BIO 365R Notes

Hakan Sahin Page 1 of 42

BIO 365RHakan Sahin

Table of ContentsUNIT ONE.................................................................................................................................................2

06 September 2007................................................................................................................................211 September 2007................................................................................................................................513 September 2007................................................................................................................................718 September 2007................................................................................................................................920 September 2007..............................................................................................................................1125 September 2007..............................................................................................................................13

UNIT TWO..............................................................................................................................................1502 October 2007..................................................................................................................................1504 October 2007..................................................................................................................................1708 October 2007..................................................................................................................................1811 October 2007..................................................................................................................................2016 October 2007..................................................................................................................................2118 October 2007..................................................................................................................................2323 October 2007..................................................................................................................................2425 October 2007..................................................................................................................................25

UNIT 3.....................................................................................................................................................2708 November 2007..............................................................................................................................2713 November 2007..............................................................................................................................3015 November 2007..............................................................................................................................3127 November 2007..............................................................................................................................3229 November 2007..............................................................................................................................3504 December 2007...............................................................................................................................3706 December 2007...............................................................................................................................39


UNIT ONE

06 September 2007Neurons have information that flows one way; arrives at receptors in dendrites. Different receptors forthe same signal can then respond in different ways. The nature of the start of the axon hillock is thepoint at which you've made a decision based on all received information whether or not to cause anaction potential.

The result of stimulus on a neuron is to change its permeability to ions. In general, sodium will enterand if enough sodium enters the axon hillock decides to start an action potential. If you were comparingcharge inside/outside cell, inside of cell usually sits at -60mv. If a stimulus occurs, such as sodiumcoming in, will depolarize the cell. Positive feedback occurs and more Na is let in until the inside of thecell actually becomes more positive than its surroundings. It's all relative; not because an enormous #of ions came in but because so few came in that drastically changed the polarity. There only has to bemore + than – inside.

Membranes sitting at rest in general are somewhere -60 to -80mv. Bringing in these few more Na+ willdepolarizes the membrane (causes it to go closer to zero). The sodium is being allowed to flow downits concentration gradient until it reaches a threshold potential.

Threshold is the membrane potential at which voltage-gated Na channels in axon hillock open.Threshhold = vgate cell chan open. As they open, sodium floods in and it goes back down again. Allthe way down, dips below -60mv and comes back up a little. K+ leaving the neuron resets themembrane potential at this peak.

In order for this to be true, there must be more Na outside than inside, and a lot more K+ inside thanoutside. This could be a result of Na-K pump working in opposite directions. Usually occurs in 2:2ratio. Membrane is permeable to potassium most of the time. Potassium leak channels are alwayspermeable to K, meaning that all neurons are permanently permeable to K+. Takes a drug or specialevent to close these leak channels.

Sodium has two reasons to go in to cell: Electrical gradient and [gradient]. After a few have gone in, itsgoing to be relatively positive inside the cell and K+ will have two reasons to leave: electrical gradientand [gradient] as well.

Above 0mv, Na+ still enters because [gradient] outweighs electrical gradient.

If membrane is permeable to K+, how does it ever reach more K+ inside than outside? Prior to sodiumentering, let's just have a pump that pumps Na+ out of the cell. In order to have a negative restingpotential, cell is impermeable to sodium. All else being equal (concentrations), K+ will run in becauseof electrical gradient. At some point, enough potassium will flow in to make it a little less negative. Themembrane potential of a resting neuron is dependent upon the flow of potassium across that membrane.The flow of K+ across that membrane is dependent upon the relative values of the electrical gradientand [K+]gradient. There are other ions in the body, but for the most part only potassium sets that.


At Huntsville, we execute prisoners. We knock them out with phenobarbital. They are killed with anonlethal, nonregulated substance. They increase the amount of [potassium] default in the cell so thatneurons fire perpetually.

Why do ions flow? They are Na, K, Cl, and Ca. And Mg too. Something to memorize: Cl, K+, and Na+usually at dendrites; at synaptic end it's almost always calcium. Channels in the membranes imbue cellswith these possibilities. Channels have variable permeabilities; signal dictates whether it can open andthe matter of gradients dictates whether or not an ion will flow. For our purposes the NaK pump ridsthe cell of sodium. That's the #1 function. The fact that K+ is brought into cell is trivial. At rest, just asmuch K+ is leaving as is coming in (flow of K+ due to pump and membrane potential coming in, flowdue to [gradient] moving out).

Voltage-gates channels: Na+, Ca2+, K+, Cl. Ligand-gated channels: Neurotransmitter receptor; Glutamate-gated Na+, Ca2+-activated K+, cyclicnucleotide-gated channel.

Relative Ionic concentratonsIn Out

K+ 140 5Na+ 12 145Cl- 15 120Ca++ .0001 2

Ca++ has a huge gradient. If you were to open up most cells to chloride, very little would flow.Calcium inside ER of the cell is topologically outside the cell (vesicled!).

One of the contributions making cells negative is that membrane proteins often have + charged portionsoutside the cell and – charged portions inside. Electrical gradients drive both K+ and Na+ into cell.Walmart neurons often rest at -70mV.

Resting potential esablished by K+*Z IS THE CHARGE. THIS WILL BE ON THE TEST. Nernst equation calculates equilibriumpotential for an ion based on relative concentrations inside and outside cell. E = (RT/zF)ln([K+]out/[K+]in)

Emphasize one more time: If K+ is the only ion that can flow at rest, its the ONLY thing that isresponsible for the resting potential; that membrane's resting potential will be the equilibrium potentialfor potassium. If an ion cannot flow through a membrane, there is no equilibrium potential for that ion.

Establishing equilibriumSeparation of charges creates an electrical gradient across the membrane, the membrane potential Vm.The equilibrium potential for a specific ion is the Vm at which there is no net flow of ions across themembrane (assuming they can cross the membrane). When you calculate resting potential you have tobring in permeability. Not a good equation for calculating resting potential of an ion.


Goldman-Hodgkin-Katz Equation

In establishing the resting potential of a membrane, brings conductance (permeability). Designed tocalculate resting potential of a neuron. Takes into consideration relative concentrations ANDpermeability to ions. How do you change permeability of a membrane to an ion? You can add morechannels or use neurotransmitters to open more channels.

Through this course, we'll describe the function of this neurons based on whether or not their channelsare affected by disease, toxin, or a drug. Some neuropathic diseases: Liddel's syndrome (Na+), deafnessand epilepsy (K+), cystic fibrosis (Cl-). Some drugs: Tetrodotoxin (TTX) is the stripped hydroxylgroup that sticks inside a Na+ channel and blocks it. A picomolar amount could poison >100people.

Permeability: Increasing permeability is the fact that the neurotransmitter has bound and has oepenedthe ion channel; doesn't guarantee conductance. Every ion upon increase in permeability will have aflow/conductance that tries to drive a cell membrane toward its own equilibrium potential.


11 September 2007Understanding the basis of a membrane potential. In order for ions to flow, they have to be controlledby a gradient (concentration or electrical). What we'll be tested on: If this happens to this ion, this willhappen to the membrane.

We;re only interested in Na, K, Ca, and Cl. Interested only in communication between neurons. Caenters, signal transduction occurs through neurotransmitters. If there's enough of a stimulus at the somaof the postsynaptic neuron, it will trigger the start of an action potential.

Moon has a neuron that's sitting there. Some stimulus will cause Na+ to flow into the cell, so themembrane potential becomes a little less negative, closer to zero. That event is making the cell not sopolarized, depolarizing the cell! That event is the equivalent to some stimulus, in particular this eventhappening at the soma/dendrites isn't enough to cause something to happen to the axon. The amount ofsodium that entered the cell is proportional to the stimulus.

A graded potential change != an action potential. The sum of enough graded potential changes(temporally and magnitudinally) causes an action potential.

The change in the membrane potential of the cell is proportional to the stimulus. The receptors in theaxon hillock are note the same as the soma receptors. The soma receptors are ligand-gated toneurotransmitters, the axon-hillock channels are voltage-gated. The voltage-gate-opening-potential ofthese channels is the treshhold potential for the neuron.

As sodium enters downstream, K+ leaves upstream to “recock” the gun. Why do ions flow the waythey do, what forces act on them, how do we describe with an equation, what exactly happens at thesynaptic end, how do we know this happens?

Membranes are going to develop gradients due to pumps, electrical potential differences, andconcentrations. For instance, potassium wants to leave the cell due to concentration gradient but enterdue to electrical potential.

The potential at which the electrical and concentration gradients cancel each other, or are balancedresulting in no net flow. The relative [K+] inside and out will pretty much remain the same. There willbe only a small amount of flow with a dramatic change on the electrical membrane potential. Therelationship between the [ ] and the membrane potential is what we're interested in.

If at -86mV K+ doesn't flow; if the membrane is at some other potential (-60, -100) potassium willflow. The Nernst equation calculates the equilibrium potential which is important to know at whatconcentrations K+ will flow.

Ek = (58/z) log ([K+out]/[K+in]) ; z=1.

The membrane potential sets the relative concentrations. Ions flow because membrane potential differsfrom equilibrium potential. For all intents and purposes, Na+ always flows in. We're interested at therate in which it flows. To change the rate in which it flows, control channels.


A stimulus is going to affect how fast sodium can flow across that membrane.

However, the cell at -70mV is sitting a lot closer to -86mV than it is to the +55mV of sodium. K+, inorder to have a greater effect, K+ has a greater conductance. At rest, the cell always has a greatpermeability to K+ than Na.

The resting potential is established by the difference in relative conductances. The GHK equation takesthis into account.

