"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. 23.10 B
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. 24.3 (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. 24.4 (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. 24.5 B
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. 24.8
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
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
(1) depression of responses during tetany in muscle cell; and
(2) post-tetanic potentiation.

Fig. 8.3 A
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
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
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
There is also sensitization another nonassociative learning

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

Fig. 8.5 B
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
(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
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
train of stimuli make response to another bigger while in another (control) pathway, the synaptic efficiency is unchanged

Fig. 8.10
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
Epilepsy is a syndrome of sensitized excitation

Cerebellum

Fig. 19.10B
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
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 - 2007 relating to this outline

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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