The molecules of memory

Moleküle des Gedächtnis
Moleküle der Erinnerung

In former times researchers believed that memories could be stored in single molecules. Thanks to a huge sea snail, they now know that thousands of molecules are involved.

Scientific support: Prof. Dr. Hans J. Markowitsch

Published: 27.07.2018

At a glance
  • The sea snail Aplysia possesses a small number of very large neurons, making it an important model organism for research into the molecular mechanisms of learning.
  • Research focuses on the animal's gill retraction reflex, which can decrease (habituation), increase (sensitization) or increase over the long-term (conditioning).
  • The basis of these changes is the coordination of various molecules in nerve cells and transmitters in the synaptic gap
  • Eric Kandel was awarded the Nobel Prize for research into this topic
The NMDA protein

NMDA is a complex of proteins which form a channel in the membranes of nerve cells through which calcium ions can enter the cell. In quiet phases, the channel is blocked by a magnesium ion. It only opens through the simultaneous occurrence of two events: the messenger substance glutamate must bind to the NMDA complex, which "unlocks" the channel, and the nerve cell must be electrically stimulated. Under these conditions calcium can flow into the cell and set off a cascade that ultimately reinforces the passage of information through a synapse. This permits the establishment of a connection between two events: the experience that led to the electrical stimulation, and the subsequent response that glutamate evokes in another neuron.

 

The title was provocative: "Memory transfer through cannibalism in flatworms." The paper, which appeared in 1962 in the "Journal of Neuropsychiatry," triggered a heated debate among experts. In it  James McConnell, whose work focused on memory, claimed that memories could be "eaten". His work was based on experiments in flatworms, which had been taught to flee from a source of light by association with an electric shock. He then pulverised the worms and fed them to other members of their species. He claimed that the worms placed on this diet learned to avoid the light faster than their control counterparts.

McConnell also claimed to have identified the type of molecule that preserved memory: RNAs, which are very similar to DNA and serve as a means by which genetic information in the cell nucleus is transported into the cell.

Today McConnell's work is regarded as flawed, and his idea that single molecules can store memories has been refuted. But the idea that memory must be physically stored somewhere – as a pattern within nerve cells in the brain – remains. So where are the molecules of memory?

An unusual animal

The best answer that can be given to this question today comes from research into an unusual animal: Aplysia californica, or the California sea hare. The animal in question is a sea snail that may grow to over 70 centimeters in length and a weight of over two kilograms. Researchers' interest lies in the fact that the snail has comparatively few nerve cells – only about 20,000 – and they are among the largest found in the animal kingdom.

Researcher Eric Kandel found a way to observe these neurons during the process of learning. The key to his success: a reflex involving the retraction of the snail's gills. Aplysia breathes through gills that extend from its posterior end. They are so sensitive that the snail retracts them when it senses danger – or a researcher's touch. This simple reflex allowed Kandel and his colleagues to investigate the molecular mechanisms that underlie learning – because Aplysia can be trained.

If a researcher repeatedly touches the animal, the gill retraction reflex weakens in a process called habituation. Kandel and other scientists demonstrated that a simple mechanism underlies this process. The reflex involves only two nerve cells: a sensory nerve that registers touch and passes it along to another cell – a motoneuron – that activates the muscles attached to the gill and triggers the reflex.

posterior

posterior/-/posterior

Eine Lagebezeichnung – posterior bedeutet „nach hinten, hinten gelegen“. Im Bezug auf das Nervensystem handelt es sich um eine Richtung zum Schwanz hin.

Learning at the cellular level

The point of contact between the two cells is a synapse, a location where the cells are separated by the tiniest of gaps. A signal arrives through the cell on one side of the synapse in the form of an electrical signal. This releases a large number of "bubbles" containing the messenger substance glutamate into the synaptic gap. The messengers dock onto receptors on the cell on the other side of the gap, which triggers another electrical charge. When the motoneuron fires, it activates the muscle that retracts the snail's gill.