Once you reach treshhold, you WILL have an action potential. It will always have the same magnitude.

Two kinds of graded stimuli: Constructive interference of stimuli waves summing to reach threshold(spatial summation). Alternatively, temporal summation occurs when three stimuli occur close enoughtogether. If the summations depolarize the membrane sufficiently it will open the voltage-gated Na+channels in the axon hillock, creating a cascade that is an action potential. The equilibrium potential ofsodium is +55. It will never reach +55 because potassiumis flowing out.

Involved are gradients, counterflow of ions, and channels opening. Before treshold, only stimulus-gatedNa+ channels are open. Then voltage-gated Na+ channels open. At the peak of the ap, voltage-gatedNa+ channels close. Suddenly, K+ is now following both is [ ] and electrical gradients and exiting.There are two gates to a voltage-gated sodium ion channel: a pinchy-voltage-gate channel and a ball-and-chain. Both are open ascending, ball-and-chain closed descending.

Past the action potential, both gates are closed. During the undershoot (hyperpolarization), the ball-and-chain opens again.


13 September 2007MS attacks the schwann cells of the axons found in the brain and the long motor neurons. Shows up asa loss of motor control. Much of what we cover today has to do with why schwann cells are critical insending a signal down an axon. The signal that goes down an axon is an action potential, a transientdramatic change in membrane potential.

Typically, a cell itself does not have an action potential. How is it possible that there is no backflow ofpotential through the axon?

Walking through an action potential:During the rising phases under the graded potentials, you have an Na channel that's open. Most

typically the Na channels are not voltage-gated ion channels. Just something that received a sitmulusand that channel increases permeability of sodium at that point. The back-and-forth is because you getfurther and further from Poktassiums E, we're also getting closer to Na's E.

Prior to major depolarization taking us up, a voltage-gated sodium channel with 2 gates(activation gate pinches, inactivation gate-ballandchain). At subtrshhold levels, the sactivation gate isclosed. The point at which activation gate opens is the treshold. As you rise up, the interior (activationgate) opens. The difference in conductance is staggeringly different, 1000x greater than non-voltage-gated channels.

At the peak, the inactivation gate for Na closes. Somewhere along the the peaking, a voltage-gated K+ channel opens right about the same time that the ap starts. The closing of the inactivation gateis the key to one-way propagation down the axon. Dropping below threshold closes the voltage-gatedNa+ channels, and undershooting opens the inactivation gates again.

To narrow the action potential, allow more sodium channels. Have potassium channels openfaster. Not all K+ channels are alike.

Some guys took a demand amplifier, capable of creating more current if it's needed. You have anelectrode stuck inside an axon to insert a current to change membrane potential. You have a detector tomeasure the potential difference. As potassium flows out to try to reach E. This is a way of measuringcurrent that's flowing across the membrane. Measures current by knowing how much it has to add tocompensate for current leaving.

The bucket question:You have a bucket is leaking water onto the ground. How much is it leaking? The leaking water is acurrent, to know how much is leaving the bucket you need to know how much you have to add to keepit at that line.

V = IR, membrane resistance doesn't change. They treated a neuron with TTX to block sodium flowing.

Na channels open quickly, K+ channels open slowly. Na channels close more slowly than they open.

Signal has to go from A to B in an axon with high fidelity. Myelinated axons are faster because thesignal enters at one spot and moves with saltatory conduction. There is a tougher issue withUnmyelinated axons: The goal is to get the signal from one spot to another. Ions are attracted to one-another, like ion-sex. The fact that the ions are stuck on each side of the membrane unable to move is


called capacitance. It means that as sodiums enter, instead of traveling down the axon it takes a turntowards the negatives on the side of the membrane (radial flow of ions). Additionally, negative ionsmove towards the +s inside and the +s outside leave. Capacitance currents look like swirls; they dont go in the direction we want them to go. Thats why weinsulate the axons with schwann cells.

Leak channels, ligand-gated channels, voltage-gated channels, other stimuli. Lots of reasons forchannels to open; channels have kinetics.

Delayed rectifier: Doesn't all open at the same time (start has some curve). These are the channels thatstay open.

Repolarization-opens channels.


18 September 2007We have an axon with ball-and-chain-gated Na chanels that spreads in both directions; it comes in andit nudges all the internal sodiums over, if the positive charges inside have a reason to shift any wayother than down the membrane to trigger the next voltage-gated channel. That shift gets smaller andsmaller, so we may not make it down the membrane to trigger the next guy. There are 2 reasons wewouldn't make it here: The sodium coming in is coming into a high density of sodium, any highcollection of nexagtive charges inside the axon would reduce its axial current. Capacitance is ions stuckin place by mutual attraction to oppositely charged ions across a membrane.

An axial current, heading in the right direction is part of the signal, nudging the next ions down. If itgoes in any other direction, that is a capacitance current (I resulting from presence of capacitance). Theactions of a neuron can be described using RC circuit equations V = IR. If Na heads toward the wall itsthe equivalent of a countercurrent to the axial flow. The fatter you get the nerve, the more ions youhave that will push through capacitance. You solve it by increasing the capacitance of an axon.

Terrestrial animals need fast small axons; We want some signals to transmit slowly. Myelinating anaxon breaks capacitance by insulating axon, preventing impact on outside ions by charges on the insideand vice versa.

What are the biophysics of an axon? Basically our fast axons are as fast as they can get; we'veoptimized #nodes as gaps between them. V=IR, voltage across membrane is dependent on current andresistance (how well channels open as well as whether or not you have a conductance across themembrane). Schwann cells increase membrane resistance radially but decrease axial resistance).

Soma have action potentials too. There is back propagation from axon hillock to the soma. Howevertraveling axially, by the time sodium reaches the next channel the previous one has not hyperpolarized

The period in which the H gate is closed, no Na will flow (refractory period).

Synapses: The neuro-muscular junctions

single axon synapses onto a single fiber; they are controlled one fiber at a time. We start at the end of asignal:

The neuromuscular junction● releases acetylcholine into synaspe● acetyl cho is manufactures in axon terminal● receptors for Ach on post-synaptic membrane's● Ach binds in a concentration-dependent manner● Ach is cleared by enzyme action (acythlcholinesterase)● choline is taken up visa transporter into the terminal● more Ach is manufactured● loaded into vesicle via Ach transporter

Each item varies from synapse to synapse. Bernard Katz: God of neuroscience. Said two things:


Quantal nature of neurotransmitter release. Why discrete quantities? How are they packaged. Ca++ dependent release of neurotransmitters. Why is second ion required? What is the link betweenCa++ and vesicles.

Looked at EPP (post-synaptic membrane potential) increasing and then action potential in neuron.Muscles have very similar properties to neurons. EPP saw that even in no stimulation, there were stillsome firing in absense of a signal. Mini-end-plate-potentials are all the same size. Neurotransmittersare packaged in same density and same volume anywhere in the cell.

A mini-MEPP is the response of a muscle to 1 vesicles worth of neurotransmitters.

As opposed to pancreatic cells, leaving insulin released slowly and quickly.

Synapsin: vesicle-loading proteinsSNAPs – priming/docking, lining upSNAREs – cause fusion to wall, time to release

Synaptotagmin -comes off vesicle, is a vSNARE, Synaptobrevin – also a vSNARESyntaxin – is a terminal tSNARE, in the terminalSNAP25 – is also a tSNARE, just these four can be reponsible for causing vesicle fusion.

Calcium comes and opens up a VGCC, the tiniest amount of calcium enter a cell will cause vesicularrelease. The calcium binds in some way to synaptotagmin.

Clostridium: Botulinum toxin and tetanus. Botulinum kills synaptotagmin.

Tetanus break synaptobrevins, botox is paralyzing kills synaptotagmin Tetanus causes you to havemaximum exertion.

SNAPs line up vesicles, synaptotagmin responds to tagmin causes release.


20 September 2007Synapse: Electrical/chemical, excitatory/inhibitory. ACh and glutamate.

The vast majority of interactions between neurons occur when a neurotransmitter is released from pre-SM and post-SM. Axonal properties: how fast, how reliably it fires. Synaptic properties: What'sreleased, what's being listened to.

Small molecule neurotransmittersAcetylcholine (+/-) Glutamate (+/-)

Are the most prevalent in body. Ach is the major neuromuscular junction transmitter. Half the synapsesin the brain use glutamate. The other half use GABA and Glycine.

GABA is inhibitory (-)Glycine (-)

DopamineNorephinephrine/epinephrineSerotoninHistamineEndocannabinoids

Neuropeptides are peptides produced by neurons to communicate to other neurons. Almost not worthtalking about.

One source of Na comes into cell: Constant Na current while recycling neurotransmitters.Acetylcholinesterase cleaves Ach, on the PostSM you have receptors.

SMNT can be grouped in a few ways. In NMJs ach is excitatory. Glutamate is excitatory almostalways. Aspartate

Bloodbrain barrier regulates amount of everything going into the brain. Glutamate is profoundly basic.Ubiquitous and excitatory, glutamine is its precursor. Loaded in vesicles by VGLUTs and cleared bytransporters. Once you release glutamate post-sm will fire until glial cells transport them back. Glialcells modulate the cells that they're wrapped around. Glial cells support a lot of the functions ofneurons.

ligand-gated channels where NTs bind to one or more units of these channels. If you are a receptor forglutamate with 5 subunits and 1 binding site.

Onotropic Glutamate Receptors

NMDA binds to some glutamate receptors and opens them. Ampa binds to some receptors as well asKainate. This is one of the ways in which the brain regulatory function occurs on the post-SM (control


of the receptors).

