Class Notes - Professor Jennifer Doherty PDF

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Professor Jennifer Doherty...

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Intro/Neuropathic pain After 4 years: Get a job, make it to graduate school, get a degree, Understand the knowledge to be applicable irl Goals: To get into the bio major Best thing: Passing,bringing up my gpa, making connections, Helpful tips: Studying one on one or in a small group, in depth reading, FREE RECALL, PRACTICE OLD EXAMS, FOCUS ON THE FIGURES Learning Goals: 1. Use powerful general models of physiology to make prediction about novel physiological phenomena 2. Provide mechanistic cuasal explanations, that cross scales for how novel physiological phenomena occur a. This cause this causes this 3. Think critically and ethically about how and by whom science is conducted 4. Implement strategies for learning majors biology that are bases on scientific evidence To do: read the textbook (don't skim) and understand mechanisms, free recall for 10 mins every night, old exam problems and correct them ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Neuropathic Pain: Nociceptive pain 1.

A nociceptor is a sensory neuron (nerve cell) that responds to potentially damaging stimuli by sending signals to the spinal cord and brain. This process, called nociception, usually causes the perception of pain.

Neuropathy = consistent pain, already healed, no cure, from crushed neuurons Tactile allodynia = touch equals pain Molecules moving = potassium and sodium in and out of the neuron, neurotransmitters diffuse b/w cells Along the neuron action potentials are moving General models of Physiology: 1. Flux = flow down gradients, direction of movement a. Caused by energy differences along the path b. Moderator = resistence 2. Mass balace 3. Control systems

Neuropathic Pain Third order neuron is where you interpet the sense as pain (in the brain) Gradients:  Diff in energy along a path  Bodies of all organisms store energy in gradients o Sodium-Potassium pump o Hydrogen o Calcium o ATP (energy), ATP-ase o Glucose moves from sodium's energy o Proton gradient (electron transport chain) powers ATP synthase  Energy gradient = driving force Resistence:  Moderates flow through the path  Ex. Membranes, closed channel  Ligand = molecules that binds to something  Energy gradient = conc gradient Sucrose Example:

No movement: Transport protein is closed (high resistence) No net movement: Concentrations are equal in and out of the cell (no concentration gradient / chemical gradient) K+ Example:

No movement: gated channel is closed when the ligand is not attched (high resistence) No net movement: when the electrical gradient and chemical gradient are equal and opposite

K+ is a Charged ion Neg on one side and Pos on the other side = attract Equilibrium Potential Membrane potential = measure of the diff in charge across membrane How is it determined? Measured by a device, gives you one number for electrical gradient Along the membrane, it's more negative, but most of the cell is neutral, proteins are negative Ca++ moves in and out bc conc and electrical gradient Cl- moves out since the electrical gradient is negative inside and conc is higher inside than outside Concentration gradient, electrical gradient, alive cells, open sodium channels (pumps) involved Leak sodium channels When allowed to move freely, eventually gets to equillibrium When allowed to move freely (open channels) net move of ion stops at equilibrium at equilibrium potential, membrane potential is equilibrium potential

Neuropathic Pain Sodium Na+  Chemical gradient is high outside the cell and low inside the cell, goes in Membrane potential E(Na) = 61.5, no net movement

Above goes out, more Positive, larger e Below 62 sodium comes in, concentration gradient is stronger than the electrical force Above goes in, positive charges repel positive ions Below goes in, since it's negative, it attracts the positive charge Out Out In Smaller arrow because it's closer to -90, -70 is less negative than -90 Canvas Assignment:

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Student Example: Outside: 350mM, Inside: 15mM Electrical Gradient: -100 All forces move in SE2:

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E(Na) = 72 mV In the cell, 100mV, 10 mM Out 150mM Moves out What is equilibrium potential? What is in the cell, which way does it have to go?

Neurons:

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Sensory Neurons Some have mylenated sheeths Cell body in the middle Talks to your body Interneuron In brain and spinal chord All different Efferent neurons or motor neurons Do things for your body Looks the same Sensory neuron: How does a nociceptor generates the first action potential?

