BIPN 100 Notes - Winter 2020 - Professor James Cooke PDF

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Winter 2020 - Professor James Cooke ...

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Lecture 2 (1/8/20) Cell Membrane 1. Will K+ move across the membrane? o Yes o ANSWER: Potassium can't cross lipid bilayer on its own because it is a charged particle  K+ requires an ion channel to move across membrane  Depends on if there is a means for K+ to move across the membrane 2. If so, in which direction will K+ move? Why o It will move into the extracellular space because it will move down its concentration gradient via ion channels while Na+ and Cl- also move down their concentration gradients into the cell to maintain the membrane charge o ANSWER: K+ will leave the cell because it is moving down its concentration gradient  K+ could also go into the cell because interior is more negative  Basically K+ can move in both directions across the cell membrane Membrane Potential  During the process of diffusion in a fluid, uncharged particles will move from high to low concentration because: o ANSWER: The random motion of particles in a fluid results in their uniform distribution o Diffusion is a totally random process o "A" is incorrect because particles don't 'want' anything  Most molecules do NOT diffuse across the lipid bilayer o Most require ion channels to move across membrane  Electrical potential difference exists on either side of the membrane o K+: High inside, low outside o Na+: Low inside, high outside o Cl-: High outside, low inside  Vm = membrane potential o When talking about membrane potential, it is always talking about the charge on the INSIDE of the cell o Refers to the potential difference as recorded on the inside of the cell  How do neurons establish this difference (high K+ inside, high Na+ outside)? o Use of active transport pumps (an ATPase)  Charge is distributed along the membrane o Rest of cytoplasm/extracellular space is electrically neutral  Na+/K+ Concentration Question: o In which direction does K+ move when K+ channels open? Why?  BOTH directions  Out of cell bc move down concentration gradient  Into the cell bc moving down electrical gradient o At what point will K+ ions stop moving across the membrane?  K+ doesn't actually stop moving  When rate going in/out of cell is equal, there is no net movement/current

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 This is the state of electrochemical equilibrium If we record the "potential" on the inside of a neuron while K+ channels open, is it getting more positive or more negative? Why?  Depends on answer to question 1  In which direction is there more K+ moving?

Lecture 3 (1/10/20) Reversal Potential/ Equilibrium Potential  The membrane potential at which there is not NET movement of an ion across a membrane that is permeable to that ion  Written as Eion  How much electrical force is required to offset/oppose the chemical gradient? o Use the Nernst equation  Nernst Equation: predict the equilibrium potential of an ion o Eion = (RT/zF) ln([x]outside/[x]inside) o R = 8.315 joules/Kmol o F = 96,485 Cmol o T = add 273 to degrees Celsius o Z = valence, or the number of moles of electrons transferred in a cell reaction  Eg: 2 for Ca2+, 1 for Na+ o On exam: Equation and constants will be provided Eion and Vm 

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Clicker Question: Reversal potential in action! o If membrane potential is -60 mV and Ek is -76 mV, K+ will have a NET movement OUT of the cell when the K+ channels open Anytime we increase the permeability(open channel) for an ion, we drive Vm towards Eion o If we decrease …, we drive Vm away from Eion If you know Eion and Vm, you will be able to predict the impact of ion on Vm when it's channels open Once you know which direction the membrane potential is going to go, you know which direction the ion is flowing Clicker Question: What determines the resting membrane potential of a neuron? o Na/K ATP pump o K+ leak channels o Na+ leak channels o ANSWER: all of the above The membrane potential of a cell at rest is called the Resting Membrane Potential

Resting Membrane Potential  Leak channels: more K+ than Na+ or Cl What's responsible for this? o Movement of ions going into/out of cell o Because Na+/K+ has set up a beautiful gradient inside  Remember: ions move the membrane potential toward their equilibrium potential

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Can we use the Nernst equation to calculate the membrane potential if the membrane is permeable to more than one ion?