Glycine is an allosteric excitatory binding. Glutmate receptors can pass many different ions. Whenglutamate binds, a gate opens which allows Na and Ca and K ions, but will never let Mg through.NMDA receptors receive glutamate signal and nothing happens. These channels have a Mg plug inthem.

However, if AMPA receptors elsewhere polarize enough to polarize the entire membrane, the Mg blockleaves. If you coincidentally have glutamate coming at the same time, calcium enters the cell and bindto proteins to change the nature of the cell. The binding of glutamate increases permeability to Na, Caand K. Mg enters because its attracted to – cell environment. Zinc could also function like Mg.

You run ATP and pump protons into the vesicle, its getting acetic. Protons flow down their gradient andglutamate is pumped against its gradient into the vesicle. VGLUT is an H+/glutamate pump. Glutamateis loaded into vesicles regulated by amount of H+ is in there.

A single neurotransmiter binding to a receptor, you can increase the complexity of the receptor.Metabotropic receptors can affect more than 1 kind of G protein, each of which affects a differentcellular pathway.

An example:NT binds, G-protein binds adenylate cyclase, it produces cyclic AMP, it affects protein kinase whichphosporalates K+ channels which shuts them down.

Agonist vs Antagonist:Agonist: Biochemistry, a substance that initates a physiological response when combined with areceptor. Antagonist: Bch, a substance that hinders the effect of agonists

Inhibitory synapses: GABA and Glycine. It can take many excitatory stimuli to cause an actionpotential in a PostSM. Quite often though it only takes a few inhibitory to shut it down. Inhibitory NTsaffect chlorine, leaving Cl- channels open. Clamps the cell at the Equilibrium potential for chlorine,compensating for positive charges opening/leaving the cell by going in our out. This is why you needfewer inhibitory synapses. 10% question: Both GABA and Glycine are effectively interchangable.

Glutamate is only one enzyme away from GABA. Theme for remainder of course: Both aremanufactured/sequestered from the Krebs cycle, packaged by VIATTs (inh ) monitored by glial cellstransported by glutamine transporters.

The important one: As you open this site, chloride leaves the cell. Chloride acts as a demand aplifier.This is the target for a lot fo steorids and the primary target for barbiturates.


25 September 2007Different properties of synapses give neuron communications their nuances. With ACh , it's clearedfrom the synapse through constant enzymatic action. You release it in discrete amounts as far as we cantell.

If an action potential exists in a motor neuron, it will depolarize the cell. If a neuron spritzesneurotransmitter, it will only respond if the post-SM is listening.

There's a predominant excitatory transmitter in the brain. Nicotinic agonist for Ach acting on anionotropic receptor; if it spritzed onto the heart it would be a muscle metabotropic receptor.

Glutamate is not broken down, its reshuffled back into the glial cells to clear it from a synapse. Glialcells convert it to glutamine before pouring it back out. When AMPA and Kainate receive glutamatethey become perm to Na and K at the same time. NMDAs are the same with the magesium block toleave.

Glycine, normally an inhibitory transmitter, acts allosterically in an excitatory fashion. In fact, thesynapses with a lot of NMDA receptors are bathed in glycine. NMDA specific synapses tend to besilent, they dont regularly tramsit signals. Only if there is a coincidence of signals entering (polarizingat one end, glutamate at the other). NMDA channels are the target site of PCP. Once calcium enters, itinvokes lots of metabotropic responses. There are many synapses that have only NMDA receptors, noKainate or AMPA receptors. Should the cell depolarize enough for calcium to enter, the synapse willrecruit AMPA receptors to the synapse.

Long-term potentiation: This is one of the basis we believe for learning and memory. Oneglutamatergic synapse varies greatly from another before of the sweep of receptors on the synapse.

Ionotropic receptors are “channels”, whereas there are glutamate receptors that dont allow ions to passthat work through a G-protein process.

GABA, Glycine: Glutamate is the precursor for GABA (one decarboxylation). Failure to inhibit is oftena way of exciting. Both glycine and gaba increase perm post-SM to chloride. Ionotropic:GABAa,GABAc. Metabotropic: GABAb. These receptors have such a powerful influence on post-SM;exciting an inhibitory receptor can have a total blockade on that receptor. A lot of barbiturates, steroids,picrotoxin (excitatory).

Allosteric binding site for benzodiazepines, allosteric associations allow yo not only to act as an agonistbut allow you to accentuate access the channel. There's a difference between us having a molecule thatworks as te same site doing the same thing and working at a different site if GABA is present.

There are nasty benzodiazzepines that are like valium and rohypnol.

Biogenic Amines:Dopamine: Coordination of movements, reward-motivation reinforcement, and anxiety. When youactivate these circuits, you relieve yourself of anxiety. Low levels of dopamine = high anxiety. Drugs


that work on these sites are so powerful in their addiction. Excitatory/modulatory, primarily in corpusstriatum, tyrosine, loaded in vesicles by VMATs, bind to g-protein coupled receptors, cleared bytransporters, mono-amine oxidases. Dopamine works solely through metabotropic receptors. Clearedvery specifically by transporters. In addition to that, it's destroyed by monoamine oxidases. Expressedin very specific regions of the brain, andhave 2-3 means to clear from the brain. V powerful with long-term effects. When MaOs work too hard, they have a tendency to clear dopamine from synapses tooquickly. Nardil and Marplan are 2 of many anti-anxiety drugs that are MAO inhibitors, they prevent thebreakdown of dopamine.

Parkinsons: The substantia nigra produces the largest amount of dopamine in the brain. We noticed 1thing: With the onset of parkinsons, One of the late set-ons of Parkinsons is anxiety. When the anxietygets really bad, one of two things could happen. The dopamine levels drop precibitably withParkinson's. Michael J Fox is currently taking L-DOPA (precursor to dopamine). Cant give peopledopamine to get across the blood-brain barrier.

Treatments for physical problems that we try to address have trouble with their specificity.

Norepinephrine/epinephrine: Excitatory/modulatory, primarily in brain stem, tyrosine, loaded invesicles by VMATs, bind to G-protein coupled receptors, cleared by transporters (Na+), MAOs. If youwere trying to handle a dominergic issue by taking MAOI, you prevent breakdown of adrenaline.Drugs that attack MAOs can often lead to worse reactions.

Know what neurotransmitters are up to norephinephrine.Almost all disease state we're aware of are not a problem with neurons themselves but receptors orability to make neurotransmitters. Side note: Peptide neurotransmitters are sometimes way outside of our realm of understanding.Enephalins are part of the most powerful painkillers in the body.

Cocaine is such a good dopamine-releasing drug it would be a good treatment for Parkinson's. SSRI'sare similar to cocain, LSD (ergot) is is an amazing SSRI.


UNIT TWO

02 October 2007We're going to talk about sensory reception. Your nervous system is made up of a lot o fneurons, yousense things! The action of moving is a product of the motor systems in the body. Motor systems arepretty basic with the exception of control of the heart. The CNS is the processing center for allincoming information.

Sensory-motor information: Can travel this in three possible loops:The first one is a reflex loop, comes up sensory neuron, goes into spinal cord, and then synapses to aninterneuron(s) then down to motor neurons (eferrent).

That same sensation goes up the spine and informs you of what's going on. This is the cerebellar loop.This is something that manipulates your behavior. The hangy-down part in the back of the brain.

The last pathway is the slowest of the bunch, the lemniscal pathway. Almost everybody knows there isa right and left side of the brain. They are connected by the corpus collosum. Females have a biggercorpus collosum. Men have a more densely packed corpus collosum.

The right brain controls and recieves information from the lefthand side of the body. One of the themesfor the next exam is to keep this in mind for remainder of course. At what point does information crossto the other side? What point does it decussate and synapse onto the other side of the brain. The sides ofthe brain handle different chores.

The left side handles speech perception and formation. Music appreciation and concept is on the rightside. Dolphins sleep one half of their brain at a time. You really can use one half at a time. Ducks, whenthey are in a row

In radical cases of epilepsy, there is a procedure known as a lobectomy. The prefrontal cortex is anincredible part of the brain we're just learning about. We want to take a tour of the brain and get into thesensory systems.

CNS consists of cerebrum, cerebellum, brainstem, and spinal cord. Your sensors are truly just dendritesand they come together and form an axon but processing occurs at a ganglia, knots of cell bodies oneither side of the spinal cord. A good deal of of what you process does not make it to the cerebrum. Thecerebrum is incapable of doing what your cerebellum can do. Cerebellum is running most of the time.

We have an entire system registering with the cerebellum at all times Then everything goes to themotor components: The Visceral Motor System and Somatic Motor system. These act on the effectors(smooth muscles, cardiac muscles, glands, and skeletal muscles).

Brain divided in 3 groups: Hindbrain, Midbrain, and Forebrain

Hindbrain is everything above spinal cord: Medula Oblungata (autonomic function, breating anddigestion), Pons and Cerebellum (motor learning, motor control and cognitive functions). The midbrai


is all by itself, handles the most innate motor control in the body (control of eye moments). Forebrain(Prosencephalon) consists of the Thalamus and Hypothalamus (Thalamus: Gateway to cortex, majorconnection point of all infoprmation coming from the body. Hypothalamus regulates endocrine control)and the cerebral hemispheres (Perception, thoughts, cognition, and language).

Pons is the thing that is attached to the cerebellum. The diencephalon is the medschool version of thethalamus. Basal ganglia (Huntington's/Parkinsons), the source of almost all of our dopaminergicpathways. The midbrain is whre most norepinephrine/epinephrine in the brain.

