C2006/F2402 '07 Outline for Lecture 22 -- (c) 2007 D. Mowshowitz -- Lecture updated 04/18/07.
Handouts: 22B (bottom) Circuits 22B (top) CNS/PNS , 22A PNS On line handouts have some features not on class handouts & are lacking diagram of summation. Extra copies of class handouts are in boxes outside Dr. M's office; 7th floor Mudd.
Note on refractory periods: As Dr. F said, there is some disagreement between authorities on the timing of the refractory periods. According to some, the absolute refractory period coincides more or less with the spike; the relative refractory period follows after the spike. All agree about the underlying mechanism. The absolute refractory period corresponds to the time when the Na+ channels are inactivated (so depolarization is not possible). The relative refractory period corresponds to the time when the Na+ channels can be activated, but the voltage gated K+ channels are still open (so depolarization to threshold requires a larger stimulus).
A few Interesting links:
1991 Nobel Prize in Medicine for Patch Clamping (Neher & Sakmann)
1936 Nobel Prize in Medicine for Chemical Nature of Transmission at Synapses (Dale & Loewi)
1994 Nobel Prize in Medicine for discovery of G proteins (Gilman & Rodbell)
The famous Harvard cell video, in case you missed it before, now on youtube
Two more animations by Steve Berg: Action Potential and Voltage gated cation channel.
I. Nerve-Nerve Synapses, cont. -- What determines if a nerve impulse will be passed on to the next neuron? For nice overall pictures see Purves 44.13 (44.16) or Becker fig. 13-19 & 13-21 (9-21 & 9-23). Some of this is review, but is included for clarity.
A. Presynaptic Side -- Transmitters -- See Purves Table 44.1 & Becker fig. 13-20 (9-22).
1. One major type of transmitter per synapse (released from pre-synaptic side)
a. In CNS, many diff. transmitters. Usually amino acids or their derivatives. Major ones are glutamate (excitatory) & GABA (inhibitory).
b. In PNS usually norepinephrine (NE) or acetyl choline (AcCh).
2. One transmitter per Neuron. Usually only one major transmitter released by any neuron. Therefore one major transmitter released -- the same one -- at all synapses made by that neuron.
3. Release of Transmitter:
a. Location of Transmitter: Neurotransmitters are in vesicles
b. Trigger for release: Action potential (AP) stimulates Ca++ channel opening in plasma membrane, raising intracellular Ca++;
c. Exocytosis: High intracellular Ca++ promotes exocytosis and release of transmitter.
4. Effects of transmitter (on target) can vary. Some transmitters are always excitatory or inhibitory; other transmitters vary in effect (depends on if you have one or more type of receptor for that transmitter -- see below.)
5. Getting rid of transmitters
a. Transmitter doesn't remain in synaptic cleft for long.
b. Different methods for getting rid of dif. transmitters
(1). Diffusion away from cleft
(2). Destruction by enzymes in cleft. For ex, acetyl choline esterase (AcChE) in cleft breaks up AcCh (Choline is reused). See Purves fig.44.14 (44.15)
(3). Reuptake by transporters (secondary active transport) -- NE, serotonin removed from cleft by reuptake. (Endocytosis recovers membrane; transporters recover transmitters.)
→ more stimulation.
c. Many drugs affect release/fate of transmitters; for ex.
(1). Prozac prevents serotonin reuptake -- transmitter stays around longer
(2). Malathion (insecticide) & nerve gas block AcChEsterase → continuous stimulation → spasms
B. Post Synaptic Side -- PSP's = post synaptic potentials = small change in potential due to release of transmitter
1. Can be inhibitory (generate an IPSP) or excitatory (generate an EPSP)
a. Inhibitory -- causes hyperpolarization or stabilizes existing negative polarization due to opening of K+ or Cl- channels. Either K+ goes out or Cl- comes in.
b. Excitatory -- causes depolarization due to opening of cation channels; Na+ in>> K+ out.
c. Terminology -- a single IPSP or EPSP usually refers to the small change in potential due to release of transmitter caused by a single AP. The total PSP depends on the algebraic sum of multiple IPSP's and EPSP's as explained below.
