"Learning"

Purves et al. Chapter 24 "Modification of brain circuits as a result of experience"
and Chapter 8 "Synaptic plasticity"
(Figs from chapter 19 and 23)

Introductory remark

There was a famous textbook in the late 1940's by Donald Hebb which proposed that there were loops of neurons with excitation, "reverberating circuits," and that excitation alters synapses. Imagine looking up a phone number and repeating it in your mind until you dial the phone, but, if you use it often enough, you will remember it always (like your friend's number from when you were a kid).

Fig. 23.11, p. 526
One example involves a story from last chapter on synaptogenesis at neuromuscular junction.
Overlapping connections of multiple spinal motor neurons onto multiple muscle cells is sorted out after birth.

Development of visual connections

repeated
from Vision and the brain lecture)

Hubel & Wiesel share 1981 Nobel for "information processing in the visual sytem"

Fig. 24.4, p. 545 (not shown again)
If a radioactive amino acid is injected into one eye, labeled proteins cross synapses at LGN and mark ocular dominance columns in cortex; this is detected by microscopic autoradiography.
Binocular cells connect up correctly at first

Fig. 24.5, p. 546 (not shown again)
Then there is a sensitive (critical) period in the first few months of life during which patterned visual input from both eyes is necessary to maintain binocular input to cortical cells.
Thus early visual defects like cataract or strabismus (cross-eyes or lazy eye) need to be corrected right away.

Here are autoradiographs. A of normal visual cortex, like Purves et al., Fig. 24.3, and B after monocular deprivation from 2 weeks to 18 months in monkey Purves et al., Fig. 24.6.

not covered before

Fig. 24.6 B, p. 547
Just 6 days of monocular deprivation right around one month of age has this effect.

There are columns early which get reinforced during early development.

Fig. 24.1, p. 538
Ocular dominance shift from deprivation sould be blocked if TTX (tetrodotoxin) were injected into the eye. In the experiment shown here, replacing activity in a synchronous way would maintain normal binocularity while asynchrouous optic nerve stimulations would let binocularity disappear. Thus alterations are activity dependent.

Fig. 24.9, p. 551
In strabismus (lack of fixation), lose binocular cells.

Recent literature
TKHensch & MPStryker, Columnar architecture sculpted by GABA circuits in developing cat visual cortex, Science 303, 1681, 2004
MFagiolini et al., Specific GABA-A circuits for visual cortical plasticity, Science 303, 1681-1683, 2004.
DFerster, Blocking plasticity in the visual cortex, Science 303, 1619-1621, 2004.
At birth, there is complete overlap, sort out in a few weeks.
Potentiating GABA inhibition with diazepam widens columns.
An agonist DMCMnarrows them.
GABA- A receptors with alpha 1, 2, and 3 subunits specifically (alpha 4 and 6 are insensitive to benzodiazepines and alpha 5 is insensitive to zolpidem, also used).

On the topic more closely related to what most people think of as learning

American Psychology dominated by Associative Learning - repeated pairings

(1) Classical conditioning
Pavlov - 1904 Nobel Prize "physiology of digestion"
UCS (e.g. food) -> UCR (salivation)
pair UCS (bell) with CS repeatedly
then CS -> CR (salivation)
(2) Instrumental conditioning from Watson's behaviorism
B. F. Skinner box response (bar press) paired with reinforcement (food, water)

Early attempts to determine cellular mechanisms of learning in mammals had problems (see memory lecture)

For that reason, some simple cellular responsivity changes which could possibly account for learning were demonstrated like:

Landmark paper
Donald Kennedy, Small systems of nerve cells, Scientific American May 1967.
Work on crayfish is in one of the early papers touting simple cell systems in invertebrates.
Kennedy has been presedent of Stanford and is now editor-in-chief of Science, the weekly journal of the AAAS (American Association for the Advancement of Science)

Aplysia

Landmark papers

ERKandel & LTauc, Heterosynaptic facilitation in neurons of the abdominal ganglion of Aplysia depilans, J. Physiol, 181, 1-27, 1965, Mechanism of heterosynaptic facilitation in the giant cell of the abdominal ganglion of Aplysia depilans. J Physiol 181, 28-47, 1965. (see also J NIH Res 2, 63-72, 1990).