When you talk about brain lobes, you're limiting to surface of brain. Frontal lobe, Parietal Lobe,Temporal Lobe, and occipital Lobe. Your vision starts at temporal lobe, processes es through thalamus,goes to occipital lobe.

Sensory channels:reflex,cerebellar, lemniscal,--dorsal column medial

- proprioception: The ability to sense joint angles, flex on muscles, orientation in space--anterolateral systems

-pain/temperature: A stretchreceptor is a sodium channel that is gated because of distorted membrane. Different sensationsare determined by how the nerves are wrapped up. Pacinian corpuscles are wrapped up in layers oflipids they detect pressure. Ruffini's corpuscles detect the stretch. Somatic-sensory motor system.


04 October 2007What we taled about before were somato-sensory channels, reflex cerebellar and lemniscal. This issense of touch, pressure, temperature, body awareness and three-dimensional orientation. The reflexstep goes through the spinal cord and triggers a motor response immediately.

Moon wants us to know that the chili-peppers near the spine are basal ganglia and all the informationcomin gin is very discrete, if you were damage the spinal cord anywhere the damage done is localizedto a portion of the body.

Reflexes try to keep things the same. Reflexes compensate for things. When you pull on the muscle, theafferent neurons sens

If you are holding onto something and you're trying to lift it, a sensor checks your golgi tendon. Thebrain talks to the interneurons and spinal cord to control all this activity. An awful lotof what we needto do to have conscious activity is to inhibit reflexes. As a side note, PCP has this same effect (horsetranquilizer). Inhibits inhibitory circuits.

Mechanosensory touch has nothing to do with reflexes. Two-point discrimination threshhold in mm isused to figure out how sensitive nerves are.

Dermatome: Skin-mapping onto the spine.

Nociception: Pain and temperature information from the upper body, follow the anterolateral system,come in on the anterolateral side entering through the dorsal horn and decussates immediately andtravels up the other side. Nociception is detecting the orientation of the body, form of reflex (don't wantto lose that).

A fibers are almost always excitatory, C fibers are unmyelinated are slow and delayed. Temperaturereceptors in the body are capcaicin receptors. The next step is the cerebellar system. We should knowthat reflex happens without us thinking about it.

Vision versus visual perceptionOne of the most heavily studied systems is the visual system. Brain interprets by contrast.


08 October 2007The retina works like a film, recieves the light (comes through series of cell bodies hitting rods andcones). Rods are long, sort of symmetrical. Cones outer membrane is invaginated whereas cones havediscs inside. There are bipolar cells (directly receiving input from rods/cones). Neither rods norreceptors nor cells have action potentials, they are all graded potential. Next in line are retinal ganglialcells. Sets of horizontal cells mediate interactions between rods and cones. Amacrine cells regulateinteraction between bipolar cells and ganglial cells. Most basic: Receptor -> Biopolar -> RetinalGanglial cell.

Your body is largely concerned in making distinction based on contrasts.

The circuit will consistently try to decide the difference in the amount of light between neighboringrods and cones.

In rods whenn in the dark, sodium flows through a channel and the rods depolarize. In the dark, whennothing's happening, these cells are firing and when you see light these guys shut off. Non-selectivecation channels (ca and Na) go quiet when they see light. In the rod there are pancake-stacked discs.Stuff happens in these discs that communicate with the ion channels in outer membrane of rod.Photoreceptors are in the discs of a rod.

There are 2 proponents to the receptor, the receptor is rhodopsin. The protein is called opsin with acofactor of Retinal. Retinol has 2 forms: cis (kinked) and trans (straight). Upon exposure to light,retinal conformation changes from cis to trans, this changes the rhodopsin that will undergo asubcellular process. Active rhodopsin effects transducin which is a g-protein. Transducin activates PDEwhich breaks down cyclic GMP out in the cytoplasm which then binds to ligand-gated cation channels.Upon exposure to light, this rod cell is going to hyperpolarize.

In the dark, you release glutamate onto bipolar cells and in light you do not. You hyperpolarize in thelight and release less glutamate. Arrestin: A strange protein that does 3 things simultaneously:Reassembles g-protein complex trabsdycub (turns off PDE which breaks down cGMP to GMP), pushesout trans-retinal from receptor by interracting directly with the receptor and removing trans-retinal,

In the back of your eye where retinol is, in the center of the back of the eye you have the optic disc. Thecones are centered right around the center of the back of your eye (the fovea). You have incredibledensity of rods 20degrees off-center either direction from the fovea.

Retinal ganglial cells report cell-per-cell to the back of the brain. There is a stop-over at the thalamuson the way, this includes vision. Then it goes to the back of your head. A single receptor reports to apair of ganglial cells; for every single point of light this happens.

The receptive field is a chunk of your visual field, ganglial cells only respond as light enters and exits areceptive field.

In episodes of greater contrast, the neuron will fire faster. This is what defines the two areas of areceptive field: the center and the surround. If there is high contrast here, the neuron will fire faster.


Ganglial cells have a behavior that they're interested in. A receptive field has a center and asurround.What is the circuit that causes one ganglial cell to be on-center and the other to be off-center?

Highest contrast exists when one of these ganglia is firing fast and the other is not at all. This centercone is hyperpolarized, it is not releasing glutamate. One bipolar cell is inhibited upon exposure toglutamate and the other is excitatory in response to glutamate.

It gets worse. The horizontal cells accentuate this process. If the surround is dark, then these two conesare releasing glutamate to the horizontal cells. Horizontal cells have dendrites in both directions, andwill trigger faster hyperpolarization and cause center cells to go quiet faster by allowing information togo from the surround to the center.


11 October 2007In the retina, you process regions of contrast. What the retina reports, cell by cell, is the part thast I amlooking at is either all one color (on) or all dark (off) or its reporting contrast.

Anything other than optimal contrast condition will fire at an intermediate rate. The neurons, as theyreport to the back are not reporting anything in between.

This is different from what books will tell you. Horizontal cells talk between rod cells, however theyalso synapse onto bipolar cells (they are being documented). A neighboring horizontal cell inhibits.

All retinal circuitry, we're interested in contrasts (extremes). All information goes through thethalamus, brain porn on tuesday.

The lateral geniculate nucleus LGN The connection of all the ganglial cells axons is the optic nerve.They chross over in the optic chiasm. In reality, what's going to the right side of the brain is everythingin the left visual field. And vice versa. The optic chiasm is a site of frequent traumas, the pretectumcontrols blinking and the superior colliculus has to do with tracking in the eyes. The ability to follow isnot a conscious thing.

Ipsalateral information is stuff that stays on the same side, contra-lateral is everything that crosses overto the other side. As the LGN feeds info into the midbrain.

The LGN has six layers. You have a left and a right LGN, the info coming in from your eye gets split(gets replicated here). Each layer is mapped just like the retinas, two magnacellular and 4 parvacellularlayer, and one conacellular (the interlayers). Parvocellular layers receive information fromretinalgangliar cells that are receiving information from cones.

You have six layers, but in the lefthand LGN, we have stained layer six, layer four, and layer one. 6, 4,and 1 receive left-fieldeverything from the

5,3,2 ipsolateral 6,4,1 contralateral.

This information in the striate cortex is then processed in groups; you have cells here that receiveinformation from the retina that say “do i see not just 1 dotted light but a row, not only a row, but at oneangle, and that is moving in one direction.”


16 October 2007Your visual field is divided up into a left zone and a right zone, and in some parts the eyeballs overlap.Each of those left and right visual fields is divided into a series of receptor field, represented by what apair of ganglial cells responds to. The circuit of the retina set it up so that you fire the most when youhave a dot in the center of a surround.

Light is really edge detection, major chunk of information into the retina is the outlines of what we'reseeing. The enforce this we have lateral inhibition: Your eyes are litterally lying to you to accentuate anedge. If an off-center cell patch. Horizontal cells allow inhibition of neighboring cells to amplifycontrast.

Ganglial parvocellular cells report color, magnocellular report edges. Red-ON-Green-Off surround.Seeing ren-on and green off is no different from an empty field. The other type is Blue/Yellow.

The rule is the Left LGN is going to receive at 1,4,and 6 information from the right eye. The Left LGNalways recieves information from the right LGN. Koniocellular cells exist between parvo and magnocells, they are a way of comparing contrast. The K-layers interpret depth of field and because of that,motion.

One myth: The LGN is not a one-way street. Some 80% of input to the brain comes back from theprimary visual cortex.

At the striate cortex is retinotopic, meaning it is mapped according to the retina The info coming fromLGN goes to only one layer of visual cortex. The neocortex in the brain is extremely complex and allthe neurons from LGN synapse at layer 4C. It basically ends as you get out of V1. Alternate layers ofthe LGN are comparing two different eyes. What your left-and-right eye see at the same point in spaceis represented side-by-side. In that cortex, you have many cells but Moon only cares about three.

Simple cells, complex cells, and hypercomplex cells.

Simple cell circuits largely interpret orientation. They say that a whole row of a ganglial cells are firingat a single rotation. From each of the cells, the cimple cell circuits fire only if a whole horizontal,vertical, or diagonal.

Complex cell circuits talks to a series of simple cells and watches the order in which they fire.

They are also called end-stop cells. They add up with spacial summation.

Hypercomplex cells They determine the size of the bar and the limits of the bar. If it's this big I'll talk,or I won't talk.

Leaving end-stopped cells up to us.

Information came out of the eye and we had 2 ganglial cells reporting information for the black-and-white field.


