Formation and Modulation of Hippocampal Ensemble Activity

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The extent to which advanced organisms can grasp and learn complex environmental patterns represents a fascinating feature. It is believed that memory is encoded by transiently co-active cells, so called neuronal ensembles, in which cells are temporally linked by underlying network oscillations. In the hippocampus, rhythms of oscillating neuronal networks are directly associated with behavioral states. For instance, gamma rhythms are linked to memory formation, whereas intermittent sharp wave-ripple oscillations are involved in memory consolidation. During coordinated neuronal ensemble activity participating cells are selectively activated although they are scattered throughout neuronal tissue. This spatiotemporal specificity requires dynamic anatomical and physiological working principles. In this work, we aimed for a deeper understanding of the apparent complexity underlying neuronal ensemble formation. We studied the recruitment of single cells into neuronal ensembles during sharp wave-ripple oscillations in vitro. In our approach, we combined recent physiological and anatomical evidence about hippocampal principal cells. On the one hand, a subpopulation of principal cells elicits network-entrained action potentials that exhibit a characteristic ectopic waveform in vitro. On the other hand, a large number of cells feature a peculiar axon location. We discovered a relationship between these two findings, showing that only cells with axons originating from a dendrite were able to participate during sharp wave-ripple oscillations. As specific network oscillations are associated with different behavioral states, we were interested in the modulation of network rhythms. It has been shown that enhanced levels of oxytocin affect the formation of long-lasting spatial memory. Here, we studied the effects of oxytocin on hippocampal network activity in vitro, showing that it selectively reduced sharp wave-ripples, while failing to modulate gamma oscillations. Furthermore, we investigated the neuroprotective mechanism, which is enabled by the amyloid precursor protein. Although being strongly associated with Alzheimer's disease, its intracellular processing provides a basis for neuroprotection. We show that the harming impact of a hypoxic condition on hippocampal network oscillations was eased by fragments of the amyloid precursor protein through modulation of L-type calcium channels, in vitro.