10; naOut = 10; naIn = 1; clIn = 11; clOut = 11`</span>
* <span class= "fragment fade-in">`(58)*log10( (Pk*kOut + Pna*naOut + Pcl*clIn) / (Pk*kIn + Pna*naIn + Pcl*clOut) ) = 0 mV`</span>
</div>
</div>
Note:
1. (58/1)*log10(1/10) = -58 mV
2. (58/1)*log10(10/1) = +58 mV
3. (58/-1)*log10(11/11) = 0 mV
1. `(58/1)*log10(1/10) = -58 mV`
2. `(58/1)*log10(10/1) = +58 mV`
3. `(58/-1)*log10(11/11) = 0 mV`
4. 0 mV:
* Pk = 0.5; Pna = 0.5; Pcl = 0; kOut = 1; kIn = 10; naOut = 10; naIn = 1; clIn = 11; clOut = 11
* (58)*log10( (Pk*kOut + Pna*naOut + Pcl*clIn) / (Pk*kIn + Pna*naIn + Pcl*clOut) ) = 0 mV
* `Pk = 0.5; Pna = 0.5; Pcl = 0; kOut = 1; kIn = 10; naOut = 10; naIn = 1; clIn = 11; clOut = 11`
* `(58)*log10( (Pk*kOut + Pna*naOut + Pcl*clIn) / (Pk*kIn + Pna*naIn + Pcl*clOut) ) = 0 mV`
* 0 mV:
* Pk = 1; Pna = 1; Pcl = 0; kOut = 1; kIn = 10; naOut = 10; naIn = 1; clIn = 11; clOut = 11
* (58)*log10( (Pk*kOut + Pna*naOut + Pcl*clIn) / (Pk*kIn + Pna*naIn + Pcl*clOut) )
* `Pk = 1; Pna = 1; Pcl = 0; kOut = 1; kIn = 10; naOut = 10; naIn = 1; clIn = 11; clOut = 11`
* `(58)*log10( (Pk*kOut + Pna*naOut + Pcl*clIn) / (Pk*kIn + Pna*naIn + Pcl*clOut) )`
* -59 mV (room temp and low Pna):
* Pk = 1; Pna = 0.001; Pcl = 0.5; kOut = 1; kIn = 10; naOut = 10; naIn = 1; clIn = 1; clOut = 11
* (58)*log10( (Pk*kOut + Pna*naOut + Pcl*clIn) / (Pk*kIn + Pna*naIn + Pcl*clOut)
*
* `Pk = 1; Pna = 0.001; Pcl = 0.5; kOut = 1; kIn = 10; naOut = 10; naIn = 1; clIn = 1; clOut = 11`
* `(58)*log10( (Pk*kOut + Pna*naOut + Pcl*clIn) / (Pk*kIn + Pna*naIn + Pcl*clOut)`
-62 mV (body temp and low Pna):
-62 mV (body temp and low Pna):
* R = 8.3; F = 9.6e4; T = (273+37)
* Pk = 1; Pna = 0.001; Pcl = 0.5; kOut = 1; kIn = 10; naOut = 10; naIn = 1; clIn = 1; clOut = 11
* ((R*T)/F)*log( (Pk*kOut + Pna*naOut + Pcl*clIn) / (Pk*kIn + Pna*naIn + Pcl*clOut) )
* `Pk = 1; Pna = 0.001; Pcl = 0.5; kOut = 1; kIn = 10; naOut = 10; naIn = 1; clIn = 1; clOut = 11`
* `((R*T)/F)*log( (Pk*kOut + Pna*naOut + Pcl*clIn) / (Pk*kIn + Pna*naIn + Pcl*clOut) )`
-69 mV (body temp and low Pna and physiol concentrations):
-69 mV (body temp and low Pna and physiol concentrations):
* R = 8.3; F = 9.6e4; T = (273+37)
* Pk = 1; Pna = 0.05; Pcl = 0.45; kOut = 5; kIn = 140; naOut = 145; naIn = 5; clIn = 5; clOut = 110
* ((R*T)/F)*log( (Pk*kOut + Pna*naOut + Pcl*clIn) / (Pk*kIn + Pna*naIn + Pcl*clOut) )
* `R = 8.3; F = 9.6e4; T = (273+37)`
* `Pk = 1; Pna = 0.05; Pcl = 0.45; kOut = 5; kIn = 140; naOut = 145; naIn = 5; clIn = 5; clOut = 110`
* `((R*T)/F)*log( (Pk*kOut + Pna*naOut + Pcl*clIn) / (Pk*kIn + Pna*naIn + Pcl*clOut) )`
Calculate the total concentration of all ions for these solutions. For every one NaCl that dissolves, two ions are produced (one Na⁺ and one Cl¯). Thus for 10 mmol/L NaCl outside there are (10 mmol/L)x(1 total Cl ions/NaCl) = 10mM. And for 1mM KCl outside there are (1 mmol/L)x(1 total Cl ions/KCl) = 1mM. Thus the total number of Cl⁻ ions per liter is 11mmol/L = 11mM
@@ -92,9 +89,11 @@ Calculate the total concentration of all ions for these solutions. For every one
---
## The voltage clamp method
## The voltage clamp technique
<div><img src="figs/Neuroscience5e-Box-03A-0R_5d20ab3.png" height="400px"><figcaption>Neuroscience 5e Box 3A</figcaption></div>
Voltage clamping provides a method for measuring electrical current and its direction of net flow across a cell membrane.