Lecture 4 (1/13/20) Membrane Potential  Can we use the Nernst equation to calculate the membrane potential if the membrane is permeable to more than one ion?  Goldman/Hodgkin/Katz equation o The role of permeability Worksheet 1. In a typical neuron, a. It is more permeable to K+ at rest b. The membrane potential is so close to Ek because the membrane is more permeable to K+ than other ions 2. Could you depolarize a neuron by increasing permeability? How? Use the graph to defend answer o Depolarize: more positive membrane potential (Vm) o Hyperpolarize: more negative Vm o Depolarize by increasing the permeability of ENa 2. Could you depolarize a neuron by decreasing permeability? How? Use graph to defend answer o Yes: decrease permeability of K+ and/or Cl3. An alien neuron is discovered.. a. A colleague claims that the resting Vm is set primarily by Cl-, and not by K+. Could they be correct?  Sure, Vm is very close to Ecl  There could be the possibility that the cell is not permeable to K+ at all  The cell could be very permeable to Clb. How could you test this hypothesis (Vm set primarily to Cl-) experimentally?  Block K+ channels. IF hypothesis is correct, and something happens: refutes somewhat  If hypothesis is correct and NOTHING happens: supports our hypothesis  If we block Cl- channels, and nothing happens, then Cl- wasn't contributing anyway  If we block Cl- and something happens (eg: membrane depolarizes substantially), then this supports the hypothesis that Cl- was a driving factor in establishing the resting Vm c. What's the most positive and most negative this cell can get?  Ena and Ek 2. If there a greater potential diff between

Lecture 5 (1/15/20)

Electromotive Force  F = Vm - Eion (USE ABSOLUTE VALUE)  The further away the membrane potential is from the reversal potential for an ion, the greater the electromotive force that exists for that ion  Current flow depends on resistance across the membrane and the electrochemical 'drive'  Movement of current can be described by Ohm's Law: o V = I x R or I = V/R Membrane Potential  Three factors contribute: 1. Concentration of ions on either side of the membrane 2. Permeability of the membrane for those ions 3. Charge of ions  Only 1 in 100,000 K+ ions must move across the membrane to change Vm from +30 to -70 mV  So there is basically no effect on the overall concentration of Na+ and K+ on either side of the membrane 1. "a tear in the sea…" o Gated ion channels can be opened and closed by: 1. Changes in voltage  Membrane potential changes that occurs across the cell membrane 2. Binding of chemicals (ligands)  Ligand binds to specific area of ion channel and opens the channel 3. Changes in mechanical force  Physically pulling the ion channel open to allow ion flow o Channels are different at different spots on the neuron 1. Ligand-gated channels mainly at the dendrites and cell body 2. Voltage-gated channels mainly at axon o Incoming stimulation causes a local change in membrane potential that is proportional to the magnitude of the stimulus (graded to magnitude of stimulus) o Strength of response is determined by strength of stimulus o Graded potentials travel by electrotonic current 1. Electrotonic current is very fast o Clicker Q: Why do graded potentials decay in space/time? 1. Answer: Because of the resistance of the cytoplasm AND current leaks out of the membrane 2. If you want signal to travel very fast, you want membrane resistant to be very high and intracellular resistance to be very low 3. High membrane resistance refers to ions not being able to leak out, so current goes farther 4. High intracellular resistance slows down current o Signal decrement is due to: 1. Leakage of charged ions across the membrane 2. Resistance of the cytoplasm o Membrane Resistance (Rm) 1. Leaky hose analogy

2. Remember: I = V/R 3. Lots of channels means lots of places for ions to "leak" out, signal gets smaller as you move away from stimulus 4. Many channels = low resistance

Lecture 6 (1/17/20) 

Membrane potential doesn't go all the way to Ena at time X when Na+ channels are opened because there are leak channels that keep the potential below Ena Action Potentials  Na+ influx = rising phase (depolarization)  K+ efflux = falling phase (repolarization)  Clicker Q: Why is the cell permeable to Na+ before K+ o ANSWER: Because Na+ are faster at opening than K+ channels  "Gating" of VG Na+ and K+ channels o K+ channels: open slowly in response to depolarization, close slowly in time o Na+ channels: 2 gates - activation, and inactivation gates  Has voltage sensing domain on activation channel (+ charge on gate)  Absolute refractory period - the period when another action potential can't be fired again because the Na+ channels are closed

Lecture 7 (1/22/20)

