The Molecules of Memory

While lesion studies have been useful in determining the brain structures
involved in memory, pharmacological techniques have been used to address
its underlying chemistry. Pharmacological manipulations have a long history
in memory research with animals, dating back to the early 1900’s and
the discovery of neurotransmitters. Neurotransmitters are chemical messengers
secreted by neurons and are essential to communication within the
nervous system. Each neurotransmitter, of which there are more than one
hundred, has its own specific receptor to which it can attach and alter cellular
functioning. By administering drugs that either increase or decrease the
activity of specific neurotransmitters, researchers have been able to investigate
their role in memory formation.

One neurotransmitter that has been strongly implicated in memory is
glutamate. This transmitter is found throughout the brain but is most highly
concentrated in the cerebral cortex and the hippocampus. Drugs that increase
the activity of glutamate facilitate learning and improve memory,
while drugs that reduce glutamate activity have the opposite effect. The neurotransmitter
dopamine has also been implicated in memory formation. In
small doses, drugs such as cocaine and amphetamine, which increase dopamine
activity, have been found to improve memory in both humans and
lower animals. Moderate doses of caffeine can also facilitate memory storage,
albeit by a less understood mechanism. Other neurotransmitters believed
to be involved in memory include acetylcholine, serotonin, norepinephrine,
and the endorphins.

Research with simpler organisms has been directed at understanding the
chemical events at the molecular level that may be involved in memory. One
animal in particular, the marine invertebrate Aplysia californica, has played a
pivotal role in this research. Aplysia have very simple nervous systems with
large, easily identifiable neurons and are capable of many forms of learning,
including habituation, sensitization, and classical conditioning. Canadian
psychologist Donald Hebb (1904-1985), a former student of Lashley, proposed
that memories are stored in the nervous system as a result of the strengthening of connections between neurons as a result of their repeated
activation during learning. With the Aplysia, it is possible indirectly to observe
and manipulate the connections between neurons while learning is
taking place. Eric Kandel of Columbia University has used the Aplysia as a
model system to study the molecular biology of memory for more than
thirty years. He demonstrated that when a short-term memory is formed in
the Aplysia, the connections between the neurons involved in the learning
process are strengthened by gradually coming to release more neurotransmitters,
particularly serotonin. When long-termmemories are formed,
new connections between nerve cells actually grow. With repeated disuse,
these processes appear to reverse themselves. Kandel’s work has suggested
that memory (what Lashley referred to as the engram) is represented in the
nervous system in the form of a chemical or structural change, depending
on the nature and duration of the memory itself. For these discoveries,
Kandel was awarded the Nobel Prize in 2000.

Modern genetic engineering techniques have made it possible to address
the molecular biology of memory in mammals (predominantly mice) as
well as invertebrates. Two related techniques, genetic knockouts and transgenics,
have been applied to the problem. Genetic knockouts involve removing,
or “knocking out,” a gene that produces a specific protein thought
to be involved in memory. Frequently targeted genes include those for
neurotransmitters or their receptors. Transgenics involves the insertion of a
new gene into the genome of an organism with the goal of either overproducing
a specific protein or inserting a completely foreign protein into the
animal. Neurotransmitters and their receptors are again the most frequently
targeted sites. A remarkable number of knockout mice have been
produced with a variety of short- and long-term memory deficits. In many
ways, this technique is analogous to those used in earlier brain lesion studies
but is applied at the molecular level. Dopamine, serotonin, glutamate, and
acetylcholine systems have all been implicated in memory formation as a result
of genetic knockout studies. Significantly, researchers have also been
able to improve memory in mice through genetic engineering. Transgenic
mice that overproduce glutamate receptors actually learn mazes faster and
have better retention than normal mice. It is hoped that in the future gene
therapy for human memory disorders may be developed based on this technique.
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