NEURO Exam 1 Vocabulary

500 BCE Brain Ideas

*500 BCE Brain Ideas* - Ideas based on observations but NOT grounded by experimentation *Aristotle* (384-322 BCE): Brain critical for cooling - Structure: Brain is covered in blood vessels in this network, so plausible to think that brain tissue could be cooling the blood - Brain filled w cerebrospinal fluid on ventricles, so maybe could be cooling structure BASED on observations - No experimentation here though - How to test this? -> Could measure temp flowing to and from brain to experiment *Hippocrates* (460-379 BCE): Brain critical for sensation - Observation: Look at major sensory organs: located on base of brain - Large nerve running from eyes and major sensory organs connected to brain BOTH STRUCTURE/FUNCTION APPROACH ! - They're just looking at structure of brain (blood vessels/connected to major sensory organs)

According to Ohm's law, which two properties define the amount of current that will flow across a membrane?

*According to Ohm's law, which two properties define the amount of current that will flow across a membrane?* 1. Ionic driving force (Vm - Eion) 2. Ionic permeabilities (conductance G)

action potential (book)

*Action Potential* (book) - think of generating action potential by depolarizing like camera click (until you click hard enough, it doesn't take a picture but then once you do, a picture is always taken) *Single AP* Assume: K+ concentrated twentyfold inside cell, Na+ concentrated tenfold outside cell, Ek = -80mV, ENa = 62mV THRESHOLD - Membrane potential at which enough VG-NA+ channels open so that permeability favors sodium over potassium RISING PHASE - thanks to selective permeability - large driving force on Na+, so when VG-Na+ channels open, Na+ rushes in and membrane rapidly depolarizes OVERSHOOT - Membrane potential overshoots 0mV and approaches ENa FALLING PHASE - VG-K+ channels finally open (1msec later) - Large driving force for K+ now bc membrane is close to ENa/strong depolarization - K+ rushes out of cell through open channels, causing membrane potential to become negative again UNDERSHOOT - Open VG-K+ channels add to resting K+ membrane permeability - very little Na+ permeability, so membrane potential goes towards Ek, hyperpoarlization relative to resting membrane potential until VG-K+ channels close again (delayed) ABSOLUTE REFRACTORY PERIOD - Na+ channels inactivate when membrane is strongly depolarized and cannot be activated again until after repolarization and 2-5 msec delay RELATIVE REFRACTORY PERIOD - Not all of VG-Na+ channels open and hyperpolarization -> takes more current to reach threshold - Stronger current makes it more likely to get over the hyperpolarization/small number of VG-channels ready *Multiple APs* - now think of fancy sports/fashion photographer where if you have continued pressure on button -> camera shoots frame after frame - rate of AP/firing frequency of action: magnitude of continuous depolarizing current - why does frequency coding happen? bc w stronger current, more likely that all VG-Na+ open/that it will happen during relative refractory period MAXING OUT frequency of APs - there is limit to rate at which neuron can generate action potentials -> maximum frequency is about 1000 Hz - Na+ VG channels inactivate -> absolute refractory period *absolute refractory period*: time period once an action potential *relative refractory period*: amount of current required to depolarize the neuron to action potnetial threshold is elevated above normal (harder to get to threshold) 1. not working w full base of VG Na+ channels open 2. Hyperpolarization from K+ channels being open

Approaches to studying the voltage-gated channel

*Approaches to studying the voltage-gated channel*

brain anatomy

*Brain Anatomy* *Cerebrum* -> makes up bulk of brain -> sensation and perception - Frontal lobe - Parietal lobe - Temporal lobe - Occipital lobe *Cerebellum* -> coordination of movement *Diencephalon* *Brainstem* *Spinal Cord* *Ventricles and Cerebrospinal Fluid* - Center of brain: hollow space - Filling holes: cerebrospinal fluid - Cerebrospinal fluid leaks out from ventricles and surrounds the brain

Nernst Equation

*Calculating Eion with the Nernst Equation* - if you know [ion] out and [ion]in

Goldman Equation

*Calculating VEq with the Goldman Equation* What you need for Goldman Equation - relative permeabilities and voltage concentration for each ion - VEq should be within bounds of the equilibrium potential of ions you are calculating

cellular/molecular neuroscience approaches

*Cellular/molecular neuroscience Approaches* 1. Structure/function analysis Assumption: can understand something about how something works by understanding something about its *anatomy*/connections ex: - We know the eyes are important for vision (function), so wherever the eyes connect (structure) is important for vision - White matter contains fibers that bring information to and from the gray matter (function) based on structure (white matter is continuous w nerves of the body) - Aristotle and Hippocrates (brain critical for cooling/sensation) 2. Loss of function analysis assumption: if function is impaired without presence of something (NECESSITY) ex: - Bell experiment: cut dorsal root (loss of sensation), cut ventral root (muscle paralysis) - Flourens' experiment: used birds to show that cerebellum has role in coordination of movement and that cerebrum has role in perception - Broca (patient who could understand language but couldn't speak): Broca's region in cerebrum in left frontal lobe responsible for production of speech - many other examples in past with injuries and effects on function 3. Gain of function analysis assumption: if you add something and function changes, able to determine function (SUFFICIENCY) ex: - typically genetic manipulation or electrical stimulation 4. Comparative analysis assumption: differences you see in structure are related to differences in behavior ex: - looking at the nervous system between different species or individuals (brain of macaque monkey -> large region in brain for highly evolved sense of sight vs brain of rat -> highly evolved sense of touch to face)

central nervous system

*Central Nervous System* (CNS) - brain - spinal cord glia: oligodendrocytes (Mike Wasowski hehe)

delayed rectifier channel

*Delayed Rectifier* - Voltage-gated K+ channel *Gating*: voltage *Kinetics*: slow *Selectivity*: K+ *Inactivation*: None *Firing pattern* - Normal style of APs (in presence of VG-Na+ and leak channels) *Voltage clamp experiment delayed rectifier* - look at notes - voltage starts at rest, small increase to -40 - as voltage remains high, channel opens with a long delay and remains open, not inactivating - so for action potential: initial rise in voltage doesn't cause channels to open, they open later and drive voltage down to EK *Density of delayed-rectifier channels* - explains how diff neurons can have diff firing patterns - large density: voltage drops very rapidly, short half-width - small density: voltage will return back to rest at much slower rate, longer half-width (half-width -> duration of single AP) - if NO delayed-rectifier channels: decrease really slowly due to leak channels towards RMP

Effect of size of neuron on time constant and magnitude of voltage change

*Effect of size of neuron on time constant and magnitude of voltage change*

Eion- the ionic equilibrium potential

*Eion- the ionic equilibrium potential* An electrical potential difference will be created under these conditions: 1. ionic concentration difference 2. selective ion permeability - electrical potential will be created if these 2 conditions are met - if there are different concentrations inside and outside membrane and that ion can move but others cannot -> then membrane potential arises Eion reached when electrical and chemical forces are exactly EQUAL and OPPOSITE -> *electrochemical equilibrium* Magnitude of Eion depends on [ion] (Nernst) - if higher amount of [K+], then you need stronger voltage to pull them back in so more negative Eion - small [ion] = small voltage - large [ion] = large voltage If multiple ions permeable, then magnitude of membrane potential depends on [ion] and relative permeabilities *Establishing Eion in a real neuron* 1. ionic concentration difference - created and maintained by Na+/K+ pump and Ca2+ pump 2. selective permeability - mostly K+ leak channels open -> source of the voltage - only K+ can diffuse and Na+ what happens if you add NaCl to cell? - nothing happens bc NaCl is balanced, so it doesn't affect voltage at all