Refractory Period  If voltage-gated K+ channels are blocked, leak channels will still allow K+ to slowly flow through o Absolute refractory period will last much longer o No relative refractory period  Relative refractory period o Open VG K+ channels both:  Hyperpolarize the cell (further from threshold)  Shunt incoming electrotonic current Mouse Question  X:3, Y:1 o X will have a smaller peak since K+ open immediately o Y is 1 because rapid repolarization occurs about 3 ms later Ion channel # and density affect AP shape and threshold  More Na+ channels = lower threshold to fire Aps  # of voltage-gated Na+ channels is going to determine threshold for firing an action potential Q: You lower a stimulating electrode into middle of an axon, while recording from both the some (near axon hillock) and axon terminal. If the stimulus is suprathreshold: Will you record an action potential at the soma? At the terminal?  Depends on the state of voltage-gated Na+ channels  Yes at both if all the voltage-gated Na+ channels are closed along the axon Lecture 8 (1/24/20) Action Potential: Speed of Propagation  Speed of AP propagation can be increased by: 1. Myelinating your axons  Makes membrane resistance super high  Almost infinite  Myelin covers leak channels and prevents ions from leaking out  Allows current to travel along more than if there was no myelin present 1. Increasing the diameter of your axons  Decreasing intracellular resistance and allows electrotonic current to travel farther o Can't speed up electrotonic current itself bc it is already super fast  As AP travels down the axon, it reaches the axon terminal, or pre-synaptic terminal o The neuron communicates with the post-synaptic cell across a synapse Synapse  Pre-synaptic cell is said to "innervate" the post-synaptic cell o Innervate means the pre-synaptic cell is talking to the post-synaptic cell  Electrical o Gap junctions connect pre and postsynaptic neurons

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o Allows 2 neurons to essentially act as one o Very fast o Not modifiable Chemical o Pre and post are "separated" at a synaptic clef o Communicate using ligands called neurotransmitters o Relatively slow o Modifiable o Most in body are chemical o Ca2+ channels  Open up in response to depolarization and calcium will come in o Neurotransmitters are packaged in vesicles  Are readily releasable o Ca2+ inside will bind to a protein and the vesicle membrane will combine with the cell membrane and release the neurotransmitters into the synaptic clef exocytosis o Neurotransmitter can stimulate a ligand-gated ion channel o Gotta get rid of Ca2+ afer it comes in  Ca2+ is a secondary messenger  Calcium can stimulate apoptosis o EPP - end plate potential  Graded potential recorded in a muscle cell

Lecture 9 (1/27/20) Classic synaptic physiology model: NMJ  Neuron releases acetylcholine (Ach) onto skeletal muscle  Ach activates nicotinic AChRs on the muscle o Results in depolarization of the next cell  Net depolarization of membrane, called End Plate Potential (EPP)  Same thing as post-synaptic potential!  Ach allows sodium coming in and potassium to come out o Leads to post-synaptic potentials usually  Terminating synaptic transmission o Enzymatic degradation (Ex. Ach-ase) o Transport (ex. Dopamine transporters, DAT) o Diffusion Drugs prolong neurotransmitter action in synapse  MAOIs: Monoamine oxidase inhibitors o Prolong duration of monoamine o For depression, anxiety  SSRIs: selective serotonin re-uptake inhibitors o For depression, anxiety  Cocaine: inhibitor of dopamine transporter o Can also be very effective local anesthetic o Prolongs action of dopamine  All of these act to prolong the action of neurotransmitters in the synapse

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Ionotropic - ligand-gated ion channels o Fast Metabotropic - second messenger pathway initiated o Coupled to G-proteins o Slow

cAMP Pathway  Metabotropic pathway  Gs: activates AC  Gi: inhibits AC PLC/IP3 Pathway  Gq: activates PLC  No inhibitory cell in this pathway 

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EPSP - Excitatory post-synaptic potential o Makes AP more likely o Have to have reversal potential of the ion above threshold IPSP - Inhibitory post-synaptic potential o Makes AP less likely

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Temporal Summation - when a single synapse is active repeatedly Spatial Summation - when multiple synapses are active simultaneously

Spinal Cord Lecture   

Info comes from brain, through spinal cord, then through periphery Afferent neuron - takes info from periphery to integrating center Efferent neuron - takes outputs info to the periphery

Pathways: Spinal Cord  White matter - type of tissue that is cells covered in myelin o Helps speed up propagation of action potentials  Gray matter o Anything that isn't myelinated o Ofen cell body  Dorsal root ganglion (DRG) o Dorsal is the back o Where all the cell bodies of sensory neurons reside o Dorsal horn - sensory information comes into the dorsal horn  Ventral root o Ventral horn - have cell bodies of motor efferent neurons  Sends projections out through ventral root into the muscles o No dorsal root on ventral side Sensory System: Pathways  Lemniscal Pathway - Touch, pressure o Has first-order neuron to take info initially

