20110105 Lecture 4 notes.txt

From Iusmphysiology

Revision as of 19:32, 8 January 2011

• 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.