Editing 20110105 Lecture 4 notes.txt

*started here on 01/05/2011


*quiz is over first three lectures (not today's).

*Botox wrinkle mechanism:
**Botox only affects lines.
**The use of facial nerve sets a precedent such that we have a static state that cuases wrinkles.

*Node of Ranvier vs. voltage gated K+ channels
**The channels are only found under the myelinated areas of the axon.
**None in the node.

===Learning Objectives===
*Review the sensation modalities 
*Understand the basic steps and mechanisms in the sensory process 
**We are interested in the mechanism of function, not the anatomy

===Steps in the process of sensation===
*First there is a stimulus.
*Then there is activation of a receptor and stimulation of a receptor AP.
**This is a translation of siganal into AP.
**It can cause an increase in AP or decrease.
*Then there is transmission to the brain.
*Then interpretation and analyzed.
*Then response is generated.

===Sensory modalities===
*olfaction (smell) 
*vision (sight) 
*gustation (taste) 
**Russians love caviar and bread
*audition (hearing) 
*somesthesis (touch, temperature, body position (proprioception), and pain (nociception))

===Oflaction===
*Air passes through cavity onto olfactory epithelium.
**Contains many types of cells:
***Olfactory neurons / receptor cells
****Have dendrites in the mucus with receptors
****must be regnerated every 4-8 weeks
***Support cells: like glial cells
***Basal cells: differentiate into receptor (olfactorY) neurons
*We can only smell water-soluble things.
*Because the olfactory neuron is a true neuron:
**we have passive spread of the AP where there is no myelination (electrotonic conduction)
**They have a voltage of -70 mv
**Once the AP reaches the axon hillock a saltatory AP is produced through the cribriform plate.

===Olfactory meachanism===
*There are about 400 receptors in the olfactory epithelium.
*Each neuron receives only one type of odor receptor.
 What?
*The receptors are g-proteins which activate adenyly cyclase (ATP -> cAMP).
*cAMP difusses up the dendrite and reaches the cAMP-ligand gated cation channel
**Allows Na and Ca+ to pass into the dendrite.
**This opens Cl- channels such that Cl '''effluxes'''.
*This depolarization spreads electrotonically to the axon hillock.
*At the hillock, an AP is generated.
*Receptor potentials look much like APs.
 Something about negative feedsback, missed it.

===Olfactory bulb neuronal network===
*A single neuron expresses a single 
*Granular and perigranule cells are inhibitory to olfactory neurons.
**They modulate stimulation and allow for desensitization to odors.
*Up to 1000 afferent neurons converge to a glomerulus which is invervated by a single olfactory neuron.

===Vision===
*The retina contains the photoreceptors.
*The fovea contains more rods than cones.
*The photoreceptor signals end up in the optic nerve (CN2).
*We will focus on the fovea.

===Fovea in detail===
*The retina is "inverted" (?).
*The rods and cones are deep to the light, so light must travel through the many supporting cells to get to them.
**However, the distance across these supporting cells is very short: 200 micrometers.
**Because it is so small, there is no need to generate APs in the supporting cells.
**We don't need to know the layers.
**Therefore, we use simple electrotonic conduction of the AP along the dendrites.
*At the point of the ganglion cells, the dendrites converge and the AP is conducted via saltatory conduction.
*GABA
**STimulated GABA sensitive Cl- channels.
**This is important for determining which path the AP takes in bipolar cells.
*Amacrine cells:
**Role is not too clear so we won't talk about them.
*Meuller cells:
**Glial cells that support bipolar cells.
*Pigment epithelium contains important supporting cells that absorb and pass on the nutrients needed by the photoreceptors and supporting cells.
*All the cells have ribbon synapses.
**Recall that these are used so we can maintain constant stimulation.

===Rod and cone anatomy===
*Cones = color vision
*Rods = greyscale
 *Synaptic terminal, what is this?
*Inner segment of rods and cones contains the nucleus and mt
*Outer layer of rods and cones contains photosensitive membranes
*Differences between rods and cones:
**Cones have infolding of outer membrane to increase area of membrane to increase photon absorption.
**Rods have free floating disks from the outer segment which express rhodopsin to be given to vesicles and disks (that is, the disk and vesicles that release NT at the synapse).
*We have 1:16 cones:rods.
*The fovea has predominantly cones, however.

