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| Tries to understand performance of the human brain |
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| tries to find out how circuits depend on properties of neurons and synapses |
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| studies individual or groups of molecules, biochemistry of ways brain cells work |
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| Move ions and molecules across membranes |
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| disease resulting from mutations in genes encoding channels, such as Hyperkalemic Periodic Paralysis, which is a mutant in SCN4A (skeletal sodium channels) |
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| refined form of voltage clamp. pressed against a small area of the cell to form a gigaohm seal. resistance allows it to electronically isolate the currents across the membrane patch with little noise. |
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| a type of clamp that sets a voltage, and monitors the amount of current required to stay at that voltage. used often, especially when not looking at the capacitive current... |
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| a type of clamp that sets a current, and then monitors the change in voltage. Used especially when viewing AP spikes. |
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| Nernst Equation (simplified) |
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| Ex = (-58/z) log(Conc(x)[in])/(Conc(x)[out])) |
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| Goldman equivalent circuit equation |
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Vm = ExGx + EyGy.../Gx + Gy...
Remember to convert ALL units to standard. |
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| current of an ion in relation to driving force |
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| i(ion) = g(ion) * (Vm - E(ion)) |
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| depending on the structure of channels, independent of concentration of ions. Physical measure of how easily a cell lets ions in. |
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| changes with the permeability of ion channels. electrical term.. |
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| Membrane time constant (tau) (formula, explanation) |
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| T = RC | how quickly the membrane comes to steady state depend |
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| Time for a cell to change a certain membrane potential (formula) |
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Delta V = I * R(m) * (1-e^(-t/tau))
or!
Vm = VRest + IR(1-e^(-t/tau)) |
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| Prove that the early inward current found at 0.5 ms in an AP is sodium (more than the fact that the x-intercept is at +50, which is Ena+) |
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| A good way to provide even more definitive proof is to first map an IV curve in voltage clamp of the cell with its normal concentrations. We should expect to see Sodium intersecting the x-axis at its equilibrium point, +50 mV. Then, we can take another recording after shifting the extracellular concentration of sodium (since the channels will be open around this voltage anyway). We can use the Nernst equation to calculate the new equilibrium point. If the new graph's x-intercept is at the new equilibrium point after changing the sodium concentration, this is good proof that Sodium is responsible for the early inward current. |
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| Prove that K+ is responsible for the late outward current |
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| The best way to do this involves the tail currents, because the K+ channels we are trying to measure are actually closed at -80mV (Ek), we need to open them before we can determine whether or not K+ is the ion responsible for the current. To do so, we can quickly pulse the cell up to +20 mV. this will open the K+ channels. Then, we return the cell to -80 mV (or even hyperpolarize it further, since at -80 it would be flat and it will be easier to see the intercept). The channels will close slowly, so we will have time to measure the current required. The current should go flat at this point on our IV curve, since Ek = -80. Then, we can repeat this process after shifting the extracellular concentration of K+, and recalculating Ek. If the x-intercept is now at the new Ek, this is good evidence that K+ is indeed responsible for the late outward current in an AP. |
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| Used to block Na+ channels. Good for focusing on the K+ current when looking at basic APs. |
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| Blocks K+ channels. Good for focusing on Na+ current when looking at basic APs. |
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| absolute refractory period |
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| ARP - defined as the time after an AP a neuron can't fire an AP. This is because of the inactivation of sodium channels. They need to be hyperpolarized to be de-inactivated. Also, however, there is a certain amount of time it takes to REMOVE the activation, so time of recovery is important. |
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| relative refractory period |
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| HARDER to fire an AP because the cell is in a hyper-polarized state. Will take MORE current to fire an AP, but still possible. |
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| Experiment to measure how long it takes sodium channels to recover from inactivation |
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| Put the cell in V Clamp (to avoid problems with the capacitive current). Next, put the cell in TEA to ignore the delayed rectifier K+ current. Then, activate the Na+ Current (and an AP), bring back down to a lower voltage, and then measure the time between succeeded depolarizations. |
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| Configuration of sodium channel |