End of BCE through the 1700s

*End of BCE Through the 1700s* *The Fluid Mechanical Model* - Soft tissues (cerebrum) critical for learning - Hard tissues (cerebellum) critical for movement - These ideas are accurate but not for these reasons - Cerebrospinal fluid (CSF) critical for communication bw regions - Galen, Descartes Additional example of observation not followed by experimentation

experimentally determining Rm

*Experimentally Determining Rm* - If you inject a known amount of current and measure the rise in voltage, then you can calculate the resistance. Can either 1. DIRECTLY CALCULATE - Use Ohm's Law (V = IR, so R = V/I) to calculate the membrane resistance 2. PLOT: IV Plot - Make a plot of current on x axis and voltage on Y -> then your slope would be the resistance - in this case, a large slope would indicate a high resistance - If current is on Y- axis, then a large slow would indicate a low resistance - Why would you calculate resistance? -> make predictions about how much voltage would rise depending on any current, not just one's you've measured

factors that can affect action potentials

*Factors that can affect action potentials* - Frequency - Latency - Duration - Inter-spike Interval - Bursting - Intrinsic firing... Picture: 4 cells w exact same excitation but very different firing patterns as a result -> different channels

frequency coding

*Frequency Coding* - subthreshold exciation: not enough to generate action potentials - inject suprathreshold: you get APs - inject even more current: you get an even larger number of APs - frequency of APs is related to intensity of excitation - they're faster and PEAKS are smaller -> decreased Na+ permeability and increased K+ permeability - lack of undershoot: very strong positive current being injected the entire time WHY??? Have to overcome things in the relative refractory period 1. VG-Na+ Channels - All VG-Na+ channels go into inactive state (absolute refractory period), and over time, more and more VG-Na+ channels exit inactivation - Not working with the full pool of VG-Na+ channels -> eventually get to 100% availability 2. Delayed Rectifier Channels - VG-K+ open during this time, so as voltage gets lower, fewer are open so the further you get you need less strong of excitation - but you still need to overcome that hyperpolarization

Given identical current injections, which neuron has a great change in voltage: the neuron with a low resistance or the neuron with a high resistance?

*Given identical current injections, which neuron has a great change in voltage: the neuron with a low resistance or the neuron with a high resistance?* The neuron with a high resistance (less conductance/fewer open channels) has a greater change in voltage according to Ohm's Law.

gray and white matter in brain

*Gray and White Matter* *white matter*: bundles of axons that connect gray matter - continuous w nerves of body - contains fibers that bring info to and from gray matter - looks lighter: axons are myelinated (myelination is essentially fat) *gray matter*: cell bodies, dendrites, axon terminals and synapses

HCN Channel

*HCN Channel* (hyperpolarization-activated cyclicnucleotide-gated channel) *Gating*: hyperpolarization AND cyclic nucleotides *Kinetics*: slow *Selectivity*: ---------- *Inactivation*: ---------- - opens in response to a DROP in voltage (only channel that does this !) vs drop in voltage THEN increase in voltage (for transient K+ and T-type Ca2+) - channel needs to be bound by cyclicnucleotides - non-selective -> if this channel opens, it'll drive voltage towards 0 - but then voltage is rising so it'll trigger action potentials - neuron w these channels will have intrinsic firing pattern - high voltage period w action potential, these channels close and then at rest, they can open again - period of spiking: HCN channels closed so no more depolarization bc no more ions, drop back down to rest w VG-Na+ closing and delayed rectifier opening, then it starts again

L-Type Ca2+ channel

*High Threshold L-Type Ca2+ channel* *Gating*: high threshold *Kinetics*: slow *Selectivity*: Ca2+ *Inactivation*: yes - they inactivate VERY slowly channels allow Ca2+ to build up in response to train of action potentials: open w high voltage and very slow to close so they allow Ca2+ to build up - buildup of Ca2+ is signal that cell has been firing for a long time - Ca2+ can signal to other proteins that can tell cell to fire less

Historical Perspectives - Studying Action Potential Physiology

*Historical Perspectives - Studying Action Potential Physiology* Squid giant axon - foundational principles of action potential demonstrated in animals like the squid - why squid? -> has a giant axon - these large axons: used for escape reflex - large axons -> conduct action potentials at very fast rate - diameter of axon is 1mm, don't need crazy intricate research techniques to use it - size of axon: very useful, can take thin wire and stick down length of axon, squeeze axon to get rid of intracellular fluid, can then control concentration of fluid inside and outside and have wires down the middle so you can measure voltage - initially not clear what exactly the voltage was doing

Hyperpolarization prior to the delivery of depolarizing current steps can evoke spikes that would otherwise not be able to occur. Using voltage-gated Ca2+ channels in your reasoning, explain in 1-2 sentences how hyperpolarization can lead to action potentials in response to a step that was previously subthreshold.

*Hyperpolarization prior to the delivery of depolarizing current steps can evoke spikes that would otherwise not be able to occur. Using voltage-gated Ca2+ channels in your reasoning, explain in 1-2 sentences how hyperpolarization can lead to action potentials in response to a step that was previously subthreshold.* Hyperpolization unblocks Ca2+ channels, so the g for Ca is increased, leading to depolarization.

Hypothesis: Membrane becomes non-selective during AP

*Hypothesis: Membrane becomes non-selective during AP* - initial voltage recordings using giant squid axon -> shows shape of AP that we're familiar with but there are no units - clear that voltage goes up and down, clear from very early reportings - not sure if you're starting at negative potential and then going to 0, starting postiive and then going even more oostiive - they thought it was literal depolarization - polarized: start w negative voltage - depolarized: literally go to 0 (we now use 'depolarization' to denote an increase in 0, but technically it means 0 voltage) so initial hypothesis: - voltage went from negative to non-selective membrane - let any ions pass, that would make voltage shoot up to 0 - then reopen K+ channels/only K+ permeability to get repolarization quantitative measures: clear that this hypothesis is not accurate bc membrane doesn't go from negative to 0, it goes from negative to positive - can't be non-selective membrane - something else has to be happening to get membrane to overshoot and go positive

Hypothesis: Permeability is dominated by Na+ during AP

*Hypothesis: Permeability is dominated by Na+ during AP* - Given measurable concentrations of K+ and Na+, reasonable to think that the overshoot could be driven by Na+ ions bc could measure solutions and see that their concentrations would allow for selective sodium permeability to make voltage go positive Experiment - electrode down squid axon - solution that axon is placed in is the control 1: Normal [Na] 2: Reduced [Na] - peak is a lot lower - why? -> goldman equation - as you lower [Na], you lower Na's equilibrium potential so peak won't be as high 3. Restored [Na] - peak back to normal - these experiments were evidence that overshoot can be produced as a result of Na+ permeability - none of data addresses Na+ channels and K+ channels - just shows Na+ and K+ conductance you need voltage clamp for channels !!!

If a monovalent anion is moving from outside the neuron into it, is the current described as inward or outward?

*If a monovalent anion is moving from outside the neuron into it, is the current described as inward or outward?* Current is outward -> inside is becoming 'less positive' bc negative charge accumulating and current flow is always describe in direction of movement of positive charge Current outward: positive charge leaving or negative charge coming in (equal and opposite) Current inward: positive charge entering or negative charge leaving (equal and opposite)

Imagine you are recording voltage from two different neurons as you inject a square pulse of depolarizing, but subthreshold current into both neurons. Neuron 1 reaches the new equilibrium potential in half the time it takes Neuron 2. Which neuron has more leak channels? Explain in 1 sentence why leak channels are important for the speed with which a neuron reaches a new equilibrium potential.

