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, 
*inner segment:
**Contains.Nucleus and mt
*Outer layer:
**Photosensitive membranes
*Diff in rod and cone
**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.
*We have 1:16 rods:cones.
*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 activate 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).
*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".
*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 neuron.
*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).
*cis-retinal is inherently and tightly bound in the receptor (it doesn't leave to be converted back to cis from meta).

===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 form chemical synapses but if they dont' 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 constinutively 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 senstivie channels
**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).
**These are through g-protein which activate Phosphorlipase 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 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.
*Our low is 20 kHz and high is 200 hz.
**The cochlea is importnat for low and the helic? is for high.
*There is a narrow membrane at the base but narrow at the apex (helic?).
 What?  Something about the two membranes being opposite...
*Place coding is the specific area of th emembrane that vibrates given the frequency of a sound wave.
*There are three important parts:
**The scalar media contains endolymnph which is rich in K+ (125 miliMolar).  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.

===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 depolarziaed, the outer cells contract and the change of physiologicl 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.

===Skin===
*We have several types of mechanically sensitive structures in our skin.
 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 oniono 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
**And locations 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).
*Mechanisms are as follows:
**P2x mechanism:
***An ATP dependent mechanism
***Nail in a hand causes cell damage.
***ATP is released
***ATP sensitive p2x anatropic channels are on the neurve 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
***back fibers (nuclei are in a specific location)
**have a spiral shaped terminals on the chain or back fibers
**When stretched, non-selective cation channels are activated which causes depolarization, vgna channels, AP
*Muscle spindles are slow adopters 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 efferten ("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 witht he extrafusal muscles.
*There are collagen fibers squish the free nerve endings sucht aht the stretch receptors are activated, vgna channels are activated, and an AP is fired.

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

===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.