===Mechanism of phototransduction===
*Our photoreceptors are still secreting NT even when asleep because they are depolarized.
**They are depolarized because the inner segment is secreting cGMP which activates cGMP-gated non-selective cation channel (Na, and Ca influxing).
*Our voltage is not zero, however, because of K+ channels that move K+ outward (effluxing).
**This will generate hyperpolarization (because we are asleep and we are effluxing more K+ than influxing Na and Ca+ so the voltage is becoming more negative).
**And hence it's hard to look at the bright light when we wake up.
*"Deem" = "dim". :)

===Visual transduction===
*The disks have opsins, a g-protein receptor (7 transmembrane domains, etc.).
**These are diff because they are bound to cis-retinal which is isomerized when it absorbs a photon.
**Cis-retinal then changes isomers to rhodopsin and we call it meta-rhodopsin because it is "activated".
**cis-retinal is inherently and tightly bound in the receptor (it doesn't leave to be converted back to cis from meta).
*Meta-rhodopsin activates transducin, the g-protein.
*Tranducin turns on phosphodiesterase which cleaves cGMP to straight chain GMP.
**This causes a closing of the cGMP-gated cation channels.
*Guanyly-cycase is constitutively activated, so there is a constant source of cGMP, but when phosphodiesterase is activated, the levels decrease.
**The constitutive activation assures that the neurons will not become too desensitized (because there will always be basal levesl of Na and Ca influx).
*K+ channels in the outer segment cause hyperpolarization of the neuron when they allow efflux of K+ from the extracellular fluid.
*There are three types of opsins which allows us to detect three colors of light.
*Rods absorb 500nm light
*Cones express three other types of opsins that absorb: 419nm (blue), 533nm (green), 564nm (long, yellow / red).

===Gustation (the sensation of tasting)===
*Innervated by facial (CN7), glossopharyngeal nerve (CN9).
**These innervate diferent parts of the tongue.
**Anterior = facial; posterior = glossopharyngeal.
*We have pillae that contain up to 150 tastebuds.
*Tastebuds have many cells in them:
**Taste cells (receptors)
***Transformed epithelial cells, not neuronal cells.
***Form electrical and chemical synapses.
***Not all taste cells form chemical synapses but if they don't they will have electrical synapses with other receptor cells that do have chemical synapses.
**Supporting cells

===Putative mechanisms of taste transduction===
*We have multiple tastes: salt, sweet, umani (aa, generally), bitter.
**Bitter is associated with toxins.
**The mechanism is different for each "taste".

*Salty comes from activity of epithelium sodium channels:
**Highly expressed in kidney, too, so we know lots about them.
***Important for Na reabsorption and water retention.
**Has three subunits.
**Protein is constitutively active: always open, allowing Na into the taste cell to cause depolarization.
**Depolarization causes activation of voltage gated Ca channels, then AP, then '''release of serotonin''' in synaptic cleft of facial nerve.

*Bitter test
**Detects acids
 **Protien sensitive channels
 I don't know how to interpret this.
**Mechanism is the same: Na permeability, Ca channels open, Ca influx, AP, release of serotonin

*Sweet and Umani and some bitter:
**Occurs through T1 / T2 (for sweet), T1 / R3 (Umani), T2 (bitter) channels.
**These are g-protein coupled such that the gprotein activates Phospholipase C which cleaves PIP2 to form DAG and IP3.
***IP3 causes IP3R on the ER to release Ca+.
***DAG cuases opening of Ca+ channels on the outer membrane (TRPM5) to augment Ca influx.
****This channel has similar structure to the others we've seen.
**Influx of Ca+ causes an AP.

*All these receptors are expressed on all receptors (we think) but it isn't totally clear the distribution and taste-differentiation mechanisms.
 *Type II taste cells don't express any voltage-gated Ca channels so they may not detect...?

===Hearing===
*The cochlea is important for sound sensing.
*We can hear sound with frequencies of 20 kHz to 200 hz.
**Note that frequency determines pitch (think musical notes); higher frequency sound waves are perceived as higher notes.
**The base of the cochlea is important for low frequency hearing (20 kHz) and the helicotrema (the apex or tip of the cochlear spiral) is important for high frequency hearing (200 hz = 0.2 kHz).
*There is a narrow membrane at the base but narrow at the apex (helicotrema).
**I think Dr. O was trying to say that the membrane divides the canal of the cochlea into two channels--one of which is narrow at the bottom and getting larger and the other is large at the bottom and gets narrower.
*Place coding is the specific area of the membrane that vibrates given the frequency of a sound wave.
*There are three important parts:
**The scala media contains endolymph which is rich in K+ (125 millimolar).  This causes a very high positive potential inside because marginal cells move K+ into that area.
**The high levels of K+ make the potential positive for cells in scalar media.
**Didn't talk about other two areas but I assume they are scala tympani and scala vestibuli.