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| The alpha subunit of the sodium channel has 4 similar ('repeat') domains consisting of 6 trans-membrane segments each. The voltage sensitivity is caused by one of the trans-membrane segments in each domain being sensitive to voltage and moving in response to voltage change. This movement causes a slight change in the shape (conformation) of the protein. This conformational change causes the pore in the center of the protein to open or close. Also there is the loop between the 3rd and 4th domains that blocks the channel causing the it to become inactivated. |
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| Brain and spinal cord Na+ Genes: |
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| cardiac muscle Na+ channel gene, heart + uterus gene, and glial gene |
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| Muscle is TOO excited...many action potentials. Seen sometimes in HPP |
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| autosomal dominant disorder that is heterogyzgous, mutation in SCN4A. Na+ channels have trouble inactivating, causing Myotonia sometimes when cells aren't depolarizing enough (trouble with muscle tensing..) because of the decreased rate of hyperpolarization (with Na+ channels not inactivating). Also can cause PARALYSIS episodes when increasing levels of potassium. If you increase extracellular potassium, you're depolarizing the cell even FURTHER, meaning the cell cannot hyperpolarize. The wild type channels (since there are some) don't have time to hyperpolarize...need longer periods of time to truly reset it. |
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| why current decreases over time in passive propgation (besides resistance) |
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| current is leaking out of channels as it goes down an axon! Capacitance ALSO slows it down and takes current. Delta v decreases. Axial resistance along cytoplasm, too |
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| Axial resistance along cytoplasm. Proportional to the diameter of the cell such that Ra is proportional to 1/r^2 |
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| Equation for finding the distance a current will travel (Vx), where V(0) is the starting point. Equation for lambda. |
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Vx = V(0)e^(-x/lambda)
Lambda = sqrt(R(m)/R(a)) |
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| detrimental potential? how far a neuron's influence spreads down an axon.. |
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| Spaces in between myelin sheath segments full of Na+ channels for AP propogation. |
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| Myelin is composed of (and by): |
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| Specific proteins and connexons that allow nutrients to cross the sheath. It increases Rm dramatically and decreases Cm dramatically (by the thickness of the sheath). Myelin is made by oligodendrocytes in CNS and Schwann cells in PNS. |
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| Myelin increases the speed of the AP in what two ways? |
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- Capacitance is gone, so this increase the rate of depolarization in the individual neurons...small nodes charge quickly
- Increase lambda dramatically, which speeds up propogation |
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| challenges with myelin spacing |
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| You need the nodes to be close enough together so that the AP doesn't fail, but long enough that it speeds up the AP. |
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| What will happen if you kill myelin? How could one hypothetically fix this functionally? |
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| APs are likely to fail to propgate since lambda is dramatically decreased, and the sodium channels are so far spread apart. To try and fix this, you either need to create more Na+ channels in the membrane (allowing SOME recovery of function, since the APs will propgate much slower), or you can remyelinate. |
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| Provide support in the Blood brain barrier, deliver nutrients to cells |
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| Difference between peripheral and central myelin? |
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Peripheral main protein is P0, which allows myelin sheaths to be tightly packed, providing some protection from damage.
In CNS, concerned more with space, so this protection is not required. |
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| What kind of disorder is Multiple Sclerosis, and how did we discover it? |
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| MS is an autoimmune disorder in which the bodies antibodies attack the myelin. We discovered it was an autoimmune disorder by injecting myelin basic protein into mice, and noticing how it affected their bodies similarly. Put us on the right track. |
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| starts in early 20s, more common in women, generally in colder climates. Generally show visual problems, peripheral weakness. |
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| transitory K+ current. Quickly activated and inactivated, and believed to be important in the rate of action potential generation, particularly at lower frequencies. |
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- MRI brain and spinal cord, look for lesions (in white matter)
- functionally, can look at peripheral conduction velocity of neurons.
- also can look for a visual problem using evoked potentials and see if there is a slower reaction than the visual cortex than in normal people
- biopsy |
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| - Interferon, which supresses immune system |
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| basic types of neurons/ion channels (for example, tonically active) and what they look like... |
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A) Silent neurons - flat..
B) tonically active - normal trains of spikes.
C) Bursters - bursts of APs, then rest (like thalamic neurons)
D) Plateau Neuron - state based neurons that are firing when "on", and silent when "off". Used in Short Term Memory.