You have slabs corresponding with the cortex with a hypercolumb in each slap. They're mre concernedabout grey, pink, or tye-dye. The “blobs” as they're called will fill in with most dominant color. Thewhole thing is like one big Seurat painting.


18 October 2007The parvocellular and magnocellular pathways get devided into 2 general pathways: Where (parietal)and What (temporal).

Two face-recognizing sections: Familiar faces and ought-to-know faces.

We have somehting called a prefrontal cortex. Hit right away by alcohol.

Phineas Gage was working on a railroad and a rod went through his cheek and came out of his skull.We rely on these events to gell us something. The rod went right through his prefrontal cortex; after thisincident, gives decision-making and consequence-action relations. One of the most profoundlyperceptive functions of the brain: anticipation. After this incident, he became an ass who was difficultto work with. This is one of the last parts of the brain to develop, develops later in males.

How you distinguish frequencies, origin of sound, how we adapt to changes in sounds.

Broca's: A lesion between frontal lobe and centers that allow him to hear what he's saying himself. Wernicke's: Lost aspect of ability to form speech and tie it in.

Cochlea is a spiral structure filled with fluid. The meat an potatos: The organ of corti is what attrs.Tectorial membrane covers organ of corti; basilar membrane is pink and smooth with a lot of structureand inner hair cells with afferent axons leading up to the brain. Three rows of outer hair cells and 1inner hair cell row. Outer hair cells have efferent axons. In the same fashion of the eye, feedbackoccurs.

The spiral ganglia accumulates the information from the inner hair cells. The inner hair cells have aresting potential of roughly -45mV; up in the endolymph there is a high K+ (80mV potential). Thescala tympani is also very lo win potassium. On one side of the hair cells you have extremely highconcentration of potassium.


23 October 2007At one end from the oval window it gets very narrow but thicket. The further from the source listens tolower and lower frequency. We have tonotopically arranged cells in the basillar membrane. We have aroughly 5 hertz discrimination range. There's a concept called phase-locking where we discriminatelow frequency sounds better than high-frequency.

The neurons can actaully fire somewhere up to 2-3000 hertz. For our purposes we go with 3,000 hertzfigure. Bats however can phase-lock 40-45,000 hertz and respond up to 60,000.

Because of the nature of this membrane, for most of the membrane we hear very very low tones up tothe range of th enormal voices. Phaselocking is the ability of the hair cell to fire as rapidly as themembrane is flickering up and down. We put that down at 3000 hertz for our class.

Outer sterocilia are arranged in rigid v-structures which are pushing the membrane up and down. Outerstereocillia amplify sound at lower intensities. In high-intensity sounds they do the opposite. As we hitthe maximum range, they will have destructive interference.

Somatic electromotility!

The cochlear nucleus detects the fact that information has come in. One of the first site it hits is theNucleus of Lateral lemniscus. Your ability to turn the head and hunt us down is dependent on the abilityto hear it. Cerebellum turns head in direction of sound.

We never regulate our eyes moving towards something. What we hear gives clues to our eyes on howto move.

We sensitize and desensitize sterocilia by

Stuff comes in through cochlear nucleus to medula, wanders up NLL to inferior colliculus which allowsus to orient things.

Superior Olive – Location Detection. Circuitry in the brain that deals with frequency determination. Ifthe input is unequal (3,000 khz>), then one olive significant inhibits the other more.

3 things: Discriminate/amplify frequency.Localize the sound.Pull this together to determine quality of sound. The thalamus does this.

Below 3KHz, we're phase-locked. The rate at which they fire and distance from left-to-right ear andmedial superior olive

Pinna changes the quality of the noise coming from above, behind, beneath you.

Vestibular system is responsible for sensing what direction your body is in. The utricle, saccule,ganglion, Somewhere in the canals is an ampulae that pushe


25 October 2007Information come sin from cochlear nerve and arrives at cochlear nuclei. You innervate superior olivein the pons and the NLL and th einferior colliculus simultaneously. Inferior colliculus does the left/rightand vertical fine-tuning, generating a space-map where sound comes form

At the cochlea and spiral ganglia and nucleus you have discriminated frequencies. The superior olive isconcerned with frequencies and so is the Inf Col but the NLL is not. NLL recieves stuff and just wantsto know where we heard it first.

This NLL recieves contralateral monaural input. The IC is receiving information from both sides. Themedial geniculate decides whether or not to pass that information to various parts of the brains.

There are 3 ampulla, one for each semicircular canal. Two sacky things: Saccule and Utricle. Roughlyhe same sensors and they tell you that you're moving lateral. They are dependent upon gravity, whereasangular momentum (dependent on mass). The gravitational force affecting the two pads has to do withour sense of proper posture.

Vestibular system talks to a lot o fstuff: It come sup through the cranial nerve and part goes to thecerebellum. That is largely responsible for our sense of balance and postural control. Then there is athalamic nucleus (VP nucleus) that has to do with we'll talk about it later. Our limb motor neurons arebeing regulated by the vestibular system also, it talks to our legs our arms and our head to keepeveryone oriented right. Also extraocular motorneurons (eye control). We have motor control ofinhibitory and excitatory strimuly

These systems are constantly firing and you have to numb them to eliminate the input.

A systems preview: MotorWe're not very good at motion control. Cerebellum is the thing that coordinates body attitude andposture as we go through voluntary motions are controlled by cerebellar motions. The cerebellum usespositive control and the basal ganglia use negative control.

Ascending pathways:VisualAuditoryVestibularSomato-sensory information

Proprioception MechanosensoryNociception (Pain/temp)

Cerebellum is under no control from the rest of the brain. Recieves information from everything but thebrain does not tell cerebellum what to do. You train it to take care of the mundane tasks of life. It haspeduncles: three of them. Superior, Middle, Peduncle. Peduncle is a big fat nerve. You have thetrigeminal nerve coming in.

Dorsal Nucleus of Clark is often called the DNC, recieves information coming up and goes to one part.


Receives sensory information from body and motor responses from the brain and says “yeah it makessense to do that.”

You already know there's vestibular information coming in through vestibular nuclei and inferior olive.Two big waves of info comin ginto cerebellum: motor intent an body action. Devided into two terms:Proprioception Pathways and Magnocellular Pathways.

Afferents come in from both frontal/parietal coreces, go through th epons to the middle cerebellarpeduncle. Proprioceptie info comes in from the inferior olive, spinal cord, and nucleus. Cerebellarcortex takes in all that info and makes a decision and sends it to the deep cereballar nuclei through thesuperior peduncle which goes to the VL complex and sends info back to the brain saying “you may takethat action and go ahead and stick your lleg out while you're doing it.”

This information come sout of Deep cerebellar nuclei, goes back up and fires on motor cortex and saystake this action.

You learn in your cerebellum. If you blow air onto the eye of a rabit it will blink. This is unconditionedstimulus (innate). Open a can of dog food and open it under the nose of a dog, it will salivate. These areunconditioned stimuli. Howver if you pair another stimulus like a tone, such as preceeding the puff ofair with a tone.

The circuit gets rewired and so the bunny hears the tone and will start blinking. What's going on is thepuff of air come sup and hits a trigeminal nucleus which goes to the inferior olivary nucleus which hasan excitatory action on another nucleus which comes down to the red nucleus. The red nucleus is themajor nucleus of th emotor area that sends a signal down to a facial nucleus that causes a blink.However, if you hear something you operate your vestibulocochlear nucleus

Moon wants us to know: There is a climbing fiber that wraps around the Purkinje cells. These areextremely well-studied. That fiber is a parallel to the mossy fiber that comes up to a granule cell. Everystimulus you can think of comes up and broadcasts in a broad circuitry of parallel fibers, which interactwith purkinje cell.

There is an attenton center in each of the Parietal lobes. One is dominant to the other. If you lose someof your right parietal attention center, you lose all attention to left visual field. responsible forcontralateral neglect.

A cone talks to at least 2 bipolar cells.

Superior Olive -> Inferior Colliculus -> Turns head towards soundInferior Olive -> Superior Colliculi -> Turn eyes/head towards visual cue

The NLL necessarily goes to the inf col to move the head. The IC all by itself can move the eyeswithout input from the NLL.


UNIT 3

08 November 2007Cerebellum to Basal Ganglia to Limbic SystemTwo pathways come out of basal ganglia: Motor control and other stuff going on in the brain (inclearning and memory and sleep and how you process subtleties of language such as intent).

The amygdala is one of the last checkpoints of information in which you process the physiologicalresponse to stimuli. It's where you house to a very large extent notions of fear. There's a link betweenthe amygdala and the rest of the body which is very strong and that link is through the hypothalamus.

The basal ganglia mediate all motor information adnt they take into considration things like the nucleusaccumbens and the VTA (pleasure center) and all of that comes through pontine reticular formation. Allthe basal ganglia affect the pontine reticular formation. Hippocampus governs learning and memory.

In the midbrain we have the red nucleus and the substancia nigra (affected by parkinson's, tremoring isa result that the substancia nigra lead to anxiety disorders and motor control. Weird dual-job of thesystem. Our activity is a function of how well we handle the situation around us. Goes throughmidbrain (prebrain and tectum; tectum contains superior colliculus and inforior colliculus). Below thatis the reticular formation which goes down to medulla oblongata. Part of a descending pathway; got aVTA coming out of basal ganglia and we're going down from there.

Upper motor systems:Motor cortex wants to do things (mediated by basal ganglia) we have a brainstem which takes ininformation from vestibular system along with cerebellum (through red nucleus). Motor nucleus +Mcortex synapse onto lower motor neurons taking into account sensory input and sensory input andgoes to muscles.