Fig. 8.2, p. 165
(1) depression of responses during tetany in muscle cell; and
(2) post-tetanic potentiation.

Fig. 8.3 A, p. 166
Studies of Aplysia (a mollusc) by Kandel (Nobel in 2000)
Aplysia - habituation - nonassociative learning

Personal reflection - I was an undergrad student at Columbia College in New York when my physiology professor said "Come on with me, there's a neat seminar," when Kandel was new at Columbia.

Fig. 8.3 B, p. 166
The nice thing is that there are big identified cells.
(Recall that invertebrate neurons are on the outside of neuropil [where synapses are made].)

Fig. 8.3 C, p. 166
Lots of work in the 1960's to 1970's - habituation of gill withdrawal reflex
Habituation is a diminution in the response after repeated stimulus administrations which is not attributable to sensory adaptation or muscle fatigue.
It is one (motor neuron L7) synapse.
EPSP gets smaller - modification is at presynaptic level - Ca2+ channels less effective.

Fig. 8.4 AB, p. 168
There is also sensitization another nonassociative learning

Fig. 8.5 A, p. 169
short term sensitization
serotonin-induced enhancement of glutamate release
5HT -> cAMP -> PKA -> close K+ channel -> C2+ influx -> transmitter release

Fig. 8.5 B, p. 169
long term sensitization
CREB - cAMP response element binding protein, turn genes on
ubiquitin hydrolase break down PKA regulatory subunit, persistent activation
In Chemistry, Ciechanover, Hershko and Rose won 2004 Nobel for ubiquitin
(There are 2 main pathways in intracellular degradation, lysosomes and proteosomes, the latter involving ubiquitin.)
Several of biology"s new faculty are interested in ubiquitinization (Wang, Downes)

There is also classical conditioning in Aplysia, mechanism not shown.

Drosophila

Fig. Box 8A, p. 170
(Earlier, there had been some shoddy work on learning, so researchers had to be more careful with controls [for sensitization], but it became clear Drosophila could be trained to avoid odors associated with shock.)
mutants Benzer and Quinn work in 1970's all involve cAMP
dunce - phosphodiesterase
rutabaga - adenylyl cyclase
amnesiac - peptide transmitter that stimulates adenylyl cyclase

Summary

Learning and memory are very complex
so simple "learning" and simple preparations predominate
but parts of the brain can be simple, if studied for simple "learning"

Hippocampus

Landmark paper

TVPBliss & TLomo, Long-lasting potentiation of synaptic transmission in the dentate area of the anesthetized rabbit following stimulation of the perforant path, J Physiol 232, 331, 1973 (see also J NIH Res 7, 59-67, 1995).

The hippocampus is involved in spatial learning (and lots of other things)

Brain slice technique
Cells can be reached by thin brain slice to keep metabolism (oxygen, nutrients) while having enough thickness (0.5 mm) to still have wiring

Fig. 8.6, p. 171
hippocampus is rather a simple neural circuit
Hippocampus anatomy: CA1 CA3 & Dentate gyrus
Long term potentiation is a simple form of learning
Input specific long-term potentiation (LTP) can last weeks
Perforant pathway (from entorhinal cortex) -> granule cell (mossy fibers) -> CA3 pyramidal cell (Schaffer collaterals) -> CA1 pyramidal cell

Fig. 8.7ABC, p. 172
train of stimuli make response to another bigger while in another (control) pathway, the synaptic efficiency is unchanged

Fig. 8.10, p. 174
NMDA receptor important, rise in Ca2+ is important, the same mechanisms of Mg2+ expulsion and spiral of ligand, voltage and C2+ activation which can lead to excitotoxicity is responsible for long lasting excitation

Box 8C, pp. 182-183
Epilepsy is a syndrome of sensitized excitation

Cerebellum

Fig. 19.9B, p. 424
recall simple wiring of few cell types in cerebellum from motor lectures
Purkinje cells use GABA for inhibitory output
climbing fiber from inferior olive makes big EPSP in Purkinje cell
yet many parallel fibers contact Purkinje cell each with one contact