*Imagine you are recording voltage from two different neurons as you inject a square pulse of depolarizing, but subthreshold current into both neurons. Neuron 1 reaches the new equilibrium potential in half the time it takes Neuron 2. Which neuron has more leak channels? Explain in 1 sentence why leak channels are important for the speed with which a neuron reaches a new equilibrium potential.* Neuron 1. More leak channels means more conductance (smaller resistance), so quicker equilibration because the time constant is smaller.

Imagine you are running a current-clamp experiment on a neuron and you add sub-threshold amount of current into the neuron. Describe a voltage reading you would expect to see on the diagram below, assuming the resting Vm is -65 mV.

*Imagine you are running a current-clamp experiment on a neuron and you add sub-threshold amount of current into the neuron. Describe a voltage reading you would expect to see on the diagram below, assuming the resting Vm is -65 mV* Voltage should rise above -65mV and then return to -65mV with no action potential ***

KCa channel

*KCa Channel/Ca2+-gated K+ Channels* *Gating*: high threshold AND Ca2+ - need increase in voltage AND large intracellular Ca2+ concentration *Kinetics*: slow *Selectivity*: K+ *Inactivation*: -------- *Firing pattern- current clamp spike pattern* - After a train of spikes, the large increase in voltage would open up the voltage-gated Ca2+ channels - Influx of Ca2+ into neuron - Ca2+ then opens up KCa channels - Then after buildup of Ca2+, NO more spikes bc Ca2+ will open K+ channels and repolarization ADAPTATION -> cell fires less and less over time - sort of process is very important for sensory systems - if you are constantly exposed to a given sensory stimulus, over time your neurons will stop responding

leak channel

*Leak Channel* *Gating*: ------ *Kinetics*: ------- *Selectivity*: K+ *Inactivation*: -------- *Firing pattern in presence of VG-Na+*: - decrease/repolarize very slowly

the length constant

*Length Constant (𝛌)* length constant: how FAR does a voltage change spread - smaller voltage increase the further away the site is - simplified version of equation: if adding distance that is EQUAL to length constant, then magnitude of voltage CHANGE has dropped by 37% (magnitude of voltage CHANGE is what matters here, just like w time constant) (ex: recorded voltage 100 mV increase at first spot, and length constant was 1 mm away, then second spot 1mm away would have voltage increase of 63 mV) *TWO FACTORS THAT AFFECT MAGNITUDE OF LENGTH CONSTANT* - large length constant: voltage spreads a long distance - small length constant: voltage drops off very rapidly these factors are main determinant for thinking about action potentials propagation FOR long length constant: 1. Rm (membrane resistance): want BIG Rm -> MYELIN - myelin (no ion channels at all under myelin, so wherever you have myelin, Rm will be extremely large) - remove channels or reduce channel conductance/closed channels - increase resistance 2. Ra (internal resistance) - resistance down the length of an axon/dendrite: want SMALL Ra -> WIDE DIAMETER - wide diameter = small Ra - longitudinal resistance: controlled by diameter - larger diameter -> internal resistance is smaller (more channels/space/easier to flow) - as diameter gets bigger, EASIER for charge to flow down so internal resistance goes DOWN Speed is main determinant for axon potential propagation Looking at pic of neuron - AP starts near first electrode - No VG-channels in cell body or dendrites at axon hillock - At same time that AP is recorded at first electrode, second electrode will show a small rise in voltage, but if it's enough to get to threshold, then you'll still get a full AP - Site 3 is so far away that you don't measure anything at all BUT site 2 is close - So it causes small bump in voltage at location 3 which will get 3rd site to threshold so it can have an action potential Exact same scenario but assume length constant much longer: then even down the line, farther away at location 2 then you have the large spike in voltage -> much faster, doesn't have to regenerate - every time you have to regenerate, that takes timeee (number of regeneration times -> determined by length constant)

neuroscience levels of analysis

*Levels of Analysis* *Molecular neuroscience* - Genetics, protein synthesis *Cellular neuroscience* - How do molecules all work together to give neurons their special properties - What we focus on most in this course *Systems neuroscience* - Collection of cells - "visual system" vs "motor system" *Behavioral neuroscience* - How do neural systems work together to produce integrated behaviors? *Cognitive neuroscience* - Thought patterns

T-Type Ca2+ channel

*Low Threshold T-Type Ca2+ Channel* *Gating*: low threshold *Kinetics*: fast *Selectivity*: Ca2+ *Inactivation*: yes - Ca2+ important bc positively charged but Ca2+ can also act as ligand -> can bind other ligands and affect voltage bc positively charged - functions VERY similarly to transient K+ channel/IA/A-type but OPPOSITE bc it excites the cell - opens at a very low voltage that it is opened and inactivated at rest - generally, channel doesn't come into play - if you have hyperpolarized cell and dropped voltage, then T-type channel would close and then could be activated after this hyperpolarization - channel EXCITES the cell after period of inhibition (think new sensory experience) *Firing pattern- current clamp spike pattern*

Magnitude of voltage change in response to injection of current

*Magnitude of voltage change in response to injection of current* - Think Ohm's Law: V = IR Current clamp experiment - You're controlling the current - But you don't know what the resistance is, and you need this to figure out magnitude of voltage change - You're measuring voltage, so you can solve for resistance, so you can make predictions for changes in voltage magnitude w certain currents V = IR *Magnitude Decreases* - Lower membrane resistance/Higher conductance (more ion channels) *Magnitude Increases* - Higher resistance/Smaller conductance (fewer ion channels)

membrane time constant

*Membrane Time Constant* - how long does it take to GET to equilibrium voltage? equation you can use to determine time course of increase in voltage has time constant - reframed equation: when t EQUALS time constant, voltage has risen to 63% of its final equilibrium value time constant = resistance x capacitance - gives you a measure of these temporal dynamics - larger time constant -> more time to peak voltage *Membrane Resistance*- number and permeability of channels (very dynamic over time) - Small resistance R (lots of leak channels/high permeability, large neuron) -> SMALL time constant - Large resistance R (not many leak channels/low permeability, small neuron) -> LARGE time constant *Membrane Capacitance*- size and myelination of membrane - Small capacitance - myelinated (thicker, charge has larger distance to travel), small neuron -> SMALL time constant - Large capacitance - not myelinated (thinner, can store more charge) -> LARGE time constant *Size of cell* - Time constant doesn't change with size bc they cancel each other out -> changes magnitude of voltage/peak voltage, but time to get there will be the same *FASTEST* - myelinated, large number of leak channels/high permeability *SLOWEST* - unmyelinated, small number of leak channels/low permeability

neuroscience methodologies

*Methodologies* - Developmental Biology - Microscopy - Electrophysiology - Genetic Engineering - Molecular Engineering - Pharmacology Radiology - Animal Research - Psychophysiology - Computer Modelling etc... brain gets studied by a lot of people in different fields... lots of names for the same thing