Junction between upper and lower neurons is very discreet. Youj have the superior colliculus whichdrives things goeing down. Superior colliculus has signal that comes out and goes to cervical spinalcords that drive motor control of head and eyes. Superior is predominantly as a result of visual, inferioras a result of auditory information. They decussate immediately. They have inhibitory arcs crossing theother direction. The cerebellum is behind all this and it talks to the red nucleus; red nucleus itselfcomes down and it deals with cerebellar modulation of all these descending pathways.

It's not the cerebellum or the basal ganglia but the reticular formation that imbues us withmost of ourgrace and motion. You can go down from premotor and motor and decussate and go down the reticularformation or you can go through a lateral tract.

We're born with the same number of motor neurons that you'll ever have.

The somatic motor system:Skeletal, smooth, cardiac muscles and their innervation. Between skeletal, smooth, and cardiac musclesgo about contracting in different ways so be sure to notice the DIFFERENCES between these systemsand how they are innervated.


Muscles: You have muscles that come in organizational units. What occurs in the smallest muscle unit(sarcomere). The two proteins involved are actin and myocin. They are contained in each myfibrile; amyofibrile is a sub-cellular structure. The motor neuron comes down and hits the membrane wrappedaround many myofibrils and the membrane is a cellular membrane. The membrane has invaginationsthat come all the way in called t-tubules. The membrane sticks in and allows for increased contact withsarcoplasmic reticulum, wrapped around each myofibril. Input from the neuron will cause a muscletwitch. Continuous input causes increased twitches. It is, to a point, gradational. It is graded response tomuscle strimulus. If you continue to fire the muscle will just stay as contracted as it can.

The primary receptor is acetylcholine receptors. Muscles rest somewhere around -100 to -90 and whenAch binds, it is highly permeable to sodium but not potassium because we're really close to potassium'sEq potential. As we depolarize, we start to move past potassium's Eq potential. Most depolarizationevents just get us to the reversal potential for that membrane and then we repolarize. The currentsresponsible are both sodium and potassium.

E(Na) = +65E(K) = -80\Reversal potential: -10

You get a motor neuron coming down, it releases Ach on Ach receptors and you depolarize themembrane to such a degree that its effect reaches down T-Tubule. Once we get to sarcoplasmicreticulum, it releases calcium which drives muscle activity. Calcium is effectively working as asecondary messenger here.

The t-tubule comes down and lays over the fishnet stockings and brings the depolarization wave asclose to sarcoplasmic reticulum as it can.

Motor activity is this: You've got something that sits there (myocin) and pulls in actin which lays oneither side and passes over it.

Calcium binds to Troponin which moves out of the way so the actin head can bind (without energy). Itflexes without any energy to bind. The energy being used is a green atp which allows the head tostretch out again. Moon will say this once: We dont need to know about the Magnesium (enzymaticcofactor for ATPase activity of myocin head).

Calcium ion nears troponin, binds to troponion and troponin changes configuration. It seems as thoughthe troponin moves out of the way. Magnesium binds myosin, atp is cleaved, and the myosin extends soit can stretch out again.

A twitch is the muscle result to a single strimulus. Te temporal summation gives us slow tension and weeventually result in a state of tetanus when you reach full contraction. The two main things we'reconcerned about: You need ATP to reset the head and you need calcium.

General stores: a few contractions. Creatine phosphate: 15 seconds. Creatine phosphate can restore adpto atp. Glycogen (1-60 minutes anaerobic v aerobic). Myoglobin is a unique form of globin in musclesand it has Mg in the center instead of Fe. It's more powerful than hemoglobin so it sucks the oxygen


away from it.

Calcium binds to triponin after going through a series of receptors. Di-hydropyridine Receptor (DHPR)is a voltage-gated channel in the t-tutuble. It senses the depolarization of the sarcolema. On thesarcoplasmic reticulum is a Ryanodine receptor (mechanically-gated). In muscles, what happens is thatDHPR detects voltage and changes conformation when a voltage gate comes through and it literally hasa tether that reaches from t-tube membrane to sarcoplasmic reticulum and it yanks open a ryanodinereceptor that lets the calcium through. Tahat calcium comes down and does its thing on troponin.

If ever there was a final exam question: Step 1 through 14, this would be it.

We have multiple kinds of muscles: Striated (voluntary) muscles (multi-nuclear, organized sarcomeres (end-to-end), and sarcoplasmicreticulum in fishnet). Motor neuron stimulus. Smooth: Monocellular, unorganized sarcomeres, have an endoplasmic reticulum as opposed to asarcoplasmic reticulum. Don't behave like regular muscles. Autonomic stimulusCardiac muscles: Mono-cellular, very organized sarcomeres but have sparse sarcoplasmic reticulum. Cardiac muscles bifurcate onto two other cells that allows once cell to attach to multiple cells. It's not alinear path of contraction. Autonomic stimulus and auto-depolarization.

Smooth muscle cells have stuff going in every direction and they just get smaller in general. No senseof linearity at all.

Moon really wants us to understand this aobut smooth muscles: There are many ways to make a smothmuscle cell fire (if you somehow let calcium in, the calcium binds to Calmodulin and this complexbinds to MLCK myocin-light-chain-kinasse. This kinase adds a phosphate group to the myocin headsand a phosphatase is constantly reversing this process. When they're being activated the myocin isgetting phosphorolated. Only when its phosphorolated does it reach over and grab the actin.CyclicAMP inhibits this MLCK.

We have a description where Calcium can enter the cell (in this case through a gap junction.Norepinephrine binds to a receptor which uses a Gq subunit which drives phospholibase C IP3, Ca++R/ MLCKwhich) Epinephrine goes and binds to a Gstimulatory subuntit which goes to adenylatecyclase which produces more cAMP and inhibits. In skeletal muscles you need neuron-per-fiber. But insmooth muscles it communicates slowly and rhytmically. A

Adrenaline as norephephrine causes excitation but epinephrine shuts down.

Cardiac muscle will branch and so a cell will have a muscle fiber which comes up and binds to the nextcell

The heart respodns to autonomci system but also beats by itself.


13 November 2007Recruitment: You have a very careful system that calculates how much force you need to lift, squeeze,which neurons to recruit. It's all cerebellar.

You control a heart in two steps: I want you to beat harder. To make a heart work well physiologically,we have to tell it to squeeze out every drop, then you tell it to really relax so it can fill with everythingso you have a larger stroke volume. Major theme in heart control is time delay.

One node is called the Sinoatrial node, the pacemaker of the heart. Pacemaker cells are only here in theSA node. In fact, if there are pacemaker cells anywhere else that is a diseased state. Cardiac cellsdepolarize to pacemaker signals. You start at the SA node then a wave (propagated by gap junctions)fire from SA node outward. You do not want atrial systole at the same time as ventricle systole. If theventricles fire early, they push the blood back into the atrium and the venous system. During atrialsystole, ventricular diastole occurs. As the signal propagates from SA node, it hits the AV node whichpasses the signal through bundle branches (down to the heart apex), Purkinje fibers depolarize theventricles almost all around

There is a sodium leak current in the pace maker cells of the sa node. The size of that current dictateshow fast you repolarize your calcium current. One more concept: SA node cells have 60 bpm. AV nodeis maybe around 45-50 bpm. We don't know why, but if you eliminate the SA node the heart will stillbeat. There is a backup in the AV node. The Bundles of Hiss and Purkinje fibers by themselves have a20-30bpm cycle on their own. Probably due to sodium leaks. If they shut off your SA node the heartwill still beat.

Striated: Motor neuron stimulus / Ach-> Nicotine receptors, Up gNa and gKSmooth: Autonomic stimulus / ach -> muscarinic receptors, up gCaCardiac: auto-depolsation autonomic stimulus / Ach -> muscarinic receptors up gK down gNa & gCa /NE -> adrenergic receptors down gK up gNa and gCa.

Dihydrophyradine channel blockers include nifedipine: Cause calcium current to be reduced.

Five types of calcium channels: N, P, T, L, Q. N type: pre-synaptic terminals, strong depolarisation. Down at the end of the presynaptic terminal thatallow calcium to come in and allow neurotransmitter release. Blocked by omega-CgTx. P type: Strong depolarisation, slow inactivation. Often called P-Q type. Blocked by atratoxin, obscuretoxin from funnel web spider. Number 1 killer of little boys in Australia.T type: Activated by very small depolarizations. The one that gets the heart going. Found in pacemakercells.L types: Heart cells (along with virtually all other cells). Blockedby verapamil.

Exam Question: What are the effects of adrenaline and atropine on the heart? Why use one over theother.

CNS-> Motor Neurons-> Internal invironment is the autonomic nervous system.


There is a sympathetic and parasympathetic system. In general, Ach is transmitter of parasympatheticsystem. Norephinephrim: Main transmitter of sympathetic system.


15 November 2007Cells in AV node unique from atrial cells. SA node is a localization of specialized cells; they effect thebundles of Hith. You can have nonfunctioning atria and still move blood around the body. There is alsoa barrier between the atria and ventricles in which there are no gap junctions. This has been known tofail.

The initial immediate drop in the cardiac myocye membrane potential is because you lose sodium flow.Then it stablizes (stable calcium currents) and

As this starts to repolarize, the HERG channels open and you have a very large potassium currentwhich causes rapid descent in later part of the curve. In human pacemaker cells, there is an inwardcurrent which is a sodium leak current. Could be a calcium leak current also.

Atropine causes dialation of the muscles in the peripheral circulatory system.


