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Tejero-Cantero, Álvaro (2012): Of memories and ripples: functional and mechanistic aspects of memory sequences during hippocampal ripples. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)



The hippocampus is one of the regions in the mammalian brain that is associated with memory of events in their spatiotemporal context. Sequences of neuronal activity in the hippocampus are the chief candidate for a neurophysiological correlate of such contextual, or episodic memory. Simultaneously to replaying these behaviorally-related activity sequences, the hippocampus engages in a powerful and fast oscillation known as sharp-wave ripples (SWR). Ripples in turn participate in a brain-wide pattern of activity and may orchestrate the local strengthening of memories and their broadcasting to the cortex. In this Thesis, both memory sequences and ripple oscillations are studied in the light of the unifying hypothesis that the coordinated activation of a neuronal assembly represents an individual memory item in the sequences, and is at the same time responsible for the individual cycles in the oscillations. To test the hypothesis, we investigated SWR in vitro and in vivo in the mouse, using intracellular recordings of currents in CA1 pyramidal cells referenced to the local field potential. Expanding current hypotheses on SWR generation, we found powerful, well ripple-locked and spatially pervasive but CA1-local excitatory inputs, indicative of presynaptic assemblies of CA1 principal neurons. Combining a novel peeling reconstruction algorithm for synaptic currents with recordings at different holding potentials, we could for the first time unravel individual synaptic contributions during ripples. Analysis of the strikingly precise timing of currents demonstrated that inhibition aligns its phase to excitation over the course of a ripple. We carried on the dissection of ripples to the theoretical domain by incorporating the effect of inhibition into a mean field model of sequence replay. Using this model, we inquired what are the neuronal assembly size and inhibitory feedback strength that maximize the capacity of a hippocampal network to store memories, so that those memories can be successfully retrieved during ripple episodes. We found that a linearly coupled inhibitory population indeed helps increase storage capacity by dynamically stabilizing replay in an oscillatory manner for lower assembly sizes than in absence of inhibition. The findings about the temporal structure of neuronal activation during ripples complement our experimental observations. Collectively, they offer new insights on the physiology and function of sharp-wave ripples, paving the way for an integrated, continuous-time model of large networks of sparsely connected neurons that replay activity sequences concomitant to transient ensemble oscillations.