<div><img src="figs/Neuroscience5e-Box-03A-0R_5d20ab3.png" height="400px"><figcaption>Neuroscience 5e/6e Box 3A</figcaption></div>
Note:
@@ -107,9 +106,9 @@ voltage clamp amplifier compares membrane potential to the desired command poten
When Vm is different from the command potential the clamp amplifier injects current ion the axon through a second electrode. This feedback arrangement causes the membrane potential to become the same as the command potential.
The current flowing back into the axon and thus across its membrane can be measured.
The current flowing back into the axon and thus across its membrane can be measured.
**This electronic feedback circuit holds the membrane pot at the desired level, even in the face of permeability changes that would normally alter the membrane potential. (such as those generated during the action potential). Most importantly, the device permits the simultaneous measure of the current needed to keep the cell at a given voltage. This current is exactly equal to the amount of current flowing across the neuronal membrane, allowing direct measurement of these membrane currents.
**This electronic feedback circuit** holds the membrane potential at the desired level, even in the face of permeability changes that would normally alter the membrane potential. (such as those generated during the action potential). Most importantly, the device permits the simultaneous measure of the current needed to keep the cell at a given voltage. This current is exactly equal to the amount of current flowing across the neuronal membrane, allowing direct measurement of these membrane currents.
>An amplifier, electronic amplifier or (informally) amp is an electronic device that can increase the power of a signal. It does this by taking energy from a power supply and controlling the output to match the input signal shape but with a larger amplitude.
@@ -121,7 +120,7 @@ The current flowing back into the axon and thus across its membrane can be measu
---
## Hodgkin and Huxley 1952
## A. Hodgkin and A. Huxley 1952
* Do neuronal membranes have voltage-dependent permeability?
* Which ions are changing their permeability?
@@ -130,7 +129,7 @@ The current flowing back into the axon and thus across its membrane can be measu
Note:
Hodgkin and Huxley published a series of seminal papers in 1952 that summarized their investigations using this voltage clamp method to examine voltage dependent ion flux.
Alan Hodgkin and Andrew Huxley from the Univ of Cambridge published a series of seminal papers in 1952 that summarized their investigations using this voltage clamp method to examine voltage dependent ion flux.
They asked…
@@ -141,15 +140,18 @@ So the experiment was to hold the membrane potential at different voltages and m
## Electric current flow across a squid axon membrane during voltage clamp
<div><figcaption class="big">negligible current (except for a capacitive transient)</figcaption><img src="figs/Neuroscience5e-Fig-03.01-1R_5455913.png" height="300px"><figcaption>Neuroscience 5e fig. 3.1</figcaption></div>
<div><figcaption class="big">negligible current (except for a capacitive transient)</figcaption><img src="figs/Neuroscience5e-Fig-03.01-1R_5455913.png" height="300px"><figcaption>Neuroscience 5e/6e fig. 3.1; from Hodgkin et al., *J. Physiol.* 1952</figcaption></div>
<div><figcaption class="big">inward and outward currents</figcaption><img src="figs/Neuroscience5e-Fig-03.01-2R_49ec352.png" height="300px"><figcaption>Neuroscience 5e/6e fig. 3.1; from Hodgkin et al., *J. Physiol.* 1952</figcaption></div>
<div style="font-size:0.7em; margin:25px 0;">Inward current is always downward deflection from zero in these traditional voltage clamp plots. Outward current is an upward deflection. </div>
<div><figcaption class="big">inward and outward currents</figcaption><img src="figs/Neuroscience5e-Fig-03.01-2R_49ec352.png" height="300px"><figcaption>Neuroscience 5e fig. 3.1</figcaption></div>
Note:
And so here are the results from this type of voltage clamp experiment.