27 November 2007Learning and memory are functions of the entire limbic system. In addition to that, it's utilizing a partof the brain which half limbic system, half cortical system (medial temporal lobes). This system, whichis also responsible for emotions is responsible for learning and memory.

From the cerebellum to the basal ganglia to the limbic system to the associative cortex to thehypothalamus to the autonomic system.

The basal ganglia are dark areas that are close to the structures of the temporal lobes. The associativecortices are everything that are not primary motor cortices.

Quick cerebellar review: Receives input from motor intent and sensory cortices. You also getvestibulular information and the inferior olive brings info from visual/auditory cues and the DNCwhich brings in proprioceptive information. The function of the cerebellum is to take over as much ofthat activity as it can. Another issue is the primary motor/premotor cortex.

The hippocampus:A structure that recieves information from Thalamus, Amygdala (inhibiroey mostly/excitatory),hypothalamus, and Vental Tegmental Area(nucleus accumbens pleasure center, the pathway thatassesses this and leads to a process of reward). The VTA hightens the activity of the hippocampus andsays don't forget that. There's a raphe nuclei that's dedicated to fine motor control but also somehowlearning and memory. The raphe nuclei synapse for all intents and purposes, everywhere. Thecerebellum, cortices, hypocampus, EVERYTHING. Activates the hypocampus for remembering things.If they are working hard, then they mediate motor control so that you're not very good at something.“Watch and pay attention” structures. The hypothalamus sends in information on body state. The wirethat comes out of the thalamus is the fornix that touches little bodies (mamillary bodies) that talk to thehypothalamus.

The CA1 cells of the hypothalamus are where long-term potentiation and long-term depression takeplace. The CA1 cells look like perkinje cells. Other cells come in and synapse on them. You receiveinformation and store memories as a result of that. You receive primary sensory information, and youcouple that with where you are (place memory), and your emotional state. You remember based onyour emotions.

Cortical association -> Parahippocampal and rhinal cortical areas -> hippocampus -> back to corticalassocation to say this is worth remembering (most of these are inhibitory) and also through the fornixto the hypothalamus.

Memory and learning:You have declarative and nondeclarative memories. Nondeclarative memories include motor skills(reticular formation, basal ganglia, cerebellum), associations and priming cues are usually found intemporal lobe structures.

Amnesia: See how it doesn't work. Lots of kinds of amnesia. Retrogradae (often cortical) amnesia(can't remember things in the past). Anterograde (often hippocampal) (not being able to form new


memories). If you remove some of the medial rhinal cortexas you are definitely going to haveretrograde amnesia. You have to be able to call upon your temporal lobes to recall information.

If you whipe out the thalamus, it kills the point at which medial structures talk to one-another. Threetheories of hippocampus modality:Cognitive map theory (spatial context): Remember things because of where you were or where theyare.Configural association theory (logical associations): You figure out what things are because they'relogically associated with it. Path integration theory (relational associations): Relational assocations where you relay a lot ofdifferent factors and you intergrate it (that's what a memory is). Supported by hippocampal wiring.

Striatal cells (caudate and putamen) relational memory:

Pretty straightforward: The CA1 cells are really the cells that are changing; their synapses areundergoing long-term potentiation/depresssion. The structure they synaplse onto are just like theparallel fibers in the cerebellum. You have a major output going to cerebral structures. The majorincoming pathway is the perforate pathway. There are structures that send this to the associative cortexand determine whether or not something is worth remembering.

Immediate memory -> working memory (memory you utilize as i write it down and hear moon say itand 5-30 minutes I recount most of it) -> (consolidation, occurs with repeated exposure or a contextualswitch; if we meet anywhere but this room and talk about this again we have ANOTHER spatialcontext to remember this in, or if we find new words to explain this concept, there's another really goodway to consolidate memory: high stress or high pressure) -> long-term memory.

Sleep: What cues us to sleep? Light controls circadian rhythm. Hypothalamus has a structure which hasa suprachiasmatic nucleus (biological clock) They will maintain a 24hr cycle for a few days. Our clockcycle is dictated by a very short series of proteins such that every 24 hrs you run out of a certainprotein. This whole cycle is reset instantly upon exposure to light.

The lack of light causes receptors to fire; so the lack of light melanopsin is being produced. Melanopsinis triggered by the loss of light and the paraventricular nucleus and it sends a signal back down thespine again to the SCG which comes back up and ttalks to th epineal gland (ancentral organ).

Serotonin levels spike that provides the resources for melatonin to be made. Natural process willconvert that to melatonin. You do lots of things in sleep: Alert cycle much higher during the day, bodytemperature is a lot higher during the day. You grow at night; if you don't sleep, you don't grow.Cortisol levels drop throughout the day and regenerate at night.

Stages of sleep: Beta waves (short waves), theta waves (longer waves), sleep spindles (final burst ofactivity), stage II and II go down, and then delta waves at stage-iv. Then finally you peak and you hitREM sleep and you're almost as active as when you're awake. Roughly every ~90minutes to hit REMsleep which lasts about 10min. Sleep apnea is what my dad has, you stop breathing and your cycleresets to stage II/III sleep. We're pretty sure that you dream during REM. You are definitely notsleepwalking sleeptalking. No night terrors; you are effectively dead to the world but brain running athigh speed. Consolidation of memories occurs during REM sleep.


Melatonin comes down to the pontine reticular formation and activates GABAergic neurons and thesedo a series of things that comes down to the DNC and inhibits it. Through another pathway it activatesa glutamitergic pathway that activates glycine also activating glutamatergic pathways that activate parts of the cortex. Sensation goes away as you fallasleep and movement is inhibited to the point where you are effectively paralyzed. Sleep Phenomena:Hypnic jerks (hypnogogia): Started to paralyze you. No matter how much you try to move, you can't.It's in full effect during REM sleep.

Lucid dreaming/false awakenings: There's a definite switch that switches off consciousness whenyou're asleep. Lucid dreaming is the case where you come up enough to consciousness and watch yourdreams occur. False awakenings: Dream that they woke up and walked to the bathroom and come to thebed, but they never went out of the bed.

When someone's asleep, they remember everything they saw. Other parts (parietal cortex) are activelybeing stored.

Narcolepsy: Bobbing along and doing everything normally, without having benefit of going intoanything, you fall asleep. In some narcoleptic cases they get a full night's rest (stage I to REM in 30s).


29 November 2007The increase in awakeness that occurs during the end of sleep also occurs during the course of the day.Hypocretin

Eating disorders go through the exact same wiring as drugs. They light up the same centers of the brainto equal intensity as some of these powerful drugs. Caffeine is just as big a drug is the same caffeine inthe chocolate bean. Chocolate has phenylthalines (emulate love pleasures, tiny amount) and caffeinethat makes you addicted to it.

Addiction: Nucleus acccumbens and Vental Tegmental Area. This is a structure that is largely midbrainbut its an area. There is no hardcore medical definition for addiction, but there is a physiological set ofsymptoms. Addiction implies dependent cravings, massive cravings for something. You cannotmaintain your normal physiological state without your cravings being satisfied. The other component isfuzzier, and that's the notion of tolerance. With increased exposure, we gain tolerance.

Cerebellum: Learning and motor controlledpairing motor intent with proprioceptive info and sensory inputbasal ganglia: reptitive motor controlreticular formation: fine motor control

Hippocampus: learning declarative memoriespairing sensory information with emotional statenucleus acumbens: cravings/pleasure centresamygdala: perception of fearhypothalamus: stress state

Neucleus accumbens: sexual arousal, waking arousal (usually the same thing for most people) , VTA isa center that branches out in every direction you can think of. Executive function makes you you.

Prefrontal cortex says “yes its chocolate, there are higher things to consider.” Abrogating that pathwayin any way leads to addictive behaviors. Pre-limbic structures directly transmit the concept of structure.VTA transmits notion of reward in response. If both the VTA (dopamine) and Pre-Limbic(glutametergic onto nucleus accumbens) fire in coincidence detection circuit, dopamine accentuateseffects of glutamate and this is called cravings. Nucleus accumbens says “do that again.”

Through the amygdala you detect a cue, a relational memory. Takes these cues and the basolateralamygdala. The extended amygdala has just been described. Those wires come from the hypothalamusand the stria terminalis also responds to hypothalamus an dthis is the component where stress and cuescome through the amygdala.

The medium spiny neurons of the NA get bigger and fatter and their complexes get more bulky inpresence of amphetamine. Amphetamines mimic the development of cravings, there is aphysiologicalchange in the nucleus accumbens called addiction.

Lateral hypothalamus is responsible for arousal and awakening.


Novelty: Hippocampus perceives novelty, a major way of activating NA. Has to do with tolerance andall sorts of stuff. Novelty seems to be able to drive addictive behavior.

Hippocampus stores a daytimes worth of experiences in the dentate structures which gets replayedbackwards in dream states. Because of those results, predictions are made and the CA1 circuit gaugeswhat we've learned about experiences and senses reality (was that really a good thng). The CA1 circuitscompare what you've already experienced to what you're experiencing and are asking “have I ever seenthis before?”

If you really have a novel experience, if its a new kind of pleasure (first time of heroine), much greaterexperience than your second or third time.

The novelty loop is the pleasure-driven acquisition.

You have a medial prefrontal cortex has a major input onto other centers (NA). Has an inhibitoryglutamatergic input on the NA and is the major mediating factor. VTA talks to mPFC and NA,hippocampus and amygdala and the take home point from this is that the mPFC can regulate thefeedback loop to avoid cravings and addiction.

Alcohol, one of the first things it inhibits is the executive function of the prefrontal cortex.