2. Any given synapse is excitatory or inhibitory -- What determines it?
a. Receptor is crucial
(1). One type of receptor for neurotransmitter at each synapse.
(2). Receptor determines which kind of synapse it is -- excitatory or inhibitory.
(3). Same neurotransmitter can be excitatory or inhibitory at different synapses.
(4). Receptor can be
(a) ionotropic(direct) -- is itself an ion channel. Fast response; Ligand binding always opens channel.
(b) metabotropic (indirect) -- uses GPCR & 2nd messenger Response is slower, but effects can be more varied & more extensive. Can be used to open or close ion channels.
b. Overall: One receptor/neurotransmitter pair per synapse. (Receptors of PNS are in table below.)
3. Features of Total PSP's (To compare to AP's)
a. Total PSP's are graded -- size is proportional to stimulus (as with receptor potentials, see below). Size is not all or none. (Unlike action potentials.)
b. PSP's are local -- die out if don't reach threshold. (Not regenerated like AP's.)
c. PSP's are caused by opening/closing of ligand gated channels. (What kind of channel is needed for AP's?)
To review IPSP's and EPSP's try problem 8-10.
C. Post Synaptic Side -- Summation -- See Purves fig. 44.15 (44.17) or Becker 13-24 (9-26 & 9-27).
→ AP. See handout 22A, bottom.
1. Inputs (IPSP's & EPSP's) to cell body/dendrites are summed -- changes spread around cell body to initial segment (or die out).
2. No AP in cell body. No voltage gated channels in cell body so no AP generated there
3. Axon Hillock. Voltage gated channels begin at initial segment (also called the "trigger zone" or axon hillock) so AP starts there. See Becker fig. 13-14 (9-16) or Purves 44.15 ( 44.17).
4. Inputs summed over space and/or time -- need to depolarize past threshold at axon hillock to
a. Spatial summation: Multiple EPSP's delivered at different spots can add up → AP
b. Temporal summation: Multiple EPSP's delivered close enough together in time can add up → AP
c. Why you need summation:
(1). A single EPSP is not enough to → AP
(2). IPSP's & EPSP's are summed: net effect depends on both inhibitory and excitatory input. Remember there are about 1000 synapses (inputs) on body & dendrites of average neuron. See Becker fig. 13-24 (9-27). (See circuits below for how you use this.)
Review Problem 8-8, parts A to H, and recitation problem 11-1.
II. Sensors Purves has a whole chapter on Sensory Systems. (Chapter # depends on which edition of the text you have.) Only a few general principles discussed here. See Purves for examples & details.
A. The Problem: How does a small stimulus (from the environment) reach the nervous system?
1. The Question: Where does input come from, if not from another neuron? How do you get input from the environment -- from sight, sound, etc. -- and send it to the CNS?
2. The Short Ans: Touch, hearing, etc., produce a small response = change in polarization by opening/closing channels in special cells (receptor cells or sensors). The small change in polarization opens voltage gated channels which generates a big response -- an AP. (The 'big bang' or the 'toilet flush,' so to speak.) See left-most case on the 'big bang' handout.
B. Receptor Proteins
1. Special (Sensory) cells contain receptor proteins for stimuli (pressure, light, heat, chemicals, etc.).
2. How do protein receptors detect stimuli?
a. Stimuli → Change in conformation of receptor → open or close channels in membrane → change in polarization of membrane.
b. How are channels opened or closed? See Purves 45.1.
(1) Directly -- receptor is part of a channel = an ionotropic receptor. Examples: receptors for mechanical stimuli (touch, hearing, balance), & temperature (heat/cold). Receptor changes shape and channel opens.
(2) Indirectly -- receptor is not part of a channel = a metabotropic receptor. Change in conformation of receptor activates a G protein. G protein or 2nd messenger opens/closes channel. Examples: receptors for chemicals (taste, smell, etc.), electromagnetic radiation (vision).
C. Receptor Potentials
1. Response to stimulus is graded. Stimulus → local graded response. The more stimulus, the more channels open (or close), and the bigger the graded potential (bigger depolarization or bigger hyperpolarization) in the sensory/receptor cell.