E) Post Inhibitory Rebound - neurons that get more excited after inhibition then before |
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| Delayed rectifiers (I(k)) |
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| turns on after the depolarization of an AP, providing an outward potassium current that helps hyperpolarize the cell. TEA sensitive. |
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| Calcium channel composition/example ions that can block it |
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| Composed of 5 subunits. Can be blocked by Co++, Mn++, Cd++ |
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| High threshold calcium/L-channel |
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| pretty much always an inward current (meaning it will help depolarize the cell). Long lasting, persistant depolarizing currents. Can be blocked by drugs selectively. |
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| Transitory. Time and voltage dependent activation. Channels need to be hyperpolarized to de-inactivated and show inward current again after the spike. |
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| Example experiment to distinguish between I(a), I(k), and calcium-activated potassium current after changing from -80 mV to +20 mV (NOTE: THIS EXPLANATION IS MY ATTEMPTED ANSWER AND COULD BE WRONG) |
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| First task is to find effect of calcium activated K+ current. The easiest way to do this is to first find the measure of all three currents combined. Then, block Ca+ channels with an ion like Mn++ or Co++, and look at your potassium currents over time. Then, subtract this from the original to get a difference current representing the Calcium-dependent K+ current. Next, we need to find a difference current between I(k) and I(a). To do so, we can hold the cell at -40 mV for a while, and then pulse to +20 to open the I(a) channels. When back at -40, they will inactivate while the delayed rectifiers work to hyperpolarize the cell. We now have the delayed rectifier current graph. Now, simply subtract that from the graph without the Ca+-activated K+ current to get the I(a) graph. |
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| Ca++ activated potassium channels |
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| Require binding of Ca++ to open the channel. Can open with voltage, but usually require a strong Ca++ current to open. This will help hyperpolarize the cell |
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| Function to regulate the cell's threshold and membrane potential. Tend to act when the cell is NOT depolarized, and keep cell at lower voltages. Open pore can be blocked by Mg++ and polyamines. |
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| Hyperpolarization-activated inward current (sag potential). Allows Na+ and K+ through. It is opened by hyperpolarization, and provides a slow inward current into the cell. Acts to slowly depolarize a cell that is hyperpolarized. |
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| Describe the thalamic burster cell, all the currents involved, and how they create the bursting effect (I feel like this will be an essay, or something close. She spent half a class on it) |
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(draw the burster cell, label the steps that she did on the board)
Going into Step A, the cell is being hyperpolarized. This will deactivate the delayed rectifier, the calcium activated K+ current, the transitory sodium current, and the low threshold Ca++ current.
Going into B, I(h) has been activated, which will start to depolarize the cell again. This will activate the low threshold Ca++ current.
Going into C, the Ca++ current is depolarizing the cell and building up calcium within it. Eventually, it will depolarize the cell to threshold, activating both the transitory, fast sodium current (causing the spike) and the delayed rectifer (which will help repolarize after the spikes).
Going into D, we see a burst because the continuous influx of Ca++ from the low threshold calcium current keeps the cell depolarized (it is working against the delayed rectifier). However, as we approach D, the Ca++ level has risen enough to activate the Ca++-activated K+ channel, which hyperpolarizes the cell (and counterbalances the Ca++ low threshold current) and pumps out Ca++, which starts to turn off the low threshold Ca++ current. The cell is hyperpolarized, and we go back to A. |
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| The period of burst depends on the interaction of... |
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| The channels. Using this principle we can create oscillators for the brain. |
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| used to describe how oscillators...well...oscillate. |
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| How do you create a phase delay? |
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| Hyperpolarize the cell right before a spike. This will delay the spike, and all succeededing spikes becasue of the delay in the first. This is a phase delay. |
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| How do you make a phase advanace? |
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| Hyperpolarize the cell mid-burst. This will advance the next and all other bursts. |
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| Neurons oscillation cycles can be entrained to external stimuli, like light, or to that of other neurons as such that we cannot stablely change them and create phase delays and advances by hyperpolarizaiton of them |
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| How would you be able to tell if a neuron in the brain is being controlled by itself or another neuron? |
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| Try to phase advance or delay it. If you cannot stablely entrain it to your electrode, it is probably being entrained by another neuron. |
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