Since the mid- sixties of the 20th Century dealt the American neurobiologist Eric Kandel, together with colleagues at New York University first, and later at Columbia University on the molecular mechanisms of memory formation in the plane of the nerve cells (neurons). Kandel was born in Austria and spent his first 11 years in Vienna, but had to with his parents and siblings before the Persecution of the Jews by the Nazis to America to escape. After a psychiatric and psychoanalytic training he finally turned to the biological neuroscience.
Prof. Eric Kandel and his wife, Denise Source: to come http://www.swedenabroad.com/
order the events in memory formation on the track is selected Kandel an experimental animal with a simple and therefore clear nervous system, the marine snail Aplysia californica (California sea hare). Aplysia has only 20,000 neurons, which is a really much better point of departure for studies in humans than, for example, whose brain alone contains about 100 billion neurons. The neurons in Aplysia are also much larger, so that electrical measurements it much easier.
Aplysia californica (California sea hare) Source: Wikipedia
Aplysia thus has a simple nervous system with strickleiterartigem construction and 5 pairs of nerve cell clusters (ganglia). A brain, so a central ganglion, which clearly surpasses the others in size is missing. In spite of all this is Aplysia amazing ability to learn and so all in all, an almost ideal laboratory animal for memory research.
Anatomy of Aplysia californica Source: http://www.geochembio.com/
Aplysia dominated three types of learning: habituation, sensitization and classical conditioning.
In habituation refers to the ability of an organism adjusting to a repeatedly presented clearly harmless stimulus and to ignore him then.
sensitization is the exact opposite. As the stimulus is repeated Helping recogni as dangerous or at least unpleasant, the reaction is increasingly stronger. In classical conditioning a neutral stimulus itself follows directly behind an unpleasant stimulus, which both Stimuli are associative. Finally, the organism responds to the previously neutral stimulus (almost) as well as on the unpleasant stimulus.
Kandel was limited in the investigation derLernvorgänge in the Aplysia gill retraction reflex, which runs through the back Addominalganglienpaar. Touching the breathing tube (siphon), the animal usually moves its gills (gill) in order to protect them. Repeated weak contact leads to habituation. A strong electrical stimulation of the tail (tail) or head (head) off after several repetitions of an increased gill retraction reflex, thus leads to sensitization.
Also a classical conditioning is possible by directly administered after a light and harmless touching the siphon a severe electric shock.
Aplysia reserves to keep what they have learned first few minutes (short-term memory). Through repeated learning sessions, but also by a series of particularly strong stimuli can be achieved, however, a long-term memory of several weeks.
Kandel now analyzed more precisely what happens to the nerve cells in these simple learning procedures. He turned his attention to the transmission of the sensory to motor neurons, which stimulate the gills, after all muscle.
A sensitization is triggered by a painful electric shock on the tail of Aplysia. This is the sensory neuron activates 2 This in turn activates an interneuron activated, then the reflex of the siphon, on the sensory neuron 1 and motor neuron increased the gill muscle. Source: Kandel, Schwartz and Jessell Principles of Neural Science. New York: McGraw-Hill (2000).
The key changes to run at the contact points (synapses) from between the sensory neuron and motor neuron of the gill muscle. Play the neurotransmitter serotonin neurons and their crucial role.