Mid 1700s through Mid 1800s

*Mid 1700s through Mid 1800s* - There are advances in physics (electricity) - Ben Franklin 1706-1790 - Popularization of brain mapping *Neural Mapping by Ablation* approach: LOSS of function - Bell and Magendie 1810: Severed either dorsal(sensation lost) or ventral root (movement) or nerve(both) - Marie Flourens 1823: Lesioned parts of the brain, birds - Paul Broca 1861: Looked at patients w injuries to the brain - Frontal lobe damage -> could understand speech fine but couldn't produce it (Broca's area) *Neural Mapping by Stimulation* approach: GAIN of function - Fritsch and Hitzig 1870 - David Ferrier: Used electrical stimulation in motor cortex *Pseudoscience of phrenology* - Shape of brain by taking measurements from skull - Skull measurements then associated w personality traits *Advances in microscopy* - Emergence of cell bio - Cell Theory (all living things made of cell)-> Theodor Schwann 1839 - We take it for granted, but not popularized till 1800s - Nissl stain: doesn't stain neurons, doesn't help determine if neurons are separate from one another - Golgi stain: stains cell and all of its neurites, if you zoom in can't tell if theres a gap or not - Electron microscopy: beam of electrons, if they pass through tissue area would be light otherwise it would be dark -> much higher precision Two diff ideas about how neuron cells might communicate - 2 ideas able to coexist bc light microscope, EVEN if you use high magnitude, can't visualize a synapse (visual light spectrum), so only able to make other conclusions when other microscopes came about *Reticular Theory*: Camillo Golgi 1843-1936 (goes against cell theory, brain cells physically connected -> proven wrong -> Wallerian Degeneration) *Neuron Doctrine*: Santiago Ramón y Cajal 1852-1934 Argued that neurites of different neurons are not continuous with each other and *communicate by contact, NOT continuity* *Wallerian Degeneration (1850s)* - if you sever axon, distal portion of that axon that isn't connected to soma will degenerate over time - part of axon connected to soma will do fine - depending, that part of the axon can regrow - so, cells MUST be distinct - you would get a degeneration of whole network if cells were all connected *Lines of Evidence that Pointed to Chemical Synapse/Neuron Doctrine* 1. *adrenal gland* mimics electrical stimulation of sympathetic nervous system - similar to norepinephrine 2. application of ACh has same effect as stimulating motor neurons - chemicals doing it 3. Motor neuron can be excited or inhibited by electrically stimulating spinal cord axons - if a cell can be both excited or inhibited, it can't be as simple as one connected network - needs to be 2 diff types of cells that can communicate in diff ways but reacting to the same chemcial (i.e. same chemical makes some excited and others inhibited)

Molecular Basis of Action Potential

*Molecular Basis of Action Potential* Proteins in action during action potential: Assume open the whole time: *Na+/K+ pump* - remember Na+/K+ pump running all the time *Passive K+ channel* - remember these leak channels open all the time!!! ^^^ these channels establish and maintain RMP *Voltage-gated Na+ channel* - structure details *Voltage-gated K+ channel* - structure details *Refractory Period* *Absolute Refractory Period* - time in which Na+ channels are inactivated - only way to get out of inactivated state -> hyperpolarize so that they go into a closed state - until voltage drops enough, IMPOSSIBLE to get another action potential *Relative Refractory Period* - time where not impossible to get second AP but more difficult -> need more stimulus - 2 important factors: 1. VG-K+ channels open and hyperpolarizing cell -> need more excitation bc have to overcome inhibition 2. Probability that VG-Na+ will go from inactive to closed state, fewer VG-Na+ open - some Na+ channels inactivated, some closed and available to open - don't have the whole pool of Na+ channels ready to open *Threshold* - not an actual number, more about a probability - even at rest, there is a VERY tiny probability that some Na+ channels will open -> think Goldman (1 to 100, etc.) - even if that one VG-Na+ opens, it won't make it more likely that other channels will open - steep part of curve: voltages where you hit threshold - you hit a few VG-Na+ channels, raises voltage, then positive feedback loop that it's way more likely to open more, etc. etc. until o

Ohm's Law and Ionic Currents (I)

*Ohm's Law and Ionic Currents (I)* I = Gion x (Vm- Eion) *Ionic currents determined by*: 1. The ionic driving force (Vm - Eion) - How close is membrane potential to Eion - Current increases as the driving force increases 2. The ionic permeability (conductance G) - How many ion channels are open - Current increases as permeability increases Current is EQUAL and OPPOSITE (think Na+ and K+ -> the point at which currents are equal and opposite in physiological conditions is resting membrane potential) Physiological conditions: INa = small conductance(G) x large driving force (Vm- Eion) IK = large conductance (G) x small driving force (Vm- Eion)

Patch Clamp Method

*Patch Clamp Method* an extraordinarily sensitive voltage clamp method that permits the measurement of ionic currents flowing through individual ion channels - can use combo of voltage clamp 2 electrodes to understand physiology of a SINGLE CHANNEL what you're doing: - take glass pipette, aid of a microscope, position against cell body - provide a bit of suction and then pull pipette away - small piece of membrane will pull away and if you're lucky, you will have a single ion channel in the piece you pulled w glass pipette - can do a voltage clamp across this one patch of membrane so that you can understand what this CHANNEL is doing at this voltage patch-clamp recordings reveal that most channels flip between 2 conductance states that can be interpreted as open or closed - time that they remain open varies - single-channel conductance value stays same (unitary)

peripheral nervous system

*Peripheral Nervous System* (PNS) - rest of the nerves - Cranial nerves (nerves connecting to brain) - Spinal nerves (nerves connecting to spinal cord) glia: Schwann cells

The Patch-Clamp Method - Na+ Channels

*The Patch-Clamp Method - Na+ Channels* *Measurements* - voltage starts at -80, goes up to -20mV, and then back down - get 2 pieces of info: recording info and stimulating electrode info - stimulating electrode gives important info about how channel operates - at -80mV, stimulating electrode not doing anything, no ions crossing membrane so voltage stays at -80 - step voltage of recording electrode up to -20mV, and Na+ now flooding so you have to inject negative charge, so that's why voltage stays at -20mV - stops having to inject negative charge bc Na+ channel inactivates - can average traces together to get average trace for a Na+ channel - CONCLUSION (from stimulating electrode): 1. INWARD current (bc had to apply outward current) if voltage is high 2. inactivates very rapidly

The Patch-Clamp Method: K+ Channels

*The Voltage-Clamp Method: K+ Channels* - have to inject POSITIVE charge (so current must be outward, K+ flowing outward) to keep voltage constant - does not inactivate like a Na+ channel does, as long as voltage remains high, K+ channel remains open - then when you drop voltage, they SLOWLY close as that current lingers if you isolate both Na+ and K+ in patch clamp, can infer info about their channels and how this relates to molecular basis of action potential

The resting potential arises because of unequal K+ concentrations, and selective K+ permeability. What protein is responsible for creating the the unequal K+ concentrations?

