Partners and International Organizations
(English)
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DKFZ and EMBO Heidelberg (D), Univ. Cardiff (UK), Istituto San Raffaele Milano (I), Univ. of Manchester (UK), Univ. of Milano (I).
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Abstract
(English)
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The purpose of this European project was to generate transgenic mouse models in which the function of signalling proteins within neurons has been impaired by targeted mutations. The role of our group was (i) to evaluate whether such changes in cellular physiology are associated with changes in behavior, memory and learning, and (ii) to develop novel testing procedures. For this purpose, the animals were transferred from our partners to Switzerland. During the 30 months, we have tested a total of 3511 mice in a variety of tests. Tests included swimming navigation learning with special protocols to assess spatial memory, open-field activity and tests measuring anxiety, learning under conditions of stress and conflicts, and memory tests for fear-related cues (contextual fear conditioning). Transgenic models included targeted deletions within the RAS/GRF signalling cascade, mice with deletions of the glucocorticod receptor in the forebrain, mice lacking the neurotophin trkB receptor and various mouse mutants with differential deletions of the CREB gene, that is, the final target of the various intracellular pathways. Among the mouse models tested, the trkB deficient mice showed remarkable deficits in laboratory set-ups that suggested impaired behavioral flexibility and inability to cope with complex tasks, while simple learning paradigms were mastered by these animals. More subtle effects were noted for the RAS related signalling proteins ERK and SOS/RAS, while the GR deficient mice showed little changes in memory and learning. GDI1 deficient mice exhibited inappropriate social behavior in aggression tests. Somewhat surprisingly, hippocampus-specific inactivation of the CREB gene did not affect performance of standard tasks measuring hippocampal function but showed remarkable deficits in conditioned taste aversion. The latter finding implies that the role of CREB for memory and learning functions in the mammalian brain needs to be re-assessed.
REPORT
In addition to routine testing mentioned in the abstract, new tests were implemented such as social transmission of food preferences, conditioned taste aversion learning, trace fear conditioning, discrimination learning with modality shifts, novel object exploration, and various smaller tests to assess neurological deficits. A completely novel test under development is learning under natural conditions. Eight computer-controlled feeder boxes were placed in a large outdoor pen populated with trkB deficient mice. The animals had to learn to find new locations for food, and to visit these places in a given order. A central computer registered visits of transponder-tagged continuously during 30 days and evaluated the search pattern and success of the mice. It was found that the mutant mice learned the locations as fast as littermate control mice, but they were unable to switch to other behavioral strategies. These studies led to the design of a novel in-cage learning system for mice, INTELLICAGE. Up to sixteen transponder-tagged mice living in a large rat cage where they are continuously tested for various forms of learning. A small computer in the laboratory controls simultaneously up to 8 cages, that is up to 128 mice. This new system will eventually permit efficient screening for memory and learning deficits in the rapidly growing number of genetic mouse models.
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