When short-term memory, only the synaptic transmission improved without the structural changes at synapses place itself:
short-term memory: Serotonin (5-hydroxy-tryptamine or 5-HT), the neurotransmitter of interneurons binds to its receptors on synapses of the sensory neuron first Through several intermediate steps (G-protein, adenylyl cyclase) is increased cAMP formed and the enzyme protein kinase wiedrum about A (PKA) is activated. PKA phosphorylated together with other protein kinases, potassium channels, so that they join, thus ensuring a prolonged action potential with increased calcium influx. The calcium influx is also a result of phosphorylation of calcium channels by protein kinase C (PKC) arrangements. As a result, more vesicles with the neurotransmitter glutamate are mobilized, leading to increased gill retraction reflex. Source: http://www.unmc.edu/physiology/Mann/
find In contrast, the long-term memory rather than structural changes. The synapses larger (more contact area) and their number are increasing. Therefore, certain structural genes turned on and a correspondingly increased biosynthesis of the structural proteins have been continued:
long-term memory: A increased secretion of serotonin interneurons leads to such a high cAMP - concentration in the sensory neuron 1 that the activated (PKA, MAPK) also migrate to the nucleus. PKA activates CREB 1, a regulatory gene that binds to the promoter (carrier) of genes for structural proteins of synapses are responsible and turn this fact. Likewise, the gene for Ubiquitinhydrolase is turned on, an enzyme, the protein kinase activity maintained. MAPK disabled CREB 2, a regulatory gene for a repressor (suppressor) which switches off the genes for the synaptic structure of proteins by binding to its promoter. The structural proteins allow an enlargement of synapses and growth of new synapses. Source: http://www.unmc.edu/physiology/Mann/
There is now a mechanism for ensuring that the structural changes only at the excited, but not at all synapses of the sensory neuron 1 . held This works because the actual biosynthesis of structural proteins only in the synapses takes place themselves and can begin there only in the presence of the neurotransmitter serotonin:
Selective Amplification: The biosynthesis of structural proteins only in the synapses for yourself. The synapses of the structural genes with the respective mRNA (messenger RNA supplied). The m-RNA, the genetic information that is transported to the synapses, but which can be read only in the presence of the active form of a specific protein, CPEB. CPEB, however, initially in an inactive form (conformation A). The neurotransmitter Seotonin but allows several intermediate steps, the formation of a small amount of active CPEB (conformation B). CPEB is a prion, ie, its active form is able to transform automatically the inactive to the active form. In this way is converted only in the synapses that bind serotonin, the inactive to the active form of CPEB and thus started the biosynthesis of structural proteins as the active CPEB yes allows a reading of the m-RNA. Source: http://www.hhmi.org/
Even in highly developed animals and humans is the formation of memory follows a similar molecular pattern as in Aplysia. Often, however, also assumes the role of the neurotransmitters dopamine, serotonin, such as the long-term spatial memory in which the hippocampus, a pair-scale structure in the two cerebral cortex participates decisively.
The memory research offers fascinating approaches to the development of drugs against the forgetfulness of age. At least in mice, it was already so successful.
mice shun bright light. If they are placed on a brightly lit from above disc, which is surrounded with 20 escape holes (sometimes 40), of which only one leads into a dark flight chamber, so they try to find the right hole. Initially at random, then in order and when it (like triangles, squares, stars, color patches) to the surrounding walls are visual cues for repetition or targeted.
Barnes maze for mice Source: http://www.jax.org/
Young mice aged 3 months to master this experiment (Barnes maze) and almost always quickly find the right escape strategy. Older mice have large but Schwierigketen. At the age of 12 months only 25% of the mice are successful, even at the age of 18 months only about 10%.
by drugs that activate dopamine receptors in the hippocampus of the mice (Dihydrexidin, SKF 81 297, to date no therapeutic significance!), It was the learning capability of the Barnes - overburdened Labyrinth older mice to increase so much that they just performed well as the very young mice. The same was also a drug, the rolipram, which inhibits the breakdown of cAMP in the synapses. In both cases, improved signal transmission and thus both Short-term and long-term memory.
For his pioneering work on the molecular mechanisms of memory Eric Kandel received the 2000 Nobel Prize in Physiology or Medicine.
Sources: Eric Kandel: In Search of Memory, Siedler Verlag, Munich 2006, Eric Kandel: Nobel Lecture ( http://nobelprize.org/nobel_prizes/medicine/laureates/2000/kandel-lecture.html ) , Michael D. Mann: The Nervous System In Action http://www.unmc.edu/physiology/Mann/
Jens Christian Heuer
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