If you command that the cell membrane potential be hyperpolarized, you get very little or negligible current flowing across the membrane except for a very brief capacitive current that you always see in these voltage clamp experiments.
If you command that the cell membrane potential be hyperpolarized, you get very little or negligible current flowing across the membrane except for a very brief capacitive current that you always see in these voltage clamp experiments.
This is because the cell membrane essentially acts as a parallel RC circuit where a resistor and a capacitor are connected in parallel and to a constant current source. Ion channels are resistors, lipid bilayer with the extracellular and intracellular environments act as capacitor, storing charge in the form of ions accumulating near the surface of the membrane. When a switch is turned on in an RC circuit current flows from the battery to the capacitor until the capacitor is charged to a voltage that is same as the battery.
@@ -161,32 +163,40 @@ However when Hodgkin and Huxley depolarized the membrane, a transient inward cur
* When the voltage is constant, the current through the capacitative pathway is zero because the capacitor has acquired the charge Q (coulombs) according to the relationship Q=CV. C is capacitance (farads) Ic is capacitive current. Ic = C(dV/dt)
* as long as V is changing with time, there will be a current flowing towards the capacitor.
* if V is constant in time, there is no capacitive current.
* product of resistance and capacitance has the unit of time and is called the time constant. Time constant defines how quickly capacitors charge or discharge over time.
* product of resistance and capacitance has the unit of time and is called the time constant. Time constant defines how quickly capacitors charge or discharge over time.
[http://nerve.bsd.uchicago.edu/med98c.htm](http://nerve.bsd.uchicago.edu/med98c.htm)
---
## Current produced by different membrane depolarizations during voltage clamp
## Inward & outward currents produced at a series of clamped membrane voltages
<figure><img src="figs/Neuroscience5e-Fig-03.02-0_5ee332f.png" height="400px"><figcaption>Neuroscience Fig. 3.2</figcaption></figure>
<figure><figcaption class="big">Voltage clamp recordings from squid axon. Capacitive artifact removed for clarity.</figcaption><img src="figs/Neuroscience5e-Fig-03.02-0_5ee332f.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 3.2; from Hodgkin et al., *J. Physiol.* 1952</figcaption></figure>
Note:
This show several different voltage steps (with the brief capacitive current omitted for clarity)
...Notice as we approach ENa the inward current disappears.
Notice a few phenonmena in this figure.
---
...Notice as the command voltage becomes more positive we start to approach ENa and the inward current disappears.
--
## Relationship between current amplitude and membrane potential
<figure><figcaption class="big">External Na⁺ 440 mM, internal Na⁺ 50 mM, therefore Nernst says **E<sub>Na</sub> = 55 mV**</figcaption><img src="figs/voltage_clamp_currents_summary_plot_7450e0a.png" height="400px"><figcaption>Neuroscience 5e Fig. 3.3</figcaption></figure>
<figure><figcaption class="big">External Na⁺ 440 mM, internal Na⁺ 50 mM, therefore Nernst says **E<sub>Na</sub> = 55 mV**</figcaption><img src="figs/voltage_clamp_currents_summary_plot_7450e0a.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 3.3; from Hodgkin et al., *J. Physiol.* 1952</figcaption></figure>
Note:
This summarizes the peak magnitude of these these two currents at different Vm
Don't get confused by this plot, look at the axes it is just Vm and current.
Bascially this just summarizes the peak magnitude of these these two currents at different Vm in the previous figure 3.2.
---
@@ -197,13 +207,14 @@ This summarizes the peak magnitude of these these two currents at different Vm
Note:
So it seems like this inward current may be carried by Na ions.