*The resting potential arises because of unequal K+ concentrations, and selective K+ permeability. What protein is responsible for creating the the unequal K+ concentrations?* Na+/K+ pump

IA channel

*Transient outward K+ channel/IA Channel/A-type K+ Channel* *Gating*: low threshold *Kinetics*: fast *Selectivity*: K+ *Inactivation*: yes - A-type K+ channel opened at rest and then becomes inactivated - so they're not contributing much at rest bc they've already opened and gone into an inactivated state - it's been inactivated, so if you depolarize, then it doesn't matter IF YOU hyperpolarize neuron: - voltage decreases and these A-type channels are no longer inactivated - voltage low enough that they go into a closed state - when you do excite cell, then the A-type K+ channel will open at low threshold - A-type will only open if cell has been previously hyperpolarized - If neuron has these channels, hyperpolarization will make it so that you transiently can't trigger any APs bc K+ channels open and prevent spiking - after K+ channels have inactivated, THEN you can get spiking - hyperpolarization makes neuron even LESS excitable, amplifies effect of hyperpolarization *Firing pattern- current clamp spike pattern* - IF there has been hyperpolarization and IA channels are present, you TRANSIENTLY can't trigger any APs bc K+ is rushing out of the cell, but then once they inactivate it's back to normal

Voltage-Clamp method

*Voltage-Clamp Method* - "clamp" voltage/keep membrane potential stable and look at membrane conductance that occurs at diff membrane potnetials by measuring currents that flow across membrane (I = VC, so solve for C) - answers: WHAT IONS ARE FLOWING/what is charge doing??? - Hodgkin and Huxley showed that rising phase of action potential due to transient increase in gNa/influx of Na+ and that falling phase associated w rise in gK/efflux of K+ OBSERVER EFFECT - if you want to know what membrane/individual channel is doing at a specific voltage, seems straightforward that you could just take measurements at a voltage - assume you could set voltage to be -20mV - all Na+ channels would open and then you'd have a spike - won't stay at -20mV long enough for you to take measurements - voltage-clamp approach gets around this Requires 2 electrodes 1. Recording electrode - just records the voltage - without any intervention, it would record spike of AP 2. Stimulating electrode - where voltage clamp comes into play - any time ions cross the membrane, they would tend to make voltage change but stimulating electrode injects opposite current so that voltage does not change, injects equal and opposite amount of current - even as ion channels open and close and ions cross membrane, stimulating electrode constantly injecting equal and opposite current - keeps membrane at a constant voltage and allows you to see what membrane is doing

voltage-gated Na+ channel

*Voltage-Gated Na+ Channel* - depends both on voltage(close/open) and TIME (ball) *Sodium Channel Structure* - Single polypeptide (think protein!) molecule that has 4 domains - Each domain has 6 transmembrane alpha helices, numbered S1-S6 (string of aa is crossing in and out of cell membrane 6 diff times within each domain) - Four domains clump to form a pore bw them - Voltage sensitivity derives from S4 (positive transmembrane region/positively charged aa on S4 region), physically changes shape of protein bc S4 attracted to inside of cell when inside is negative, repelled when inside is positive - Na+ sensitivity derives from pore loop selectivity filter (diameter and R groups!) - Blocking particle mediates inactivation -> terminal domain of polypeptide more details from book: - Na+ ions stripped of most, but not all, of associated water molecules as they pass into channel - retained water serves as sort of molecular chaperone for ion, necessary for ion to pass selectivity filter - ion-water complex then used to select Na+ and exclude K+ how S4 region works: - sodium channel gated by change in voltage - *** voltage sensor resides in S4 of each domain*** - positively charged aa, so the segment can be forced to move by changing membrane potential - Depolarization twists S4, and conformational change in molecule causes gate to open *Functional Properties of the VG Na+ Channel* - changing from -80mV to -65mV -> very little effect on VG-Na+ channels: remain closed bc depolarization hasn't reached threshold - changing membrane potential from -65 mV to -40 mV: channels pop open (S4 segment) VG-Na+ channels: 1. open with little delay 2. stay open for about 1 msec and then close (inactivate) 3. cannot be opened again by depolarization until membrane potential returns to negative value near threshold - action potential doesn't occur from a single Na+ channel -> it's the effect of many of them (probability thing) *CYCLE OF VG-Na+ CHANNELS*: Resting membrane potential (-65 mV): CLOSED - Pore closed, channel not inactivated VOLTAGE CHANGE- DEPOLARIZATION Depolarization past threshold (-55 mV): OPEN - Pore opened, channel not inactivated TIME CHANGE 1 ms later!!! - Pore closed, ball swings to inactivate channel: INACTIVATED VOLTAGE CHANGE- REPOLARIZATION Repolarization past -65mV: CLOSED - Pore closed now TIME CHANGE 2-5 ms later!!! Resting membrane potential again - Pore closed, channel not inactivated *Effect of Toxins on Sodium Channel* - *Tetrodotoxin (TTX)*: clogs Na+-permeable pore, blocks all sodium-dependent action potentials (puffer fish) - Saxitoxin: toxin in clams, mussels, - Toxins disrupt channel function by binding to diff sites on protein, helped researchers deduce the 3D structure of Na+ channel

voltage-gated K+ channels

*Voltage-gated K+ channels*(delayed rectifier channels!!!) - K+ set off by threshold of -55mV BUT delay for them to open - K+ conductance serves to rectify/reset membrane potential -> delayed rectifier *Structure* - 4 polypeptides clustered together to make a single protein(quarternary) vs 1 polypeptide of VG-Na+ channel - Voltage-gated/sensitive but voltage sensitivity is really slow in VG-K+ channels, they have slow gating compared to very fast gating in VG-Na+ channels (similar conformational change to open) - DOESN'T INACTIVATE (no blocking particle) ion selectivity: pore diameter, R groups (and also water molecules interacting)

What additional feature does the Goldman equation take into account that allows it to calculate membrane potential from multiple equilibrium potentials?

*What additional feature does the Goldman equation take into account that allows it to calculate membrane potential from multiple equilibrium potentials?* - relative membrane permeabilities

What can the half-width of an action potential tell you about the density of delayed rectifier Kv channels on a neuron?

*What can the half-width of an action potential tell you about the density of delayed rectifier Kv channels on a neuron?* Greater half-width means smaller density of the delayed rectifier channels

What structural feature allows ion channels to be voltage-gated? Why when NaV channels are opened do they not continue to drive the membrane potential toward ENa?

*What structural feature allows ion channels to be voltage-gated? Why when NaV channels are opened do they not continue to drive the membrane potential toward ENa?* - Positively charged transmembrane domains/residues (like S4 regions in each domain of VG-Na+ channel) allow ion channels to be voltage-gated - Inactivation gates/inactivation blocking particle that stops positive feedback loop

Which two features dictate the selectivity of a channel to a particular ion?

*Which two features dictate the selectivity of a channel to a particular ion?* 1. pore diameter 2. R groups in pore/charges from proteins in pore loop

Why doesn't action potential back-propagate?

*Why doesn't action potential back-propagate?* 1. VG Na+ inactivation - Doesn't matter how large voltage is, you can't open an inactivated channel 2. hyperpolarization of K+ channels bc they're open -> this also spreads over distance - increase in voltage has to combat the decrease in voltage

Why is selective permeability during an action potential necessary to allow the membrane potential to jump above 0mV?

*Why is selective permeability during an action potential necessary to allow the membrane potential to jump above 0mV?* - Without selective permeability, the action potential would top out at 0 mV (completely depolarized) - gNa increases before gK, so the Vm jumps up past 0mV towards ENa = 62mV -> selective permeability allows it to do that

brain vs smartphone

*Workflow* - Identify Function - Identify Components - Assess their connections - Determine their roles *Approaches* - Watch people use it - Use it yourself - Take it apart - Watch it be assembled - Break single components - Categorize malfunctions - Measure signals - Compare different models - Look at simpler examples

You shine yellow light on a neuron with Halorhodopsin channels (Cl- channels activated by yellow light). The neuron has a resting membrane potential of Vm = -65 mV and the equilibrium potential for chloride is ECl = -75 mV. Will this lead to a depolarization, hyperpolarization, or no change in the membrane potential of the neuron?