===Organ of corti===
*There is a basalar membrane which helps determine the coding of place.
*There are two types of hair cells:
**Outer hair cells:
***Insures fine tuning of inner hair cell sensitivity.
***Contain '''prestin''' which is able to contract when depolarized.
***When depolarized, the outer cells contract and the change of physiologic location fine-tunes the inner hair cells.
**Inner hair cells:
***Important for hearing sound.
*The rate of AP in cochlea is proportional to the sound amplitude.
**This is called '''rate coding'''.

===Mechanotransduction in the hair cells of the 
inner ear===
*Hair cells have a potential of about -40 mV at rest.
**This makes sense because the tectorial membrane pushes the villi toward the hair cells and cuases opening of some channel.
*When Tectorial membrane goes up, the hair cells are caused to open K+ channels such that K+ rushes in.
*This stimulates Ca+ channels which causes the cell to release '''glutamate''' at the synapse.
**We use disks, not ribbons, for release as a mechanism of modulation.
*Note that there is no AP in the hair cell, only an ionic signaling even that causes glutamate to be released.

===Skin===
*We have several types of mechanically sensitive structures in our skin.
**Meissner corpuscles: think about misers who need some light touch and who would probably adapt quickly to it.
**Merkel's disks: think about erkel's suspenders applying steady pressure.
**Pacinian corpuscles: think pac man and vibrations of picking up a big dot.
**Ruffini endings: think ruffles stretch.
**Free nerve endings: chemicals and temperature
**Krause's end bulbs: lips and external genitalia
 See slide for a nice table

===Pacinian corpuscle===


*stopped here on 01/05/11.


*This is a bundle of naked nerve fibers surrounded by an onion of schwann cells.
**Can be thought of as a form of myelination.
*The schwann cells provide and regulate a viscous solution that moderates the depolarization of the nerve fibers.
*The nerve fibers have DEG / ENac on their terminal which moves Na across the membrane to cause depolarization.

===Spatial discrimination of skin mechanoreceptors===
*The ability to distinguish between two points is a function of:
**the densitiy of specific mechanoreceptors
**the receptive field size of specific mechanoreceptors
***one cannot distinguish between two stimuli in the same field so when receptive fields are large, two distinct stimuli must be farther apart than when the receptive field is smaller
*Pacinian and ruffini have large receptive fields
**Within the field, there is an area of highest sensitivity--near the nerve terminal, presumably.
**Example: medial half of the hand from the 5'th digits proximal filange to the distal end of the ulna.
*Meissner's corpuscles, Merkel's disks, and free nerve endings have small receptive fields
**Example: about the size of a pea


*started here on 01/06/11 at 11AM.

===Pain (stimulus noxious to the body)===
*The major information is that sharp pain is transmitted by a-delta fibers (myelinated) and dull / burning pain is by c-fibers (unmyelinated).
*Some NT peptides can sensitize for pain (increase the sensitivity):
**histamine, Substance P, CGRP (Calcitonin Gene-Related Peptide), bradikin
*Mechanisms are as follows:
**P2x mechanism:
***An ATP-dependent mechanism
***Nail in a hand causes cell damage.
***ATP is released
***ATP sensitive p2x ionotropic channels are on the nerve terminals and are depolarized
***This causes opening of voltage gated na channels and the propagation of an AP.
**ASIC mechanism:
***Proton-sensitive
***Organelles release protons
***Proton sensitive channels cause depolarization and an AP via T2D channels
**K+ release:
***Cells are damaged and release K+
***Increases the ECF K+ concentration which causes depolarization of the neuron.

===Mechanisms of Thermosensitivity===
*Pain and temperature are somewhat related.
*A high temp induces burns, damages cells, causes pain.
*It is important to know which mechanism is being used to sense temperature.
*TRP channels are crucial for mediating temperature sensing.
*TRP channels are thought to be mechanically activated, or kind of ligand gated; it's a little unclear, maybe kind of a form of voltage "sensitive".
*These cover the entire range (30-C to 60+C).
*Fibers that express TRP channels at nerve channels are unmyelinated.
**These are the c-fibers we spoke of previously.
*There are also nerve endings with TRPA1 and TRPM8
**These are called sensors.
**When temperature goes up, the channel opens; it is normally closed.
**Then cations influx, voltage-gated Na open, AP occurs.
**TRPA1 and TRPM8 are closed at room temp but open as temperature drops (and an AP occurs).
**These receptors are expressed on different nerve terminals.
**These are formed by 4 subunits, 6 transmembrane domains, d loops for selectivity.
*All TRP proteins are non-selective cation channels.
*C fibers are slow because they are unmyelinated.
**These innervate the hot receptors: TRPV1-4
**Dull or burning pain
*A delta fibers are fast because they are myelinated.
**These transmit cold sensors: TRPA1 and TRPM8
**Sharp pain

