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Freie Universität Berlin Charité University Medicine Berlin Humboldt University Berlin Max-Delbrück-Center for Molecular Medicine, Berlin-Buch |
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Freie Universität Berlin Charité University Medicine Berlin Humboldt University Berlin Max-Delbrück-Center for Molecular Medicine, Berlin-Buch |
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GRK 1123: |
Cellular Mechanisms of Learning and Memory Consolidation |
This Research Training Group is funded by the German Research Council DFG
| AG Ahnert-Hilger | AG Behr | AG Braunewell | AG Haucke | AG Heinemann |
| AG Kempermann | AG Kempter/Schmitz | AG Kuhl | AG Multhaup | AG Nitsch |
Prof. Dr. Uwe Heinemann
Institut für Neurophysiologie
Charité Universitätsmedizin Berlin
Tucholskystr. 2
10117 Berlin
uwe.heinemann@charite.de
Title
Role of sharp wave ripple complexes and activation of the EC layer III pathway in memory consolidation.
Question of the projectWe are interested in understanding processes which lead to consolidation of memory in normal and disease affected brain structures using models of temporal lobe epilepsy.
Scientific backgroundInitial memory formation leaves labile traces in the brain that only develop into stable memories through a series of dynamic changes known as memory consolidation (Squire and Alvarez, 1995) . Memory consolidation may depend on frequent recall of stored information or depend on reactivation of hippocampal ensembles of neurons off-line, for example, during sleep (Buzsaki, 1989) . This is likely dependent on synchronized firing of relevant neurons during specific rhythmic oscillatory patterns (Buzsaki, 1998) . During slow wave sleep and relaxed resting states sharp wave ripple complexes were observed which consist of about 40 ms long field potential transients superimposed by high frequency (~ 200 Hz) population spikes (Chrobak et al., 2000; Csicsvari et al., 1999) . Synchronization of involved cells is in part mediated by gap junctions, presumably at axonal compartments (Draguhn et al., 1998; Schmitz et al., 2001) . Up to now however it is unclear whether stimuli, which induce LTP, can also induce sharp wave ripple complexes. The second pattern of synchronized neuronal activity occurs during REM sleep. In this condition neuronal activity patterns generated for example during exploration of a new environment are replayed superimposed on similar rhythmic network activity, as observed during explorative behavior. This network activity is characterized by gamma oscillations superimposed on theta oscillations (Wilson, 2002) . The gamma oscillations are dependent on synchronized activity in interneuron networks partially mediated by cholinergic or gluatamatergic activation, mutual inhibitory interaction and partially dependent on electrical coupling. The increase of knowledge of these mechanisms permits now to interfere with the underlying mechanisms either by use of transgenic animals or by use of specific pharmacological agents and transfer of this knowledge to studies in vivo and into models of temporal lobe epilepsy
Previous work of the group in the field
We have developed a combined entorhinal cortex hippocampal slice preparation which we have used to characterize the properties of different neurons in the peri-rhinal cortex and entorhinal cortex and of interneurones in the hippocampus including studies on network oscillations under physiological and pathophysiological conditions. By retrograde staining we could identify properties of projection cells in the EC (Gloveli et al., 2001) and by use of EGFP expressing mice under the parvalbumine promoter we characterize interneurones in these structures and their involvement in different network oscillations ( Schreiber et al., 2004) . These studies revealed that EC layer III cells possess low pass filter properties wwhich are latered in epilepsy (Gloveli et al., 1997; Gloveli et al., 2003) . These cells project to the subiculum and area CA1 where they activate prominently inhibitory interneurones and drive only a small number of select pyramidal cells (Empson and Heinemann, 1995) . Surprisingly repetitive low frequency stimulation of this pathway which is involved in recall of stored information causes heterosynaptic LTP in the commissural associational pathway of area CA1 and thereby could contribute to memory consolidation (Wöhrl et al, submitted).
We subsequently studied different forms of gamma oscillations and found that two distinct rhythm generators are available in the hippocampus (Stenkamp et al., 2001;Poschel et al., 2002;Weiss et al., 2003) . Asynchroneous stimulation during carbachol induced gamma oscillations seemed to induce LTD (van den Boom, in prep). We now developed a method to stimulate in phase and therefore can test whether such stimulation induces LTP.
During studies on plasticity of stimulus induced gamma oscillations we discovered that repeated application of stimulus series which normally induce LTP could also induce sharp wave ripple complexes with properties similar to those of spontaneous sharp wave ripple complexes (Behrens et al, submitted). It is unclear, however, whether other protocols used for induction of LTP can also induce sharp wave ripple complexes and whether these findings can be reproduced in vivo.
From April 1st, 2004 Livia de Hoz from the lab of R. Morris and E. Woods will join our lab. She is trained in behavioral analysis and also in tetrode recordings in freely moving rats (de Hoz et al., 2003;Riedel et al., 1999) . She has observed that place cell activation patterns change after a consolidation period. Interfering with mechanisms involved in gamma oscillations and in generation of sharp wave ripple complexes will now permit to test the significance of such mechanisms for memory consolidation and to verify whether mechanisms studied under in vitro conditions can be expanded to in vivo investigations.
Goals
We will test the hypothesis that reverberating activation of the EC layer III CA1 pathwayand of phase synchroneous stimulation during network oscillation can augment LTP, and that repeated application of protocols inducing LTP can induce sharp wave ripple complexes. We will analyse involved transduction processes and use this information to interfere with memory consolidation processes in vivo
MethodsSimultaneous recordings of neuronal activity with extracellular and intracellular electrodes; Repetitive stimulation of different paths in the EC hippocampal preparation. Phase locked stimulation during theta gamma oscillations. Application of drugs which interfere with GAP junctions in normal and transgenic animals lacking neuronal gap junction proteins and or in animals which lack certain activity regulated genes. Recordings in vivo with electrodes and multi contact probes during and following explorative behavior. Application of drugs through inserted cannulas into the hippocampus. Studies on spatial orientation behavior using the Y arm paradigm and / or the multi arm paradigm. Circumscribed lesions into the EC the DG and the subiculum.
Studies ex vivo in slices from animals which have been kindled and thereby present with temporal lobe seizures or which have been exposed to pilocarpine, developed a status epilepticus and subsequent spontaneous seizures.
Dissertation topics
Cooperation with other Members
Scholarship Holders:
| AG Ahnert-Hilger | AG Behr | AG Braunewell | AG Haucke | AG Heinemann |
| AG Kempermann | AG Kempter/Schmitz | AG Kuhl | AG Multhaup | AG Nitsch |