*You shine yellow light on a neuron with Halorhodopsin channels (Cl- channels activated by yellow light). The neuron has a resting membrane potential of Vm = -65 mV and the equilibrium potential for chloride is ECl = -75 mV. Will this lead to a depolarization, hyperpolarization, or no change in the membrane potential of the neuron?* This will lead to a hyperpolarization in the membrane potential because there is a higher concentration of Cl- on the outside of the cell compared to the inside, and the resting membrane potential is -65mV. When you shine the yellow light, it will cause the Halorhodopsin channels to open and Cl- will enter the cell, making the membrane potential more negative.

axon

*axon*: threadlike extension of a neuron that carries nerve impulses away from the cell body *axon hillock* - part of cell body that connects to axon *axon terminal* - any of button-like endings through which axons make synaptic contacts w other nerve cells *myelin* - most axons myelinated (oligodendrocytes or Schwann cells)

basic principles of electric signaling

*basic principles of electric signaling* *CURRENT* (I): movement of charge - ions are moving and ions are charge, so if ions are moving then there is current *VOLTAGE* (V) - separation of charge, electrical/membrane potential, axon potential *CONDUCTANCE* (G) - ease with which charge may move, many channels open -> high conductance *RESISTANCE* (R) - inverse of conductance (1/G), how difficult it is for ions/charge to move - very few channels open -> high resistance *CAPACITANCE* (C) - ability to store charge, amount of charge that accumulates in membrane

basics of electrical signaling in neurons

*basics of electrical signaling in neurons* *CHANNEL*- passive diffusion - pore through membrane - can have ion selectivity - can be gated - if channel is open, passage is PASSIVE (diffusion!!!) *CARRIER PROTEIN* - passive diffusion and nonpassive active transport - 2 types: *transporter*- diffusion - uniporter: one ion - symporter: 2 ions in one direction - antiporter: 2 ions in opposite directions *pump*- active transport against gradient - ATPase

current clamp

*current clamp* setup for both voltage and current clamp: - 2 electrodes in whole cell OR associated w patch of membrane: recording electrode and stimulating electrode -voltage clamp: voltage constant, current not (stimulating electrode has real data about current) current clamp: data look almost identical - stimulating electrode: constant amount of current - then you measure amounts of voltage as a result - current clamp: spike patterns!!!

electrical current

*electrical current* (I) - measured in amperes (amps) - current always described in terms of net positive charge, so it's outward when positive charge leaves/positive in direction of positive-charge movement *WHAT DETERMINES HOW MUCH CURRENT WILL FLOW?? ** -> Ohm's Law 1. electrical potential/voltage(V): force exerted on a charged particle - measure in volts - more current will flow the larger the potential is 2. electrical conductance: relative ability of an electrical charge to migrate from one point to another(g) - measured in siemens (S) - conductance depends n number of ions/electrons available to carry electrical charge and the ease w which these charged particles can travel through space opposite is *electrical resistance* (R)- relative inability of an electrical charge to migrate - measured in ohms - R = 1/g I = gV - current is product of conductance and potential difference - if conductance is 0, no current will flow even when potential difference is very large - likewise, if voltage/potential is 0, no current will flow even if conductance is very large - for current to flow, requires that: 1. membrane possesses channels permeable to that ion (to provide conductance) 2. there is electrical potential difference across the membrane (V)

ion pumps

*ion pumps* - ATP is energy currency of cells -> bc ion pumps use ATP *K+ more concentrated on inside, Na+ and Ca2+ more concentrated on outside* *Important Pumps* *sodium-potassium pump*: enzyme that breaks down ATP in presence of internal Na+ - chemical energy released by this reaction drives pump, which exchanges internal Na+ for external K+ (3K+ in, 2 Na+ out) - responsible for MAINTAINING ion concentrations (NOT setting them/membrane potential -> that's leak channels) *calcium pump*: enzyme that actively transports Ca2+

ionic basis of the resting membrane potential

*ionic basis of resting membrane potential* - resting potential of a typical neuron is about -65 mV equilibrium: chemical and electrical forces are EQUAL and OPPOSITE, net movement of ion ceases *ionic equilibrium potential* (Eion): electrical potential difference that exactly balances an ionic electrochemical gradient to establish an electrical potential, you need: 1. ionic concentration gradient 2. selective ionic permeability *4 main points about membrane potential* 1. large changes in membrane potential are caused by minuscule changes in ionic concentrations - action potentials don't cause concentration gradients to change!!! 2. the net difference in electrical charge occurs at the inside and outside surfaces of the membrane - phospholipid bilayer is so thin -> possible for ions on one side to interact electrostatically w ions on the other side - charge is localized at inner face of the membarne - in this way, membrane stores electrical charge -> *capacitance* 3. ions are driven across the membrane at a rate proportional to the difference bw the membrane potential and the equilibrium potential - ionic driving force (did we reach equilibrium yet? if we're super far, it's faster than if we're close) 4. if the concentration difference across the membrane is known fro an ion, the equilibrium potnetial can be calculated for that ion (Nernst equation!) EK+ = -80mV ENa+ = 62 mV ECa2+ = 123 mV ECl- = -65 mV

membrane properties determine temporal and spatial dynamics

*membrane properties determine temporal and spatial dynamics* *post-synaptic current at synapse* - measure a large change in voltage *post-synaptic current at point A, closer to synapse* - measure slightly smaller change in voltage *post-synaptic current at point B, further away from synapse* - might not have any measurable change at all - graph of current, assume that current is more or less instantaneous - as receptors open, you immediately get influx of positive charge - voltage changes a lot slower than the instantaneous current - takes time for voltage to increase and decay so 1. temporal dynamics of a voltage change are SPREAD OUT in time as opposed to current that caused that voltage 2. the further and further away you are, the smaller magnitude voltage change

modeling the neuron as an electrical circuit

*modeling the neuron as an electrical circuit* electrochemical gradient - battery - both can be used to drive the movement of ions ion channels - resistor - regulates how easy it is for ions to leave - channels closed: high resistance, low conductance - channels open: low resistance, high conductance cell membrane - capacitor - stores and separates charges - charges accumulate on surface of thin membrane, just like electrical charge accumulating on plate of capacitor think about flow of water through pipes like flow of electrons through a circuit - pump is the battery here: makes diff in pressure, water flows from area of high pressure to area of low pressure like electrochemical gradient - movement of water itself -> current - resistance: makes water more difficult to flow - inflatable membrane: capacitor, higher the pressure the more it'll stretch the membrane so this region stores water up so imagine you inject additional water (more than the given pressure already in circuit) - we have a difference in pressure - water takes path of least resistance, so it goes to the stretchy membrane - water stretches membrane out but no pressure increase bc water flowing into the capacitor - once you've stretched membrane as far as it can be stretched, then any additional water is going to directly increase pressure on that side of circuit - so in neuron, first thing it does is charge up membrane THEN voltage changes 1. increasing size of capacitor -> takes longer 2. bigger resistance -> harder for water to travel

myelin and saltatory conduction

*myelin and saltatory conduction* Action potential conduction wo myelin: walking in small steps, heel-to-toe action potential w myelin: skipping (saltatory conduction)