So it seems like this inward current may be carried by Na ions.
---
## Dependence of the early inward current on sodium
<div><img src="figs/Neuroscience5e-Fig-03.04_0d877f5.png" height="500px"><figcaption>Neuroscience 5e Fig. 3.4</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-03.04_0d877f5.png" height="500px"><figcaption>Neuroscience 5e/6e Fig. 3.4; from Hodgkin and Huxley *J. Physiol.* 1952a</figcaption></div>
<div><iframe src="https://www.youtube.com/embed/Wd_gKJoo25Y" width="420" height="315"></iframe><figcaption>Squid giant axon voltage clamping</figcaption></div>
@@ -218,7 +229,7 @@ Note:
## Voltage clamp method summary
<div><video height=400px controls src="figs/Animation03-01TheVoltageClampMethod.mp4"></video><figcaption>Neuroscience 5e Animation 3.1</figcaption></div>
<div><video height=400px controls src="figs/Animation03-01TheVoltageClampMethod.mp4"></video><figcaption>Neuroscience 5e Animation 3.1</figcaption></div>
Note:
@@ -243,7 +254,7 @@ Note:
* Fugu (puffer fish or blow fish)
* TTX concentrated in their livers (don’t eat it)
* TTX blocks voltage-gated Na⁺ channels
* TTX blocks voltage-gated Na⁺ channels
</div>
@@ -258,12 +269,12 @@ Its mechanism of action, selective blocking of the sodium channel, was shown def
## Pharmacological separation of inward and outward currents into Na⁺ and K⁺ dependent components
<figure><img src="figs/Neuroscience5e-Fig-03.05-0_99fe22f.png" height="400px"><figcaption>Neuroscience 5e Fig. 3.5</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-03.05-0_99fe22f.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 3.5; from Moore et al. *J Gen Physiol* 1967 and Armstrong and Binstock *J Gen Physiol* 1965</figcaption></figure>
Note:
Tetramethylammonium chloride is one of the simplest quaternary ammonium salts.
Tetramethylammonium chloride is one of the simplest quaternary ammonium salts.
[https://en.wikipedia.org/wiki/Tetramethylammonium_chloride](https://en.wikipedia.org/wiki/Tetramethylammonium_chloride)
@@ -279,13 +290,13 @@ TTX and TEA experiments from Moore 1967 J Gen Physiol; Armstrong and Binstock, 1
* Another way of describing permeability is using membrane conductance (*g*). Conductance (measured in siemens, *S*) is the reciprocal of resistance
* *g = 1/R*
* Ohm’s law:
* Ohm’s law:
* *I = V/R*
* *I = gV*
* For an ion *x*,
* *I<sub>x</sub>* = ionic current flow, *E<sub>x</sub>* = equilibrium potential
* The membrane potential (*V<sub>m</sub>*) minus the equilibrium potential (*E<sub>x</sub>*) is the electrochemical driving force acting on an ion, thus *V = V<sub>m</sub> - E<sub>x</sub>*
* *I<sub>x</sub> = g<sub>x</sub>*
* *I<sub>x</sub> = g<sub>x</sub>V*
* *I<sub>x</sub> = g<sub>x</sub>(V<sub>m</sub> - E<sub>x</sub>)*
* Solve for *g*:
* *g<sub>x</sub> = I<sub>x</sub>/(V<sub>m</sub> - E<sub>x</sub>)*
@@ -296,7 +307,7 @@ TTX and TEA experiments from Moore 1967 J Gen Physiol; Armstrong and Binstock, 1
Note:
For our purposes, we can consider conductance to be another way of describing permeability.
For our purposes, we can consider conductance to be another way of describing permeability.
technically conductance is the degree to which an object conducts electricity, calculated as the ratio of the current that flows to the potential difference present. It deals with the movement of charge, whereas permeability refers to the ability of a specific ion to move across the cell membrane.