>Change in pressure (push or pull) at the wound >> Gated ion channel opens (mechano-gated), Na+ channel opens >>> Na+ would go in (enters) 150mM out, 15 mM in, -70 mV in >>>> Depolarization, membrane potential is more positive >>>>> Trigger zone at the base of the axon (dendrite) >>>>>> Current flows to trigger zone >>>>>>> Causes Action Potential if at threshold dendrites

2 Action Potentials We are talking about nociceptors, motor, mechanosenor Depolarization has to flow to the gates to open them up Electrical signalling moves fast Positives by the dendrites, attract electrons Resting membrane potential = when the membrane potential is not changing Standard is -70 for our cell Graded potential, receptor Mammalian cell More leaky K+ To go to equilibrium, there should be low resistance If the cell is going to eq, it has to move, and have low resistance Nociceptor: Na+: Voltage gated sodium channel protein (Closed) Positively charged, attracts

Opens the activation gate when at threshhold (Open) Ball of amino acids can inactivate the gate (Inactivaed) K+: When the cell is more neg the gate is closed More positive, gate opens No ball of amino acids to block the gate Mechanosodiums open at threshold Sodium channel opens, voltage Na+ gate opens, causes depolarization (chemical gradient is in, electrical gradient is in)

3 Neural paths and Synapses

Nerve cells The synapse

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Flow Diagram: Action Potentials are made by opening and closing of Na and K channels > The axon terminal is depolarized V-Ca+ open, At synaptic terminal, release of Ca+ ions into presynaptic terminal Ca ions bind to vesicles containing neurotransmitters Vesicles fuse with the plasma membrane (exocytosis) Releasing neurotransmitters in the synaptic cleft Bind to NT-R (neuro transmitter receptors) Open cation channels (NT-R), ions flow Changing charged across the membrane/changed the membrane potential Ligands are removed Exitatory = more likely to AP Inhibitory = neuron is less likely to generate an AP Both expresses = no AP (cancel out)

Synaptic transmission:

Chemical synapse: AP> Na+ voltage gated channels open, allows Na+ into the cell > Depolarization Depolarization > Ca+ channels to open > Ca+ ions rush in Ca+ ions attach to vesicles of neurotransmitters (Acetylcoline) Vesicles fuse> release neurotransmitters into the cleft Neurotransmitters attach to receptors on post-syn Na+ enter the channel into the post-synaptic cell Inactivated by braeking down neurotransmitters and closes channels

Do the ions continue to enter the cell at the same rate at point X as compared to point Y? No because the membrane potential is being reached as time goes on There's an inc in resistance Or Yes, bc the gradient at X, not all Na+ gated ions are open yet How do APs proagate along an axon? Repeling forces of pos and pos open Na+ channel, allows ions to flow quickly AP go in one direction, bc there's a delay before another to fire What are two mechanisms that make it unlikely that a new action potential will start before that region of the axon returns to RMP? There has to be an undershoot, K+ open, relative refractory period Absolute refractory period, the amino acid ball is stuck, inactive gate When the neurotransmitter releases, what does it do? Neurotransmitter binds to channels and opens a sodium channel Then causes a small change in mV (graded potential), can cause an AP

Rubbing (activates skin mechanoceptors), which inhibits pain to the brain Proteins: Voltage gated Na and K Na+/K+ Pump Leaky channels Neurotransmitter receptors To stop the signal - NTs difusse away or break down/recycle Glutamate (Glu) GABA When Glu binds to GluR, what would you record on post-synaptic membrane? Depolarization, more positive The post-synaptic neuron sums exitatry and inhibitory input

3 Mass Balance and Synapses What is Summation? Addition of Post-Synaptic Potentials Temporal Summation: ~ One neuron sends a signal

Spatial Summation: ~ two neurons send signals

4 Glu binds to Glu-R which allows depolarizing (more positive) more sodium comes in than potassium. At -70, the gradient for Na is larger and the resistence is larger. Both c ane e arrow point in. Glutamate diffuses away what happens to the post-synaptic membrane? The cell would repolarize Exitatory-post-synaptic potential (EPSP) Not hyperpolarizing bc no voltage gated K+ are open, K+ has low resistence Not AP bc not at the trigger zone, voltage gated Na+ channels only at the trigger zone

For Cl- you need to know the concentration gradients and electrical gradients

What determines chloride concentration in a neuron? To differ the mass, you could:  More or Less KCC2 proteins  More or Less K+ ions (change concrentration gradient)  More or Less Na+ ions (Change in gradient)

Primary active transport uses ATP to power it, needs energy Secondary uses the conc gradient and changes the shape of the protein to pull or oush something against their gradient (Power source) Mass Balance = determines the mass of something

Bathtub model: water in tub = water out thru drain (or evaporating or person) Cl- comes into the cell, by GABA-R >> Hyperpolarize b/c tends to move from -70 to -83 by moving into the cell Inhibitory Post synaptic potential IPSP Cl- comes out b/c K+'s gradient wants to come out, which brings Cl- with it Cl- in at -70 mV The amount of neurotransmitter determines a lot of things What determines the amount of NT in synaptic cleft? Amount of vesicles Amount of Ca+ ions into pre-synaptic cleft Rate of AP Leaves: NT diffuses by the concentration gradient It depends Glu is excitatory if enough Glu is released. It could depolarize, but not enough to fire a AP Glu+Gaba cancel

temporal summation = over time, same neuron just over time adds Glu Spatial Summation = 2 different events (EPSP + IPSP) Inhibitory interneuron = AP -> V-Ca2+ open -> Ca2+ into the cell -> Ca induces the GABA vesicle to fuse with membrane -> NT's (GABA) release into synaptic cleft-> GABA binds to GABA receptor -> GABA-R opens Cl- enters -> IPSP -> Difference in charge that opposes what's coming in.