04 December 2007Major function of higher-order function is Memory! The main driving form of memory as we considerit (declarative memory) is via the hippocampus, which is affected by the nucleus accumbens. It makes acontribution to the hippocampal decision as to whether or not a circumstance is worth rememberingbased on imput from prelimbic cortex (pleasure), medial PFC (executive function), vta (reward),basolateral amygdala (cues, stimuli that are being percieved and if they are only innocuous cues theamygdala says “that is not bad” and it relieves an inhibitory effect on NA), hypothalamus (low-levelstress activates NA).

Cravings are the activity of the VTA on the NA (the dopaminergic afference onto the NA that starts itshightened level of response). They are long-lasting, meaning that after the stimulus you want thatstimulus again. They make a psycological/neurological distinction between a craving and a desire oraddiction. Desire invokes an emotional state and that evocation of state can be tied to a physiologicalform. There is actually a hormonal release.

Then there's lust. Lust is something that people try to decide is a form of love as they try to define itthat's based purely on the physical stimuli rather than prefrontal stimuli. There is a profoundphysiological need to maintain homeostasis with regard to a stimuli as a result of modifcations in thebrain. If you don't satisfy a craving and are physiologicaly depressed because of it, you are addicted.

There are paths of addiction and the thing that breaks addiction most often is executive control; youhave a prefrontal cortex...

If you have some notion (novelty or input) causes NA to inhibit the Ventral Pallidum (which normallyinhibits VTA),

To finish up with addiction: Orbital frontal cortex and medial OFC are the parts of the brain thatgenerate pre-executive function ( i really shouldnt do this) they can mediate the vta and actuallymediate the substantia nigra but they discovered that there are lots of different types of addictions;sexual addiction and appetite are almost indistinguishable from oneanother.

What happens with lack of executive function; (Phinnaes Gage); the spike functionally wiped outprefrontal cortex. Went from being a very nice guy to being a dick. No loss of motor control and littlememory loss, but pretty much lost ability to determine consequences.

Notion of love seems to elude executive function. You seem to abandon executive function quiterapidly when you're in love.

Theobromine is an analogue to caffeine and has a stimulating effect in your body; is present in goodchocolate in 450x the level in caffeine in coffee. Chocolate increases the levels of norephinephrine inthe system.

Lust is part of the desire pathway. We have dopamine saying i like this state, we have noreph andtestosterone eing hightened awareness and aggressiveness. Oxytocin is a bonding hormone. Also fear,love has a fear component


Things that go bump in the night: amygdalaAll the primary visual and secondary cortices have afference to the amygdala. Visual, auditory,gustatory, olifactory, and somatosensory all talk to amygdala bypassing a lo tof the secondary cortices.However there is some neocortical imput here; amygdala talks to hypothalamus saying 'we are scared,something is wrong.”

It is the last of the limbic systems other than when all of this talks to hypothalamus. Sensory cortextalks to amygdala which talks to hippcoicampus, VTA, and hypothalamus.

The amygdala drives that fear, that sensation going through your guts. The amygdala themselves have 3general regions: central, lateral, and basal. Info comes in through the basolateral structures and getsprocessed in somewhat scentral area and leaves through central amygdala. Cortical inputs comethrough and fuse into central. Hippocampal omes in theough basal. There is some hypothalamicfeedback to the medial amygdala.

In general, you have inputs of meny differenct tyes (GABA, NE, and Opioid) which bring amygdala upto heightened sensityivty and then back down. It has a feedback mechanism which gets you more andmore and more frightened.

There are two paths: Innate (sensory thalamus to amygdala) and learned (sensory thalamus -> sensorycortex -> amygdala), one of the reasons we have binocular vision is so we can accommodate fear(darkening skies, hissing noise of a snake, a flashing light) makes amygdala fire. Amygdala talks totemporal lobes which are hotbeds for epilepsy; flashing lights can cause enough stimulus coming fromanygdala to cause a temporal lobe seizure. Only left-temporal epilepsy leads to “spiritual accensions,”vs right-temporal which is lack of ability to perceive fear.

The amygdala consolidates information and creates a stimulus which leads to a behavioural response. Ifyou have a body language that invokes a fearsome stance you can put fear into people even by smilingat them.

Amygdala: Fear, Freezing, Fleeing. Triggers parasympathetic system and leads to hypothalamicresponse: Fleeing, Fighting, Feeding, and Fucking. Auditory stimulation to amygdala is non-learned.Visual stimuli are ipsalateral; eyes send stimulus to thalamus to visual cortex.

Aprosodia: Affective language disorder in which speech is devoid of emotion; alexithymia: Patientshave diffculty recognising emotional content of speech.

Aprosodia and Alexithymia are unilateral; comes from right amygdala to a part opposite wenicke's areaand its only the right amygdala that does this.

Toxoplasmosis: 83-85% of france, up to 25% of US. It's a protist that is transmitted in a hand to mouthfashion and its spreading apart the world. Cats have this protist in the system and they develop in thecats (they have a sexual life course in cats) , if it infects people it will get into children (as far as we cantell to no effect). The real pathway: cats eat things, and those things are infected with toxoplasmosis. Inthe cat it can go to sexual cycle and it can go into humans; the infected rodent undergoes behavioralmodifcation; in rodents it shuts down the amygdala and we don't know if this has an effect on people.


Men basically get dumb when infected by this, and women get lower fear levels and they become morecalm and happy.


06 December 2007Hypothalamus is the link between what you perceive and what your body wants to do. The amygdala isthe major input into hypothalamus, hippocampus does too.

The hypothalamius sends singals down through gangliaParasympathetic system calms you downstreamSympathetic system makes you alert

Memory is sensory infromation, gets stored along with everything else in the hippocampus and theamygdala provides cues as to whether or not this information is worth keeping. The autonomic systemwhich is drivign sleep through hypothalamus is feeding back through the hippocampus thatconsolidates memoery and sends it to frontal/parietal lobes.

The hypothalamus talks to hippocampus, the amygdala largely tells hippocampus about things youdon't want to remember. At low levels amyg has stimulatory effect on hippocampus. If fear gets toogreat it inhibits hippocampal activity.

Whereas pleasurable stimuli at low levels is largely forgettable (inhibitory), the NA talks to the VTAwill have an input that causes it to disregard this information. At high levels it is largely strimulatory.

We become addicted to things when our control functions (mainly involvement of prefrontal cortex) isbroken.

The thalamus receives all primary sensory input (key player), if it gets inhibited then the informationdoesnt cue prefrontal cortex. Amygdala recieves secondary sensory input. Amygdala all by itself candrive low levels of stimulation (cues) or high levels (fear). You can engage your fear levels just byperceiving danger.

Ergo, the amygdala can shut down NA with lots of fear. Slightly stimulatory causes hippocampus to bemore alert. We are more likely ot remember stimulatory experiences; things that are novel and a bitmore extreme than normal drives generation of craving moreso. Because you're stimulated you havemore norephinephrine which drives more activity in the hippocampus.

Oxytocin has a phenomenal effect. If oxytocin is released, all voles look the same but a prarie vole is amonogamous creature. Oxytocin works on the amygdala as well. With the placebo the amygdala firesso many times but with oxytocin it induces trust between random invidiuals.

Amygdala perceives danger directly through a sensory pathway, through the cueing (recognizingindividuals who we don't trust).

Sensory input: primary, secondary, physiologic, proprioceptive -> limbic system -> motor output:emotions, memory, autonomic, physiological

Body attitude drives the limbic system. (Pyramidal smile) Muscle flexes -> Cerebellar Responses ->Emotions -> Autonomic Responses -> Muscle flexes (Duchenne smile)


Thalamus -> Hippocampus -> Hypothalamus (circadian rhythms, thirst/hunger, blood pressure,autonomic systems)

The difference btween the sympathethic and parasympathetic system is the liver. When you liberateglucose, carbohydrates, and steroids. No parasympathetic control of the adrenal gland. The sympatheticcontrol of adrenaline releases epinephrine (heart to beat faster, muscles to pump up, state) and thenorephephrine hightens the activity of amygdala and makes you more stressed. If the amygdala stillperceives more danger, it drives this harder and harder. Under stress you drive the looping sympatheticsystem.

Two events occur: Animals living in tanzania etc constantly find themselves in stressful situations(OMG LIONS MEW MEW MEW) and then go back to normal within 90s. This zebra handles theseevents that you get so stessed out so much that the sympathetic system drives you into a state of shock(opiates flow out of brain at incredible rate), DNC is completely numb and dopamine/endorphin levelsare higher than you would ever get in a living creature, higher [ ] than morphine would kill them.

Humans perceive dangers at a far greater danger than we ever have in the past, but they do perceivereal danger. As a natural preservation, they have a way of releasing themselves from this sympatheticloop. The amygdala eventually says “screw it, everything's ok.”

Some of us go through this cycle on a regular basis. We have an extraordinary [pacinian(sp?)corpuscles], they can be in the 10s of millions per square mm in certain parts of body. If they arestimulated a low rate, it will cause the nucleus accumbens to engage, do it again. If you continue tostimulate them, you start to engage centers that release hormones that normally affiliated with bonding(oxytocin and norephinephrine), as you continue norephinephrine triggers sympathetic response, evenfaster then the norephinephrine triggers adrenal glands which releases epinephrine and stimulatesamygdala.

You're afraid. A good 5-20 minutes later you don't feel anything, and your sense of bonding isphenomenal. It is your amygdala that is responsible for the totallity of the orgasm driven by fear to thepoint where your body turns off its sympathetic system and prepares to die.

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