2. Terminology -- graded response in receptor/sensory cell is called a generator potential or receptor potential.
D. Receptor Cells. Two types of Sensory Cells (aka receptor cells) = special cells with molecular receptors for detecting stimuli
1. Modified neuron -- sensory cell is a modified neuron capable of generating AP itself. (See Purves 45.2 & below for an example.)
2. Cell that cannot generate an AP itself
a. How get an AP? Sensory cell releases transmitter and triggers AP in next cell (a neuron). See Purves 45.5 for an example.
b. Type of cell. This type of sensory cell can be a modified neuron or epithelial cell.
Question to ask yourself: What type of channels does a cell need in order to generate an AP?
E. How Does Graded response generate an AP? -- Note there are two issues here: How many cells? (Either one or two) and whether receptor is ionotropic (direct) or metabotropic (indirect). See Purves 45.2.(6th ed. only) for 1 vs. 2 cell system.
1. AP is in modified neuron -- one cell system. Graded potential (generator potential*) triggers AP in same cell (if stimulus is over threshold) → input to CNS.
a. Example #1 -- direct (ionotropic receptor) -- stretch. Purves 45.2 (7th ed.) for example.
Stimulus = stretch on nerve endings → open channels → depolarize to threshhold → AP (in sensor cell itself).
b. Example #2 -- indirect (metabotropic receptor) -- smell (olfaction).
Stimulus = Ligand (odorant) → Receptor → G protein → adenyl cyclase → cAMP up → open cation channel (cyclic nucleotide gated channel) → depolarize cell → AP.
Question: Where will the action potential start? In what part of the cell? See Purves 45.2 (45.3)
2. AP is in separate (post-synaptic) cell -- two cell system
a. Graded potential (receptor potential*) triggers release/inhibition of transmitter by receptor/sensory cell.
b. Amount of transmitter released by sensory cell is proportional to stimulus.
c. Transmitter generates IPSP or EPSP in neuron (next cell = post synaptic cell).
d. Transmitter triggers AP in post synaptic neuron if stimulus is over threshold → input to CNS.
e. Examples: vision, taste, balance, hearing.
* In older editions of Purves, the terms "generator potential" and "receptor potential" are used to refer to these two different cases respectively. Most texts stick to "receptor potential" or use the two terms interchangeably.
Which type of receptor cell are you dealing with in problem 8-16?
E. All stimuli (whatever the modality) give same message to CNS (= AP's). If AP is all or nothing, how do you know which stimulus it was? And how much?
1. Number, frequency of AP's indicate length (duration) and strength (intensity) of stimulus.
2. Wiring (what part of brain is stimulated) = labeled lines = indicates location of stimulus and type (modality) of stimulus -- taste, stretch, etc. If you get a punch in the eye, you set off light receptors. For a less violent example, take a very sharp pencil and tap your upper lip. What sensors did you trip off?
To review sensors, try Problem 8-16 . To review electrical communication overall, try 8-15.
III. Circuits -- how nervous system is organized
A. Simple circuits -- see handout 22B, bottom or Purves 46.3 (46.4)
1. One synapse, 2 neurons -- monosynaptic circuit -- how sensory neuron signals an effector.
2. Circuit with multiple synapses -- how antagonistic muscles are controlled. (Signal to skeletal muscle is always +; + = signal to contract; no signal = relax.)
3. Role of brain -- adds up/down (as vs. in/out) component
4. FYI: Where is all this located? see Purves 46.3 (46.4); will not be discussed in class.
B. How is NS organized overall? See handout 22 B, Becker 13-1 (9-1) or Purves 46.1 (46.2)
a. CNS = brain + spinal cord
b. Interneurons. Most neurons of CNS are interneurons (99%)
c. White matter = axons
d. Grey matter = cell bodies, interneurons, and dendrites
2. PNS -- Names of Divisons
a. Afferent vs Efferent.
(1) Afferent = carrying info into the CNS
(2) Efferent = carrying info away from the CNS
b. Efferent subdivided into: Somatic vs autonomic
(1) Somatic = controls skeletal muscle
(2). Autonomic = controls everything else
c. Autonomic subdivided into: Parasympathetic (PS) vs Sympathetic (S)
Try problem 8-8, part I.
