Memory

• the sea slug Aplysia
• Drosophila
• mice
• ourselves,

• Short-Term Memory

  As its name suggests, this only lasts for a short period. It involves an increase in the efficiency with which nerve impulses pass across synapses. It does not require any protein synthesis or remodeling of the synapse.

• Long-Term Memory

  This lasts for a long period. It involves the formation of new synaptic connections. These require new gene expression; that is, gene transcription and protein synthesis (translation).

Sensitization

Sensitization is an increase in the response to an innocuous stimulus when that stimulus occurs after a punishing stimulus.

An example:

When the siphon of Aplysia is gently touched, the animal withdraws its gill for a brief period. However, if preceded by an electrical shock to its tail, the same gentle touch to the siphon will elicit a longer period of withdrawal.

The sensitization response to a single shock (blue bar) dies out after about an hour, and returns to baseline after a day (yellow). So it is an example of short-term memory.

However, it the animal is sensitized with multiple shocks given over several days, its subsequent response to a gentle touch on the siphon is

• much larger and
• is retained longer (tan and gray bars).

These findings are the work of Eric R. Kandel (who was awarded a Nobel Prize in 2000) and his associates. Over the years, they have worked out the neural circuitry that the sea slug uses in this response.

• a sensory neuron (green) that picks up the touch stimulus at the siphon and
• transmits it through a synapse to a motor neuron (red) that
• transmits it to the muscle of the gill.

• a sensory neuron (blue) that picks up the stimulus from the tail connecting to
• interneurons (only one shown here) that terminate on the sensory neuron in the siphon-gill pathway.

Facilitation

Short-Term Facilitation

• A single shock to the tail triggers the release of the neurotransmitter serotonin at the terminals of the interneuron.
• Serotonin binds to receptors in the cell body and terminals of the sensory neuron in the siphon-gill pathway.
• These are G-protein-coupled receptors (GPCRs) that
• activate a G protein.

  Link to detailed discussion of G proteins.

• This initiates production of adenylyl cyclase, which catalyzes the formation of the "second messenger" cyclic AMP (cAMP).
• The rise in cAMP activates a cAMP-dependent protein kinase (PKA) which
• increases the release of transmitter at its synaptic connection to the motor neurons (red arrow pointing up).

Long-Term Facilitation

• The level of cAMP in the cell body becomes still higher.
• Some of the activated PKA moves into the nucleus where it
• phosphorylates and thus activates CREB-1 (cAMP Response Element Binding protein-1) which
• binds the cAMP Response Element — a DNA sequence in the promoters of many genes whose transcription and translation produce the proteins needed for
• strengthening existing synaptic connections and forming new synaptic connections between the sensory and motor neurons in the siphon-gill pathway. (The number may be more than doubled.)

Long-Term Depression

Applying another neurotransmitter, a peptide containing 4 amino acids called FMRFa (for Phe [F], Met [M], Arg [R], Phe-NH₂) [Link to table of the abbreviations for the amino acids] to these in vitro preparations produces an opposite effect from facilitation — the synapses become less responsive.

Long-term depression also requires changes in gene expression. A different CREB, CREB-2, displaces CREB-1 from the cAMP response elements. Not only is the positive signal, CREB-1, removed, but CREB-2 actively shuts down the promoters by recruiting a histone deacetylase (HDAC) to remove acetyl groups from the nearby histones, thus preventing RNA polymerase from beginning gene transcription. [More]

Implicit Memory

These responses of Aplysia are examples of implicit memory (also called procedural memory).

They involve changes in the efficiency with which motor activities of the body are carried out in response to a stimulus.

The cerebellum plays a crucial role in implicit memory in both mice and humans.

Explicit Memory

Explicit memory (also known as declarative memory) involves recall of objects, events, etc. outside the animal's body.

An example:

If a mouse is placed in a pool of murky water, it will swim about until it finds a hidden platform to climb out on. With repetition, the mouse soon learns to locate the platform more quickly. Presumably it does so with the aid of visual cues placed around the perimeter of the pool because it cannot see or smell the platform itself.

Explicit memory is also acquired in a short-term process followed by a long-term process.

In mice (and humans) it requires the functioning of the hippocampus.

Reconsolidation

What happens when a long-term memory is recalled?

One possibility is that the stored memory remains unchanged — ready to be recalled again and again as needed (rather like a stored computer file that is copied into RAM as needed).

But this may not be what happens. There is some evidence that the very act of recalling a stored memory erases it from storage and to preserve it, it must be stored anew (rather as if a "SAVE" of an unchanged computer file actually replaced the original just as a "SAVE AS" with the same name does).

This phenomenon has been named reconsolidation.

• gene transcription (it is blocked by actinomycin D)
• mRNA translation (it is blocked by inhibitors of protein synthesis like the antibiotic anisomycin).

Some of the genes needed for consolidation — CREB, for example — are the same as those needed for the original storage of the memory.

A study (Lee, et al, Science, 7 May 2004), using rats, provides strong evidence for the need for reconsolidation of recalled memories.

• a single shock to the feet being the unconditioned stimulus (US)
• the surroundings in the chamber being the conditioned stimulus (CS)
• "freezing" — the rat stopping all motion — the conditioned (fear) response (CR)

All rats were conditioned by placing them in a chamber and giving them a single shock to their feet (the US).

24 hours later (Test 1), the rats were placed in the same chamber (the CS), but not given a shock (the US). If their long-term memory was not impaired, they froze (the CR). No matter what the treatment, all the rats froze when tested 3 hours after conditioning showing no effect on their short-term memory.

• treated with inhibitors of all gene expression (actinomycin D and anisomycin — done after Test 1)
• treated (just before Test 1) with an antisense oligodeoxynucleotide (ODN). This ODN blocked expression of the Zif268 gene; that is, prevented synthesis of the Zif268 transcription factor.

After another 24 hours, the rats were tested again (Test 2) by placing them in the same chamber (again, no shock). As the table shows, any treatment that impaired gene expression in the hippocampus caused the recalled memory to be lost between the first test and the second. But if they were not given the first test, then even though Zif268 expression had been blocked, their memory was unimpaired on the second test (bottom row).

Much research remains to be done on reconsolidation. But if the phenomenon turns out to be a general one, it may shed light on the frequent failure of humans to recall correctly events that are repeatedly dredged up from the past ("false memories").