prototypical neuron

*prototypical neuron* *Soma*: cell body - contains all of the organelles *Axon* - axon diferent from soma: 1. no rough ER into axon, and few, if any, free ribosomes in mature axons (not rly doing protein production) 2. protein composition of axon membrane is fundamentally diff than soma - *Axon Hillock*: tapers away from soma to form initial segment of axon - *Collateral*: branches of axon, can travel long distances - axon collateral that returns to communicate w same cell that gave rise to axon or w dendrites of neighboring cells -> recurrent collaterals AXON TERMINAL - *Terminal Bouton*: same thing as *axon terminal* -> swollen disk where the axon comes in contact w other neurons, release neurotransmitter on to them - *Bouton en Passasnt*: axons form synapses at swollen regions along their length and then continue on to terminate elsewhere - diff from axon: 1. no microtubules in terminal 2. terminal contains synaptic vesicles 3. inside surface of membrane that faces synapse has dense covering of proteins 4. axon terminal cytoplasm has lots of mitochondria (high energy demand -> membrane proteins) *DENDRITE* - *Dendritic Tree*: collectively all of the dendrites - *Spine*: where receptors are densely clustered, location of individual synapses *Synapse*: point of contact bw presynaptic axon terminal and postsynaptic dendrite - Vesicles: small bubbles of membrane in the terminal - Transmitter - Receptors -> there can be receptors anywhere along dendrite or axon - Microtubules: relatively large, run longitudinally down neurites, smaller strands made of tubulin *Axoplasmic transport* - axon and axon terminal does not have ribosomes -> proteins have to be synthesized in soma and then shipped down axon - axoplasmic transport -> flow of materials from soma to axon terminal - kinesin does the work, walks like legs along microtubules - kinesin does movement from soma to terminal along microtubules - *anterograde transport*: transport of materials from soma to terminal *Retrograde transport*: movement of material up the axon from the terminal to soma - dyenin: protein that does work of transport in direction of terminal to soma

recording voltage with the micro-electrode-> current clamp

*recording voltage with the micro-electrode-> current clamp* inject constant amount of current, and then you get different spike patterns - current clamp used to deliver subthreshold excitation -> they're important to study bc when you remove the action potential, it makes it easier to understand temporal dynamics of voltage change - same current clamp but looks different bc subthreshold excitations vs spikes patterns of lecture 5

review of electrochemical forces at play during action potential

*review of electrochemical forces at play during action potential* movement of ions guided by: *Ohm's Law* Iion = conductance (Gion) x ionic driving force (Vm - Eion) - that Vm is determined by: Goldman's Equation

temporal dynamics of changing Vm

*temporal dynamics of changing Vm* - takes time for voltage to reach equilibrium value - things that affect this time course are RESISTANCE and CAPACITANCE

the prototypical cell

*the prototypical cell* *Rough ER*: site of protein synthesis for organelle proteins, membrane proteins, and export proteins *Mitochondria*: ATP production *Nucleus*: DNA *Smooth ER*: gives proteins their 3D structure *Golgi apparatus*: post-translational chemical processing of proteins - very important for neurons -> need efficient transport of proteins (think neurotransmitters, etc.) *Cytoskeleton*: important for scaffolding and transport *transcription* (occurs in NUCLEUS) DNA ----- (transcription w/RNA polymerase) ----> RNA ---- (splicing) -----> mRNA - DNA has a *promoter region*: site of DNA before gene that dictates where RNA polymerase begins to read segment of DNA and make RNA transcript - transcription factor -> very important because all cells have same DNA but produce diff proteins - presence of certain TFs help determine whether certain gene is read - TF interacts w promoter region, so genes won't be transcribed wo appropriate TF Transcription proceeds and you get specific transcript - splicing: introns spliced out, exons stay in (expressed) *terminator*: stop sequence *Location of translation* FREE RIBOSOME - Protein destination: protein floating in cytosol - So translated on free ribosome floating in the cytosol - polyribosomes: several free ribosomes may appear to be attached by a thread BOUND RIBOSOME - Protein: protein destined for organelle, membrane, or for export - So translated on bound ribosome on the rough ER

two paths that positive charge can take

*two paths that positive charge can take* - if axon is narrow and there are many open membrane pores, most of current will flow out across membrane - if axon is wide and there are few open membrane pores, most of current will flow down inside the axon - the farther the current goes down the axon, the farther ahead of the action potential the membrane will be depolarized, and the faster the action potential will propagate (ahhhh, how length relates to speed) - bigger diameter = faster conduction velocity! THINK SQUID

what two functions do proteins in the neuronal membrane perform to establish and maintain the resting membrane potential?

*what two functions do proteins in the neuronal membrane perform to establish and maintain the resting membrane potential?* 1. proteins in membrane provide selectivity -> leak channels, mainly 2. Na+/K+ pump to maintain concentration gradients (3 K+ in, 2 Na+ out) - not primarily responsible for setting membrane potential

potassium channels

- K+ channels have 4 subunits arranged like staves of a barrel to form a pore - subunits each have pore loop which contributes to selectivity filter -? channel permeable mostly to K+ *Importance of Regulating External Potassium Concentration* - membrane potential extremely sensitive to changes in concentration of extracellular K+ - increasing extracellular K+ DEPOLARIZES neurons - blood-brain barrier, astrocytes -> potassium spatial buffering - some excitable cells, like muscle cells, not protected from increases in K+

Before modern techniques like recording the action potential, scientists understood that the nervous system was important for movement and sensory perception. Briefly describe one neural function discovered by the structure/function correlation approach

- Nerves connecting the eye to the brain lead scientists to the conclusion that the brain is important for sensory perception - Aristotle/Hippocrates - white matter/gray matter

cell body/soma/perikaryon

- central region of neuron that contains the nucleus

channel proteins

- hydrophobic portion inside membrane and hydrophilic/polar ends exposed to watery environments on either side *ion channels* - functional channel requires 4 to 6 familiar proteins to make a pore bw them - this subunit composition varies from one type of channel to next, what determines diff properties of channel PROPERTIES OF CHANNEL 1. *ion selectivity* -> diameter of pore and nature of R groups lining it 2. *gating* -> channels w this property can be opened/closed by changes in local microenvironment (voltage, chemical gating, etc.)

neuron

- one of two types of brain cells - nerve cell - equal numbers of neurons and glia (85 million of each) *FUNCTIONS* sense changes in environment, communicate these changes to other neurons, and command the body's responses to these sensations *Classifying Neurons* *Number of Neurites* *Unipolar*- one neurite branching off the soma - usually sensory neurons (pseudounipolar) *Bipolar*- two neurites *Multipolar*- 3 or more neurites - most neurons in brain are multipolar *Shape* *Stellate*- star shaped - can be spiny or aspinous - cerebral cortex: local *Pyramidal*- pyramid shaped - always spiny - cerebral cortex: projection *TYPES OF NEURONS* *motor neuron* - neuron that goes from brain to muscle - bring signals from CNS to PNS - in the PNS - ventral root *sensory neuron* - neuron that goes from skin to brain - bring signals from PNS to CNS to be integrated - in the PNS - dorsal root *interneuron* - majority of neurons - form connections w other neurons - found only in the CNS - involved in processing information both in reflex circuits and more complex circuits - two types: 1. local: connects 2 neurons within same structure - ex: one part of spinal cord to another 2. projection: connects 2 neurons of diff structures - ex: spinal cord to brain, axon going to distant site, projection

gene targeting w Cre-Lox Recombination

1. *knockout in cholinergic neurons* 2. *transgene of interest expressed exclusively in cholinergic neurons* see images

if neuron A is presynaptic to neuron B, in which direction is information flowing? A to B or B to A?

A to B

A-type K+ channels have an _______________ and _______________ effect on the firing of action potentials.

A-type K+ channels have an *inhibitory* and *immediate* effect on the firing of action potentials.

dendrite

Branchlike parts of a neuron that are specialized to receive information *dendritic spine* - small membranous protrusion from neuron's dendrite that receives input from single axon at synapse - tiny projections off of dendrite where synapses are occurring - can have thousands of spines off of a single dendrite *neurotransmitter receptors* - class of receptors that specifically binds neurotransmitters - found on dendrites

Compare resting potential to the rising phase of the action potential, explain how each of the following variables changes: Sodium Conductance (GNa), Sodium Current (INa), Sodium Equilibrium Potential (ENa).