@@ -311,7 +322,7 @@ Can use this to calculate the dependence of Na and K conductances vs. time and m
## Membrane conductance changes are time and voltage dependent
<div><img src="figs/Neuroscience5e-Fig-03.06-0_757dbce.png" height="400px"><figcaption>Neuroscience Fig. 3.6</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-03.06-0_757dbce.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 3.6; from Hodgkin and Huxley *J Physiol* 1952b</figcaption></div>
Note:
@@ -322,7 +333,7 @@ Note:
## Depolarization increases Na⁺ and K⁺ conductances of the squid giant axon
<div><img src="figs/Neuroscience5e-Fig-03.07-0_fdae974.png" height="400px"><figcaption>Neuroscience Fig. 3.7</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-03.07-0_fdae974.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 3.7; from Hodgkin and Huxley *J Physiol* 1952b</figcaption></div>
Note:
@@ -336,8 +347,8 @@ Determine the peak conductance of ions at different membrane potentials.
<div style="font-size:0.8em;">
<div></div>
* At rest (-70 mV), voltage-gated Na⁺ and K⁺ channels are closed. Non voltage-gated K⁺ channels are open and dictate the resting potential, together with the distribution of ions across cell membranes
* A stimulus raises the membrane potential in the cell. Depolarization causes voltage-gated Na⁺ channels to open, which allows Na⁺ to rush in the cell which increases the membrane potential, which causes more Na⁺ channels to open, which causes more Na⁺ to rush in which causes higher membrane potential (a positive feedback loop). As membrane potential is approaching E<sub>Na</sub>, the further depolarization causes Na⁺ channels to inactivate which prevents more Na⁺ from from flowing through these channels
* At rest (-70 mV), voltage-gated Na⁺ and K⁺ channels are closed. Non voltage-gated K⁺ channels (K<sub>leak</sub>) are open and dictate the resting potential, together with the distribution of ions across cell membranes
* A stimulus raises the membrane potential in the cell. Depolarization causes voltage-gated Na⁺ channels to open, which allows Na⁺ to rush in the cell which increases the membrane potential, which causes more Na⁺ channels to open, which causes more Na⁺ to rush in which causes higher membrane potential (a positive feedback loop). As membrane potential is approaching E<sub>Na</sub>, the further depolarization causes **Na⁺ channels to inactivate** which prevents more Na⁺ from from flowing through these channels
* Depolarization also opens voltage gated K⁺ channels, which causes K⁺ to flow out, thus lowering the membrane potential
</div>
@@ -349,11 +360,17 @@ Note:
## Ion conductances underlying the action potential
<figure><img src="figs/Neuroscience5e-Fig-03.08-1R_efbfb99.png" height="400px"><figcaption>Neuroscience 5e Fig. 3.8</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-03.08-1R_efbfb99.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 3.8</figcaption></figure>
Note:
Summary of the conductances for Na and K during an action potential.
Based on Hodgkin and Huxley's mathematical model for the action potential (1952d).
Can see that the neuronal membrane becomes much less resistant to Na flux during the rising phase of the AP.
Can also see increases in K conductance during the AP, but this K+ conductance (underlying the outward current) are slow and sustained reaching peak permeability during the falling phase of the AP. Note when the cell is back to Vrest, the gK is still moderately high before ramping down. This is important for the refractory period.
<!-- ## Feedback cycles responsible for membrane potential changes
@@ -366,10 +383,10 @@ Note:
<div style="font-size:0.8em;">
<div></div>
* Question– Why do APs exhibit an all-or-nothing threshold?
* Answer– When membrane potential (V<sub>m</sub>) is below threshold there is not enough Na⁺ channels open to raise V<sub>m</sub> high enough to open more channels. When V<sub>m</sub> is above threshold the 'explosive' action potential cycle is activated.
* Question– Why to APs exhibit an undershoot?
* Answer– During the AP voltage-gated K⁺ conductance slowly increases (delayed activation of voltage-gated K⁺ channels) and during the falling phase these K⁺ channels are still open and active whereas voltage-gated Na⁺ channels are inactivated… as V<sub>m</sub> approaches E<sub>k</sub> there is briefly more K⁺ flowing out than at rest and the hyperpolarization inactivates voltage-gated K⁺ channels. K⁺ leak channels and ion transporters bring back cell to resting potential.
* Question– Why do APs exhibit an all-or-nothing threshold?