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o Takes message to medulla oblongta o Sends info to synapse and goes to a second-order neuron o Second-order neuron decussates the median o Goes to 3rd-order neuron up to the cortex o Whole point of pathway is to stimulate cells in cortex o Tells your brain what is happening in the outside world o Takes path of the dorsal column o Decussation occurs in medulla Spinothalamic Tract - Pain, temp o Has synapse in the dorsal horn and second order neuron decussates in the spinal cord o Info sent up spinal cord and through medulla all the way to thalamus o Then stimulates 3rd-neuron o Then stimulates in the cortex again to give brain info about pain o Anterolateral tracts o Decussation occurs in spinal cord

Motor system: Pathways  Tract starts in sensory cortex  Motor cortex initiates movements  Some info decussates in medulla and some doesn't  Same side - Decussates goes down and stimulates motor-efferent cell to the lateral corticospinal tract  Lateral corticospinal tracts controls limbs Motor (efferent) tracts  Lateral corticospinal tract o Ipsilateral o Info about arms and legs o Info the goes to limbs decussates at the medulla  Anterior corticospinal tract o Postural o Controls muscles near the core o Info that decussates in spinal cord causes stimulation of postural muscles  Only 2 cells in the motor system Spinal cord: level is important  Cervical - arms, fingers  Thoracic - core  Lumbar - legs, feet  Sarcal - genitals END MIDTERM 1 MATERIAL Lecture 10 (1/29/20) 

A = lef lateral corticospinal tract

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o Decrease in motor function of lef leg B = right lateral corticospinal tract o Decrease in motor function of right leg C = right lemniscal pathway o Decrease in sense of touch from the right leg Top half decussates at medulla; bottom half decussates in spinal cord

Nervous System  Main question: How is the nervous system organized to do its job of gathering information, processing it, storing it, and producing responses?  Nervous system separated into 2 parts  Central Nervous System o Brain and spinal cord  Peripheral Nervous System o Everything else besides central  Brain: cortex o Motor cortex responsible for eliciting movement o Parietal lobe is somatic sensory cortex for sensing touch o Occipital lobe is visual processing area o Temporal lobe for hearing  Sensory receptors transform info from the outside world into action potentials for our brains to decipher Somatosensory Pathway  Q: A blunt is applied to the tip of your right index finger. A "merkel's disc" in your skin responds to this tactile info, and sends info about the stimulus to your brain o How can you tell the difference between a slight, sof touch and a hard touch?  Cortex will be stimulated  Cortical cell has to know intensity of the touch  Depends on how cells communicate with each other  Hard touch has more neurotransmitter released to interneuron in brain  More Ca2+ will trigger more neurotransmitter release  More Ca2+ comes from stronger action potential  Increase action potential frequency for harder touch o Why might a very light touch not even be felt?  Graded potentials didn't reach threshold in the sensory neurons  So no action potential fired o How do you know that you are feeling pressure, and not pain?  Different pathways - lemniscal and spinothalamic  Different sensory cells with specialized endings  Pain neurons are very specialized to respond to pain  pH levels and chemicals  Specialized ending that is capable of detecting damage  Pressure cells are not encoded to feel pain/damage  Pressure cells respond to the mechanical touches o How do you know that you are feeling pressure, and not seeing blue light?  Different cortical regions respond to different types of stimulus

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 Modalities are represented by diff cortical regions How does your brain know the duration of tactile stimulus?  Duration of action potential firing  Entirety of the action potential field  Duration of stimulus is encoded by action potential firing

Lecture 11 (1/31/20) Sensory Receptors  Need to know about stimulus: o Intensity o Duration o Modality o Location Modality  Is an aspect of a stimulus or what is perceived afer a stimulus  The basic sensory modalities include: light, sound, taste, temperature, pressure, and smell  A broadly acceptable definition of a sense is: A system that consists of a group of sensory cell types, responding to a specific physical phenomenon, and corresponding to a particular group of regions within the brain where the signals are received and interpreted  Encoded by different and specific regions of the cortex  You could elicit the same sensory experience if you stimulated the relevant regions of cortex directly  Some areas of the periphery send very little innervation to the cortex Stimulus Intensity  AP frequency  Receptors generate a graded potential in response to stimuli  Encoded by the # of AP generated Stimulus Duration  Tonic = slowly adapting o AP gradually stops firing to change but it takes a long time  Phasic = rapidly adapting o Changes as stimulus is changing o Once no more stimulus, firing stops o Optimized to adapt change  Adapting is the rate at which the neuron stops firing AP Location  Convergence o If many sensory neurons 'converge' on a single second-order neuron, the receptive field of that second-order neuron quite large, with low discrimination o Receptive field is region of the skin that is capable of producing AP for a particular cell  Receptive field size is INVERSELY proportional to our ability to discriminate  Have to say what cell we are talk...