Comparing resting potential to the rising phase of the action potential, explain how each of the following variables changes: Sodium Conductance (GNa), Sodium Current (INa), Sodium Equilibrium Potential (ENa). *Sodium conductance- GNa rises* - At resting potential, sodium conductance (GNa) is very low because there are not nearly as many Na+ channels open and NaV channels are closed due to the low membrane potential, making sodium current low - When a neuron reaches threshold, then NaV channels open, which greatly increases sodium conductance(GNa), thus increasing sodium current (INa) by Ohm's Law as Na+ rushes into the cell.(INa) *Sodium current- INa rises* - see above explanation Sodium Equilibrium Potential- ENa stays the same - Sodium equilibrium potential (ENa) remains the same (around +66 mV) from the resting potential through the rising phase of the action potential, as the small number of ions that move across the membrane greatly change voltage/membrane potential but have no effect on concentrations of ions inside and outside the cell. However, the rising phase brings the membrane potential closer to this sodium equilibrium potential (reaches about +40 mV) compared to the resting potential (about -70mV)

If the slope of a current vs. voltage graph (current on the y-axis, voltage on the x-axis) has a high slope, that means the neuron has _________ [high resistance, low resistance].

If the slope of a current vs. voltage graph (current on the y-axis, voltage on the x-axis) has a high slope, that means the neuron has *low resistance*.

If a neuron's membrane had a low resistance, that would lead to a ___________ [short, long] time constant

If a neuron's membrane had a low resistance, that would lead to a *short* time constant.

In current-clamp experiments, we hold the ___________ fixed and monitor the change in ________________ . In voltage-clamp experiments, we hold the _______________ fixed and monitor the change in ______________.

In current-clamp experiments, we hold the *current* fixed and monitor the change in *voltage*. In voltage-clamp experiments, we hold the *voltage* fixed and monitor the change in *current*.

Which combination of myelin and leak channels makes the membrane potential rise fastest?

Membrane potential rises fastest with a myelinated neuron with a lot of leak channels/high permeabilities

If a specific part of the brain is damaged and a particular behavior is altered, is this demonstrating necessity or sufficiency

NECESSITY Gain of function -> sufficiency

The __________________ axon terminal is separated from the ________________ dendrite by the _________________ cleft

The *presynaptic* axon terminal is separated from the *postsynaptic* dendrite by the *synaptic* cleft

Imagine you are recording the potential difference of a neuron by inserting a microelectrode. You measure Vm = -70mV. Given that that EK = -80mV, if the conductance to potassium ions increased, would the neuron depolarize, hyperpolarize, or remain at the same potential difference?

The neuron would hyperpolarize bc ionic current of K+ would increase and K+ would efflux

Phases of the Action Potential

You can have many different ionic currents going on, but the current that is DOMINATING will move Vm towards Eion of that ion, resulting voltage will be calculated using Goldman's (concentrations not changing, just permeabilities when we calculated in class) *** REMEMBER*** - even if you're talking about 100 action potentials -> number of ions that cross the membrane to change voltage is orders of numbers too small than would be necessary to change concentration - doesn't matter how many action potentials occurred, concentrations DO NOT CHANGE. Resting membrane potential - 2 membrane proteins: passive K+ leak channels and Na+/K+ pump establish resting potential Rise and fall of action potential - Combo of all K+ leak channels, Na+/K+ pump, VG-Na+ channels, VG-K+ channels/delayed rectifier channels RISING PHASE: Na+ current dominating - VG-Na+ channels opened by depolarization, not inactivated - Conductance of K+ still low bc delayed rectifier not open yet PEAK: +40 mV - VG-Na+ inactivation (1msec) kicks in - Delayed rectifier opening -> conductance of K+ increases by a lot FALLING PHASE: K+ current dominating - K+ efflux due to delayed rectifier - VG-Na+ opened but inactivated UNDERSHOOT: K+ current still dominating - Delayed rectifier still open -> hyperpolarization - VG-Na+ close, 2-5 msec later (absolute refractory) no longer inactivated and ball moves out of the way - Even as you get down to relatively hyperpolarized potentials, it takes a while for VG-K+/delayed rectifier channels to close -> why you have the undershoot, bc increased conductance of K+ than at RMP HYPERPOLARIZATION back to RMP ONCE VG-K+ channels/delayed rectifier channels close: 1. Primarily Na+ leak channels, Na+ comes back into cell down electrochemical gradient and increases (high driving force) 2. K+ retention inside bc inside of cell super negative

knock-in mice

approach: GAIN OF FUNCTION - native gene replaced w modified transgene - specific targeting

transgenic mice

approach: GAIN OF FUNCTION - genes have been introduced and overexpressed - random integration

knockout mice

approach: LOSS OF FUNCTION - one gene has been deleted - study progression of a disease w/goal of correcting it

neurite

axons and dendrites *axon* - usually a single axon from a single cell body - any branches are usually right angles - like "wires" that carry output of neurons - very long *dendrite* - rarely longer than 2 mm - many dendrites extend from cell body and generally taper to a fine point - act like "antennae" to previous axons to receive input

histology

histology: microscopic study of structure of tissues *Nissl stain*: class of basic dyes would stain nuclei of all cells as well as clumps of material surrounding the nuclei of neurons 1. distinguishes bw neurons and glia 2. enables histologists to study arrangement/*cytoarchitecture* of neurons in diff parts of the brain cons: doesn't show that much *Golgi stain*: soak brain tissue in silver chromate solution, so small percentatge of neurons become darkly colored in entirety - revealed that neuronal cell body is only small fraction of total neuronal structure *Reticular theory*: Golgi - Golgi: neurites of different cells are fused together to form continuous reticulum/network - brain is exception to cell theory (states that individual cell is elementary functional unit of all animal tissues) *Neuron doctrine*: Cajal - Argued that neurites of different neurons are not continuous with each other and *communicate by contact, NOT continuity*

glial cell(glia)

insulate, support, and nourish neighboring neurons *TYPES* *astrocytes* - most numerous type of glial cell/cell in brain overall! - maintain homeostatic ion concentration -> VERY important for action potentials/membrane potential changed if ion concentration messed up - for diff systems, plays role in clearing neurotransmitter from synaptic cleft - variety of functions: regulate blood flow in brain, maintain fluid around neurons, regulate communication bw neurons at synapse - not myelinated *microglia* - macrophages of immune system: clean up dead brain cells/debris *MYELINATING CELLS* *oligodendrocytes*: CNS, produces myelin (sheath around axons) which greatly increases speed of action potentials *Schwann cells*: PNS, also produces myelin *Ependymal cells*: line ventricles of brain and central canal of spinal cord, have cilia that beat to promote circulation of cerebrospinal fluid inside ventricles and spinal canal

proteins

monomer: amino acid polymer: polypeptide (aa held together by peptide bonds primary structure: aa chain linked together by peptide bonds secondary structure: alpha helix/beta sheet tertiary structure: interactions among R groups that change 3D structure of protein quaternary structure: how diff polypeptide chains can bond together to form larger structure

synaptic cleft

narrow gap that separates the presynaptic neuron from the postsynaptic cell

presynaptic neuron

neuron that sends the signal across synaptic cleft

synapse

the junction between the axon tip of the sending neuron and the dendrite or cell body of the receiving neuron