Fig. 8.16BCD, p. 180
describes LTD (long term depression)
two synaptic activations must come at about the same time
decrease in effectiveness of glutamate AMPA receptor

(LTD was first mentioned on the second messenger system outline)

Exam questions from 2005 - 2012 relating to this outline

Learning with electrical stimulation of the brain -- Say something about the more traditional situation for this kind of learning (e.g. what that kind of learning is called, the nature of the behavior, example reinforcements).

operant condition, bar press, water or food if water- or food-deprived

You are studying habituation as a model of learning. Convince us that the phenomenon is habituation instead of sensory adaptation or muscle fatigue.

you would need to show that it is a change in a synapse, like change of EPSP strength

The fruit fly Drosophila is given electrical shock repeatedly in the presence of a specific odor, and it learns to avoid the area where that odor is present. Eventually, it was found that the cAMP signal transduction pathway was important in this learning. What strategy allowed them to make this conclusion?

obtain mutants with learning defects

"After a train of stimuli to axons of CA3 pyramidal axons (Schaffer collaterals) the response of the postsynaptic cell (CA1 pyramidal neuron) is larger." Answer either (1) What is this simple kind of learning called? or (2) What part of the brain was being studied?

long term (lasting) potentiation, hippocampus

If excitation of the climbing fiber and the parallel fiber are paired, there is a decrease in the effectiveness of the glutaminergic AMPA receptor. Answer either (1) What is the postsynaptic cell? or (2) What is this simple model of learning called?

purkinje cell, long term depression

What is the modification of PKA that characterizes the difference between short term sensitization and long term sensitization?

ubiquitin hydrolase breaks down regulatory (inhibitory) subunits, making the activation persistent.

What is the difference at birth vs. at maturity of how many spinal motor neurons can innervate one end plate?

at maturity, only one, more earlier

Long-term-potentiation is a synaptic model for learning. What is the analogous model for change in efficiency of transmission at the neuromuscular junction?

post-tetanic potentiation

"Pairing parallel and climbing fiber activations cause AMPA receptors to be internalized (from the post-synaptic membrane into intracellular vesicles)." Answer either (1) On what cell? Or (2) What is this model of learning called?

Purkinje cell, long term depression

"Potentiating GABA inhibition with diazepam widens columns." Why was this statement offered in the context of cellular bases of learning?

applies to the (re) establishment of ocular dominance columns

After half an hour in a dark room, you are much more sensitive. After a prolonged forceful muscle contraction, that contraction becomes weaker. Why is Kandel's work on habituation of the gill withdrawal reflex considered a model of learning while the other two examples are not?

at a synapse, not receptor adaptation or motor fatigue

How was ubiquitin hydrolase shown to be relevant in long-term sensitization?

breaking down inhibitory subunits activates PKA long term

Using Diazepam, how was GABA implicated in visual experience and cortical connectivity?

GABA-A receptors needed for developmental maintenance in visual experience, diazepam blocks

"Habituation of the gill withdrawal reflex in Aplysia:" What aspect of this work shows that it is not receptor adaptation or muscle fatigue?

it is at a synapse, not receptor or muscle

Classical (Pavlovian) and operant conditioning are referred to as "associative learning." What are the properties of the performance of a rat in a Skinner box that qualify it as "associative learning?"

repeated pairings of reinforcement with bar press

With the help of the ubiquitin system, how is long term sensitization achieved via PKA?

the inhibitory subunits are gone long term

A Schaffer collateral is stimulated to "tetanus" to show long term potentiation at the synapse with a CA1 pyramidal neuron. What is the control for this experiment?

another collateral is not prestimulated but it is tested (and shows no LTP)

"Hold that thought." How did Donald Hebb propose that was achieved in the 1940s?
 
reverberating circuits of neurons with excitatory connections with each other
 
Why would a congenital cataract in one eye need to be treated quickly?
 