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Inhibitory to exitatory neuron, How: No Cl- ions in extracelluar fluid, Cl- move out Increase Cl- concentration in secondary neuron No V-Ca2+ channels open NT Releases Glu instead of GABA Glu binds GABA Inflammation Inactivation of CNS immune cell (microglia) Release BDNF Down regulate KCC2

KCC2 = neurons are more exitatory

6 Problem Day Protein: V-Na+ How the protein changes: Activation gate Opens

Cause for the protein change: Membrane potential increases to threshold Protein: V-K+ How the protein changes: Opens Cause for the protein to change: Depolarization Protein: M-Na How the protein changes: opens Cause for the Protein to change: Pressure by mechanical force Protein: V-Na+ How: Inactivate gate closes Cause for protein change: 1ms passes, gate binds to pore Protein: V-K+ How the protein changes: Closes Cause for the protein to change: Repolarization/hyperpolarization, or below -55 Na+ out of the cell? Membrane voltage: Logic/use general models reasoning: more positive than Ena because at Ena there's no net movement, at resting electrical gradient is inward. If the mV is 62, electrical moves out

Neural Path Problem: Decrease KCC2 lead to tactile allodynia KCC2 brings Cl- out of the cell. Different Cl- ions, no IPSP, EPSP instead Because Cl- leaves 2nd order neuron when GABA binds to GABA-R an EPSP is generated. The depolarization will flow to trigger zone and trigger an AP in second order neuron which signals pain to brain.

6 Biol220 Workshop Nervous System: How the body relates info from the outside world to our body Pain Sense comes from nociceptors Electrical signal to chemical (NTs) signals at the synapses… to Electrical signal to Chemical signal…etc Membrane potential = difference in charge inside and outside the cell  Usually -70mV inside Na+  

High conc. Out Low conc. In

Wants to flow in

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K+   

Low conc. Out High conc. In Wants to flow out

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A protein, Na+/K+ pump Moves 3Na+ out Moves K+ in By ATP

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Cl- Chloride [Hi] Out [Lo] In (like Na+)

Ca++ Calcium  [Hi] Out  [Low] In Charges govern which way the ion moves, Nernst Potential/Equilibrium Potential Nernst Equation: Goves the magnitude of electrical charge that is equivalent to the concentration force, but oppsite no net flow of ions, equal magnitude Resting membrane potential: Approx. -70mV Equilibrium in electrical balance More L-K+, less resistance, -91mV Less L-Na+, more resistance, +62mV Sensory Neurons: Sensing things, form external environment Interneuron: Talks/Connects from neuron to other neurons Motor neurons: Takes information from interneurons to other parts of the body/ effectors like muscles Mechanoreceptor: Responds to stimuli from the cell membrane, temp changing the resting membrane potential Electroreceptor: An electric current opens a Ca++ channel Action Potentials:

Trigger zone only has V-Na+ Once open (-55), large influx of Na+ At -55, both driving forces tend to bring in Na+ V-K+ opens slowly while V-Na+ is open After time, V-K+ opens AP begins to move down the axon: Positive spreads and neg pulls away, and opens channels Inactivation gate prevents AP from going backwards, only goes forward bc V-Na can become open

A. I agree because it would keep depolarizing the cell and the membrane potential would be more positive. It wouldn't be more positive than ENa+ because then it would repel the positive ions. B. If the inactivation gate was removed, the protein channel would be either open or closed. It could lead to APs firing in the opposite direction (backwards) instead of forwards only, because the inactivation gate prevents the AP to go backwards. From

10 Anesthesia What are Aja's sympotms? Red face, sweat/temperature, high ventilation rate, higher breathing rate, muscles contrated What does Dr. Kim think is causing them? Sevofluorane Muscles = tissue Made of muscle fibers = cell In cell, myofibrils Sarcomere in myofibrils Contracted muscles: Shorter Rigid, hard Relaxed:  Soft, no tension  Molecular level = actin and myosin heads are apart, Ca+ allows the myosin head to interact

