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Out of phase

München, 07/09/2015

LMU researchers have shown that a brain region known as the medial entorhinal cortex, which processes spatial information, controls the temporal pattern of neuronal activity in the hippocampus, and is essential for episodic learning.

Source: Sebastian Kaulitzki /

Nerve cells in the hippocampus and the medial entorhinal cortex (MEC) play a central role in the formation of long-term memory and are essential for spatial orientation in mammals. Thus, the so-called grid cells in the MEC respond in a spatially and directionally specific fashion to an animal’s location in space. Functional links between the MEC and the hippocampus (which also contains location-responsive neurons) ensure that this information is transferred to long-term memory. As a consequence, the two systems together serve as the neuronal substrate for navigation. The coding and storage of navigational information is highly dependent on precise coordination between the spatial modulation and temporal structure of patterns of nerve-cell activity in the two brain structures. Understanding the mechanism that underlies this process of information transfer is one of the primary goals of modern neuroscience. Now a new study carried out by neurobiologists led by LMU’s Professor Christian Leibold and Professor Stefan Leutgeb of the University of California in San Diego reveals that the activity of the MEC primarily affects the temporal structure of neuronal responses in the hippocampus. The findings appear in the journal Nature Neuroscience.

In the collaborative project, the two teams reanalyzed data previously obtained in animals that had suffered lesions in the MEC. “As the hippocampus and the medial entorhinal cortex are functionally connected by reciprocal negative-feedback circuits, animals in which these links are lacking provide a unique opportunity to investigate patterns of neuronal activity in each of the two brain regions in isolation,” says Christian Leibold.

The trick is in the timing

Most of the data that formed the basis for the new analysis come from experiments that were performed in San Diego by Magdalene Schlesiger, a PhD student at LMU. The aim of her project was to ascertain whether location-dependent modulation of neuronal activity could be detected in the hippocampus in freely moving animals that lacked a functional MEC. Using electrophysiological methods, Schlesiger monitored the form and sequence of action potentials of nerve cells in the hippocampus of lesioned rats, as the animals ran back and forth along a linear track.

In the transatlantic study, which was funded by the Deutsche Forschungsgemeinschaft, these data were subjected to further analysis, this time focusing on the timing of the trains of neuronal activity in the hippocampus. “The temporal coordination of neuronal activity is critical for the phenomenon of synaptic plasticity, which is the physiological basis of learning and memory formation. This is because the temporal relationship between incoming nerve impulses modulates the efficiency of signal transmission at the synapses” Leibold explains. The new analysis demonstrated that the MEC is primarily responsible for the temporal organization of neuronal activity in the hippocampus. The importance of temporal encoding in this system is underlined by the fact that lesions in the MEC have a drastic impact on brain function: “As previous experiments and theoretical models have suggested, all aspects of memory that have to do with episodic learning should be disrupted in the absence of a functional medial entorhinal cortex, even though the hippocampus itself is intact,” Leibold says.

(Nature Neuroscience 2015)

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