Appropriate development/maintenance of binocularly innervated cells in the visual cortex requires patterned vision from both eyes
 
Food can be repeatedly paired in classical and instrumental conditioning. How does the presentation of food differ in these two models of associative learning?
 
Classical, food is unconditioned stimulus paired with conditioning stimulus (bell), instrumental (operant) food is positive reinforcing stimulus paired with behavior (bar press)
 
Why is habituation of the gill withdrawal considered to be a simple model of learning instead of sensory adaptation or muscle fatigue?
 
It is change in synapse, not sensory receptor or muscle
 
In the difference between the shortest term "learning" and long term sensitization in Aplysia, why was ubiquitin hydrolase found to be useful?
 
Mediates longer term activation of PKA by targeting the inhibitory subunits for degradation
 
In a study of long term potentiation, a Schaffer collateral is stimulated repeatedly while recording from a CA1 pyramidal cell. Answer either (1) What changes? Or (2) What is the control?
 
The response of the CA1 cell gets bigger, but not for stimulation of another collatoral that had not been repeatedly stimulated
 
In a study of long term depression in Purkinje cells, how is the sensitivity of AMPA receptors decreased?
 
Receptors got internalized (pulled from membrane)

Even though it has been over 50 years since his famous textbook, Donald Hebb is still mentioned frequently in neuroscience. In what context?

reverberating circuits of excitation for short term memory

How does transcription of ubiquitin hydrolase promote long term sensitization?

breaks down regulatory (inhibitory) subunits of PKA

Why has the brain slice technique proved useful in studies of long term potentiation in the hippocampus?

enough neural circuitry remains, yet neurons can be reached by electrodes

In addition to Na+, what ion is expecially important in the signal transduction cascade from the NMDA receptor to long term potentiation?

Ca2+

What is the output neuron of the cerebellar cortex?

Purkinje

Habituation of the gill withdrawal reflex was used by the Nobel Prize winner, Kandel, as a model of learning in what organism?

Aplysia

One question implied that the NMDA receptor is a channel. The AMPA receptor is invoked in addition to the NMDA receptor in long-term potentiation and depression.
What kind of a receptor is the AMPA receptor, and to what transmitter does it respond? (2 points)

channel, glutamate

Drosophila were shocked each time they went toward a particular odor, and mutants like dunce did poorly. What kind of learning is this?

operant

To what kind of molecule does CREB (cAMP response element binding transcription factor) bind (other than cAMP, of course)?

DNA

A difference between short- vs. long-term sensitization was the breakdown of PKA's regulatory subunit. How would this change the duration of the cellular effects?

regulatory is inhibitory so catalytic stays activated

Suturing a cat's eye closed alters the occular dominance columns. How can this be when light can still pass through the eyelids?

it deprives of patterned input

Adaptation and fatigue are decreases in responsivity at sensory and muscle levels. An analogous decrease, mediated at the synaptic level, is considered a simple type of learning. What is this called?

habituation

"EPSPs are bigger in CA1 pyramidal cells after stimulation to Schaffer collaterals." What simple type of learning is this, and in what location in the brain?

LTP long term (lasting) potentiation, hippocamus

"In summary, a cellular explanation of learning involves changes in synaptic signal transduction." Give an example from Drosophila.

dunce - phosphodiesterase, rutabaga - adenylyl cyclase, amnesiac - peptide transmitter that stimulates adenylyl cyclase

Internalization of AMPA receptors weakens the Purkinje cell's response at the parallel fiber synapse. What simple type of learning is this, and in what location in the brain?

LTD long term depression, cerebellum

What happens between birth and maturity that makes the wiring of motor neurons to striated muscle cells a model of plasticity?

muscle end plate may have more than one motor neruon connected at first, only one later

What model of learning is "a diminution in the response after repeated stimulus administrations not attributable to sensory adaptation or motor fatigue?"

habituation

By what molecular mechanism would breaking down a PKA regulatory subunit cause long term sensitization?

the catalytic subunits would be activated long term

Drosophila are shocked repeatedly in the presence of a particular odor, then they avoid that odor. What kind of learning is that?

beyond habituation and sensitization, this is associative learning (operant (instrumental) conditioning)



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