C. How do PS and S co-operate? (See Purves 46.10 (46.11)) What do they do?
1. What do they innervate?
a. Many organs innervated by both
b. Some organs innervated (stimulated) by only one
(1). liver, sweat glands -- S only
(2). tears -- PS only
2. What results does stimulation produce?
a. Not always S excites; PS inhibits. Ex: salivation -- S inhibits; PS excites
(1). S → response needed in a crisis
(2). PS → response needed in relaxed state.
(1). S → heart rate up; liver releases glucose; bladder relaxes (to hold more);
(2). PS → heart rate down, digestion, salivation up.
d. Stress Response -- A response co-coordinated by both the nervous and hormonal systems. All nerves involved in stress response (and adrenal medulla) are part of sympathetic division. (We'll go over it next time.)
D. General Set up of wiring of efferent PNS -- see handout 22A
1. First neuron -- same in Somatic and Autonomic.
a. Location -- body in CNS
b. Neurotransmitter -- releases AcCh
c. Receptor -- AcCh receptor (on effector/next neuron) is nicotinic
2. Second neuron (post ganglionic) -- found in autonomic only
a. Location -- Body in ganglion
(1). Parasympathetic -- releases AcCh
(2). Sympathetic -- usually releases NE
c. Receptor (on effector)
(1). AcCh (cholinergic) receptor is muscarinic;
(2). NE (adrenergic) receptor can be alpha or beta (see table below)
d. Adrenal medulla ≡ second neuron. Medulla composed of many neurons with short axons. Release neurotransmitter (mostly E) from end of short axons (within medulla). E goes into blood, so E acts as neuroendocrine instead of neurotransmitter.
Try problem 8-8 part J.
E. Receptors in the PNS -- Reference & summary
→ open or close ion channels or have other effects (i.e. act like hormones); relatively slow. See Purves 44.16 (44.18)
1. Reminder: Response to a particular transmitter depends on receptor as with hormones.
2. Receptors can be direct or indirect (as with hormones or sensory receptors)
a. Direct or ionotropic: Receptors (for transmitters) are ligand-gated ion channels; relatively fast. For examples see Purves 44.17 (44.19) or Becker 13-23 (9-25). Also see many pictures in both books of neuromuscular junction, or handout 19.
b. Indirect or metabotropic: Receptors are coupled to G proteins, generate 2nd messengers
3. Agonists and antagonists used as common tools to study receptors, as with hormones. Some receptors named by their most common agonist or antagonist -- see table below.
4. Examples -- Major types of receptors in the PNS
Basic Type of Receptor
Detailed Type of Receptor
Direct (It's a Na+/K+ channel)
Contract skeletal muscle
Indirect; 2nd messenger & effect varies
Toxin from Amanita muscara (muscarine)
Slow heart beat
Epinephrine (adrenalin) & NE; NE> E
Indirect; 2nd messenger & effect varies
Contract smooth muscle
Epi. & NE; E> NE
Indirect; cAMP is 2nd messenger
Relax smooth muscle (bronchodilates); increase heart beat
*Both alpha and beta have subtypes that differ in location, mechanism & effect; same receptors used for epinephrine acting as a hormone or neurotransmitter. (See also table at end of lecture 12.)
** This is the receptor at the neuromuscular junction. See Becker fig. 13-23 (9-25). This is the AcCh receptor people mean when they talk about "THE" acetyl choline receptor.
Look at problem 8-16, part C. Assume you are looking at a standard synapse between two nerves that uses AcCh as a transmitter. What are the answers to parts 1-5? What effects will you expect on transmission at a standard synapse? (Note -- this problem as written does not refer to a standard synapse between two nerves. However the answers in the back of the book are still okay except for part 4. What is the right answer to part 4 for a standard synapse?)
F. PS vs S -- factors to compare and contrast (see handouts and Purves fig. 46.10 (46.11))
1. Where are ganglia? Near spinal cord or target organs?
2. Where are bodies in CNS = where in spinal cord/brain stem do axons of first neuron come from? (FYI only -- see Purves 46.10.)
3. What type of synapse with effector? Cholinergic or adrenergic?
4. General effect -- stress or relaxation?
To review the organization of the nervous system, try Problems 8-12 to 8-14. By now you should be able to do all the problems in problem set 8.
Next time: How do nerves and muscles work to give contractions?