* <span>Answer– When membrane potential (V<sub>m</sub>) is below threshold there is not enough Na⁺ channels open to raise V<sub>m</sub> high enough to open more channels. When V<sub>m</sub> is above threshold the 'explosive' action potential cycle is activated.</span> <!-- .element: class="fragment fade-in"-->
* Question– Why to APs exhibit an undershoot? <!-- .element: class="fragment fade-in"-->
* <span>Answer– During the AP voltage-gated K⁺ conductance slowly increases (delayed activation of voltage-gated K⁺ channels) and during the falling phase these K⁺ channels are still open and active whereas voltage-gated Na⁺ channels are inactivated… as V<sub>m</sub> approaches E<sub>k</sub> there is briefly more K⁺ flowing out than at rest and the hyperpolarization inactivates voltage-gated K⁺ channels. K⁺ leak channels and ion transporters bring back cell to resting potential.</span> <!-- .element: class="fragment fade-in"-->
</div>
@@ -407,7 +424,7 @@ During an action potential, inward current through Na⁺ channels
## Passive current flow in an axon
<figure><figcaption class="big">subthreshold changes diffuse rapidly</figcaption><img src="figs/Neuroscience5e-Fig-02.03-1R_aac41b9.png" height="400px"><figcaption>Neuroscience 5e Fig. 2.3</figcaption></figure>
<figure><figcaption class="big">subthreshold changes decay rapidly</figcaption><img src="figs/Neuroscience5e-Fig-02.03-1R_aac41b9.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 2.3</figcaption></figure>
Note:
@@ -418,13 +435,13 @@ bottom graph shows the peak Vm
## Propagation of an action potential
<figure><figcaption class="big">suprathreshold depolarizations propagate down the axon</figcaption><img src="figs/Neuroscience5e-Fig-02.03-2R_4bea3b6.png" height="400px"><figcaption>Neuroscience 5e Fig. 2.3</figcaption></figure>
<figure><figcaption class="big">suprathreshold depolarizations propagate down the axon and don't decay</figcaption><img src="figs/Neuroscience5e-Fig-02.03-2R_4bea3b6.png" height="400px"><figcaption>Neuroscience 5e/6e Fig. 2.3</figcaption></figure>
Note:
bottom graph shows the peak Vm
<!--
<!--
## Action potential conduction requires both active and passive current flow
@@ -454,7 +471,7 @@ Active and Passive current flow.
<div style="font-size:0.8em;">
<div></div>
* Remember during the falling to undershoot phase of an action potential K⁺ channels are still open but Na⁺ are channels inactivated (decreased g<sub>Na</sub>), leading to temporary hyperpolarization more negative than the resting membrane potential
* Remember during the falling to undershoot phase of an action potential K⁺ channels are still open but Na⁺ are channels inactivated (decreased g<sub>Na</sub>), leading to temporary hyperpolarization more negative than the resting membrane potential
* Therefore (1) inactivation of Na⁺ channels and (2) slow K⁺ channel kinetics are responsible for the refractory period
* This makes it harder to initiate a new AP either from a new stimulus or for an AP to propagate backwards
* Different axons will have different refractory periods (and thus different maximal firing rates) depending on the particular subtypes of Na⁺ and K⁺ channels they express
@@ -505,7 +522,7 @@ Note:
saltatory action potential condution along a myelinated axon
<!--
<!--
## Nodes of Ranvier
@@ -539,13 +556,13 @@ action potential genaration occurs only at specific points, the nodes of Ranvier
<div style="width:300px; float:left;"><img src="figs/q002_155484b.jpg" height="200px"><figcaption class="big">
Alan Lloyd Hodgkin
Alan Lloyd Hodgkin
</figcaption></div>
<div style="width:600px; float:left;"><img src="figs/q003hux_505f8c6.jpg" height="200px"><figcaption class="big">
Andrew Fielding Huxley
Andrew Fielding Huxley
</figcaption></div>
@@ -587,7 +604,7 @@ onset between ages 20-40.
blindness, motor weakness, paralysis.
ultimate cause of MS remains unclear. Immune system contributes to damage and is key component. Immune cells in CSF and injection of myelin in animals can cause EAE. Autoimmune disorder. Or persistent infection with a human retrovirus?
ultimate cause of MS remains unclear. Immune system contributes to damage and is key component. Immune cells in CSF and injection of myelin in animals can cause EAE. Autoimmune disorder. Or persistent infection with a human retrovirus?
* women to men ratio 3/2