===Proprioception: the muscle spindle (MuS)===
*We have two types of skeletal muscle:
**extrafusal: actually make things move
**intrafusal: detect the position of our muscles
*We have muscle spindles which are found on the interfusal muscle fibers.
**These are deep in the muscles.
**They measure the length.
**They measure the rate of change of length of the muscles.
**They have a complex structure:
***chain fibers (nuclei are found in a chain)
****important for static chain
***bag fibers (nuclei are in a specific location)
**have a spiral shaped terminals on the chain or bag fibers
**When stretched, non-selective cation channels are activated which causes depolarization, vgna channels, AP
*Muscle spindles are slow adapters which allows us to detect our muscle location very precisely.
*More on intrafusal muscles:
**Aligned in parallel with extrafusal muscles.
**We need them to measure the length and stretch of our extrafusal muscles.
**Chain fiber intrafusal muscles
***Receive some motor efferent ("exit" the cns) fibers which can induce the contraction of the intrafusals.
***However, there is no contractile apparatus in the middle of the fiber--only found at the periphery.
***We need this motor stimulation so that the length of the intrafusal muscle will stay the same as the extrafusal muscles.
*The brain integrates the information of the efferent motor stimulation and the afferent proprioception from intrafusal muscles to know precisely where the muscle is and is heading.

===Proprioception: the golgi-tendon organ===
*In addition to the MuS, we have the golgi-tendon organ.
*It senses the force generated by the muscle and the tension in the tendon.
*It is set in series with the extrafusal muscles.
*There are collagen fibers that squish the free nerve endings such that the stretch receptors are activated, vgna channels are activated, and an AP is fired.

===Primary sensory afferents innervating human skin===
*There are several different types of afferent ("at" the cns) fibers for communicating sensation back to the CNS.
*a-alpha
**For proprioceptors
**myelinated
*a-beta
**myelinated
**for touch or mechanosensitivity
**some proprioception
*a-gamma
**Motor to intrafusal fibers
**myelinated
*a-delta
**sensation of sharp pain
**called stimuli
**some touch receptors
**myelinated
*All a-fibers are myelinated
*b
**pregangliotic fibers of the autonomic nervous system
*c
**pain stimuli
**heat
**some touch
**unmyelinated
*Sensations ordered by speed (fastest to slowest):
**Proprioception
**mechanosensitivity
**sharp pain
**pain stimuli
**heat

===References===
*Baron W.F., Boulpaep E.L. Medical physiology, Elsevier Saunders, Second Updated Edition, 2009 
*Koeppen B.M., Stanton B.A. Berne and Levy Physiology, 6th Updated edition, Elseiver-Mosby, 2010 
*Guyton A.C., Hall J.E. Textbook of medical physiology, ElsevierSaunders, 11th Ed., 2006 
*Purves D., Augustine G.J., Fitzpatrick D., Hall W.C., LaMantia A-S., McNamara J.O., Williams S.M. Neuroscience, Sinauer Associates, Inc., 3rd Ed., 2004 
*Netter F.H. Atlas of human anatomy. Elsevier Health Sciences, 2006 

===Review session===
*With regards to questions about how ECF (or serum) K+ levels affect resting membrane potential of neurons:
**An example of ECF K+ increasing:
***Initial case:
****e = 61.54 / z * log ([xo] / [xi])
****e = 61.54 * log ([xo] / [xi])
****e = 61.54 * log ([4] / [40])
****e = 61.54 * log (1/10)
****e = 61.54 * -1
****e = -61.54
***With higher ECF (Xo) K+ (as in the case of cellular damage):
****e = 61.54 * log (40 / 40)
****e = 61.54 * log (1)
****e = 61.54 * 0
****e = 0
***So we see that the neuron will become less negative and will hit it's AP-generating threshold and thus be stimulated.
**An example of ECF K+ decreasing:
***Initial case:
****e = 61.54 / z * log ([xo] / [xi])
****e = 61.54 * log ([xo] / [xi])
****e = 61.54 * log ([4] / [40])
****e = 61.54 * log (1/10)
****e = 61.54 * -1
****e = -61.54
***With lower ECF (Xo) K+ (as in the case of dysregulation at the kidney):
****e = 61.54 * log (1 / 40)
****e = 61.54 * -1.60205999
****e = 61.54 * 0
****e = -98.5907718
***So if ECF K+ [] goes down, the neuron will hyperpolarize (become more negative).


*stopped here on 01/07/11.