If this reflex is triggered many times in sequence, releasing ever more glutamate into the synapse, at some point the cell has less of it to release and the signal is weaker. At the next stimulus, fewer glutamate molecules are delivered into the synaptic gap. At some point the stimulus no longer suffices to activate the motoneuron.

The mechanisms of sensitization

An opposing effect can also be observed in Aplysia. If a touch is preceded by an electrical shock to the tail, the snail draws its gills together particularly quickly and firmly, wherever it is touched afterwards. This phenomenon is known as sensitization.

This process involves a third nerve cell called an interneuron. Both it and the motoneuron are activated by the sensory neuron at the tail. The interneuron has connections to the synapses of the many sensory neurons that are linked to the motoneuron. It releases sereotonin, which is taken up by receptors on the surfaces of sensory neurons. This leads the target cells to activate a protein called adenylatcyclase, which uses adenosintriphosphate (ATP) to produce the molecule cyclic adenosinmonophosphate (cAMP). cAMP activates a further molecule, called protein kinase A (PKA), which ensures that enough bubbles containing a neurotransmitter are present at the synapse for release at the next stimulation.

If the snail is touched shortly afterwards, a particularly strong reflex is triggered. These processes govern the formation of a short-term memory in the snail. But if the second touch comes later than a second after the electrical stimulus, the reaction is normal.

cAMP

Zyklisches Adenosinmonophosphat/-/cyclic adenosine monophosphate Cyclo-AMP

Das zyklische Adenosinmonophosphat ist ein zweiter Bote, ein second Messenger in der intrazellulären Signalweiterleitung. Es dient insbesondere der Aktivierung von Proteinkinasen. Diese lösen eine Aktivierung von Enzymen und Genen aus.

Processes of learning in a sea snail

These short-term cellular processes were only the first discovery Eric Kandel and his colleagues made using the Aplysia model.  Another phenomenon, classical conditioning, permitted them to explore the development of longer-term memories as well. When an electrical shock and touch were always delivered in conjunction, and repeated several times, the snail began to draw in its gills firmly and quickly whenever it was touched. The effect lasted days, weeks, and sometimes even months – the snail had learned something.

Kandel and his colleagues pursued this process by isolating cells from Aplysia and growing them in Petri dishes. This permitted them to determine exactly what happened within cells that increased their activity: in this case as well, things began with cAMP. If enough protein kinase A molecules were activated, they entered the cell nucleus and activated another protein called CREB1.

CREB1 stimulated the activity of numerous genes and promoted the production of a range of proteins. These included neurotrophine, signaling molecules which strengthen synapses. No wonder further experiments showed that without CREB1, memory couldn't take place. The findings led to a Nobel Prize in medicine in the year 2000 for Kandel, "for his discovery that the efficiency of synapses can be altered and the molecular mechanisms responsible for this effect."

cAMP

Zyklisches Adenosinmonophosphat/-/cyclic adenosine monophosphate Cyclo-AMP

Das zyklische Adenosinmonophosphat ist ein zweiter Bote, ein second Messenger in der intrazellulären Signalweiterleitung. Es dient insbesondere der Aktivierung von Proteinkinasen. Diese lösen eine Aktivierung von Enzymen und Genen aus.

Molecule of memory

Is CREB1 "the memory molecule"? "No," replies André Fischer, a neuroscientist at the University of Göttingen. When a gene plays an important role in synapses, it is no surprise that an animal completely lacking it would not be able to learn. "But there isn't a single molecule responsible for memory," Fischer says.

NMDA, in fact, plays a role similar to that of CREB1 in the formation of memory. And Fischer and other scientists have added more molecules to the list. Most of them lead to the hereditary material stored in the cell nucleus. "It's there that specific genes are switched on for long periods, or silenced," Fischer says. This process places more or less of a particular molecule at a synapse, and makes an electrical stimulation easier or more difficult. In the final analysis, memory also involves DNA and RNA – in that regard, at least, McConnell was correct.

Veröffentlichung: am 07.09.2011
Aktualisierung: am 29.01.2018

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