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Lengthen Muscles need to have antagonistic muscles What causes muscles to contract? Excitiation contraction coupling AP and sarcomere contraction needs Ca+2 When the trigger zone reaches threshold -> fires an AP Muscle cells always have enough NT to fire an AP

Neural AP and skeletal muscle AP look the same What would happen when acetylcholinesterase inhibits

11 Anesthesia 2 What is the function of the T-Tubules? Pathway for the AP, invaginations of the cell membrane Where would the V-K+ and V-Na+ found on a muscle fiber cross section? Ca+ channels on the membrane will open, allowing Ca+ into the cytoplasm V-Na+ channels on a muscle cell membrane will open, allowng Na+ into the Cytoplasm Ca++ channels in the muscle cell will open, allowing Ca++ into the cytoplasm Ca++ channels on the SR will open, allowing Ca++ into the cytoplasm

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DHP = protein, changes shape, causes RUR to open RYR = protein, opens the channel, mechanically gated by the DHP What determines the rate that Ca2+ leaves the SR? how many RYR to open (due to AP) How strong the gradient is, in SR = 6mM, out = 10^-4 Where does the Ca+ move to in the cell? Ca+ moves to the binding site on troponin, by diffusion of conc. gradient (randomly moves) Ca+ pumps Everywhere

Tropomyosin is lifted off after Ca+ binds to TN, uncovers binding sites for myosin and actin Binding changes shape to make it favorable for thee P to comeofff, the myosin head moves and flips (power stroke), contracting the muscle With ATP, it unbinds the myosin head At rigor mortis, there's no ATP to unbind the myosin head to actin. Calcium causes pop in force

12 Diffusion Muscle rigidity and High Temperature Lots of ATP production, more ATP causes high temperature (ATP causes heat) Constant Ca+ causes muscle rigidity ATP being used at pump and muscles moving High Ca+ high ATP, High thermal, inc, cross bridge cycling

Why Calcium is always around: membrane potential problem, RYR is always open (binded by sevofluorine) ATP is made in the mitochondria. High ventilation gives high CO2 What determines the amount of CO2 in a person's lung? The amount in and the amount out The more ATP production, the more CO2 in the lung Out: caused by exhaling Gas exchange at capillaries Flux: Partial pressure: oxygen is 21% of gas in atmosphere, so 21% of the pressure is due to Oxygen, less air at higher elevation Diffusion is very fast in the lungs, .25sec b/c really small distance (one cell layer thick) Velcity is greatest at the arteries (out of the heart), and veins (narrow path) Slowest in the capillaries (wide path).

13 Breathing BW which points does pO2 appreciably change? A&B and D&C Because the tissues are using up a lot of oxygen How does O2 move from air in lungs to blood? How does O2 move from blood to cells? Why is the concentration always lower in the red blood cell than the outside? Oxygen gets bound to hemoglobin and is no longer free oxygen, not involved in partial pressure When H os saturated, red blood cell comes to PO2 to 100, an comes to equilibrium Where Oxygen is = Stuck on Hb, dissolved in plasma Oxygen comes off of Hemoglobin = the law of mass action, as O2 decreases so the reaction moves in that way Oxyhemoglobin dissociation curve: relates the amount to partial pressure to the amount of hemoglobin At rest in arterial: ~100% At rest in venous blood: 75% there's a buffer When would it make sense for someone to get supplemental oxygen? When your lungs aren't at 100mmHg, Hemoglobin is overworking, taking too much O2 If the trachea narrows, you couldn't get alveola to 100

If you have pneumonia, there's water in the lung which is more difficult to diffuse through bc higher resistence, more pO2, increases the gradient If you take supplemental oxygen, there's more pure O2 in the lung

Bio review session Thyroid Hormone =Thyroxine = T3 T4 All increase metabolic rate Rate of CO2 production Rate of O2 consumption Tyrosine based hormone

Hypothalmus TRH Anterior pituitary gland TSH Thyroid gland T3 and T4

TSH has a receptor on the epithelial cell, causes a signal cascade, stimulates production of thyroglobulin Iodide comes in with Na+ via transporters There's still Na+ and K+ channels Hypothyroidism = low iodide, enlarged thyroid gland, no iodide, no thyroid hormone, TSH continually produces, continually makes thyroglobulin in the lumen Hyperthyroism = immune system makes an antibody which has a strong afinity fo the TSH receptor cell, production of thyroglobulin and thyroid hormones, should shut off TRH and TSH, antibody stays there to stimulate, best fixed by having less thyroid gland Biological Clock Signal = Environmental Signal Receptor = eyes (Photoreceptors), Ganglian cells senses blue light (melanopsin), sends AP to the brain, stimulates production of Per and Cry Input = Circadian oscilator Output = gene expression, protein activity levels, producing hormones at a certain time of day