Why are some memories easy to retrieve, while others are more difficult to access? Here, we tested whether we could bias memory replay, a process whereby newly learned information is reinforced by reinstating the neuronal patterns of activation that were present during learning, towards particular memory traces. The goal of this biasing is to strengthen some memory traces, making them more easily retrieved. To test this, participants were scanned during interleaved periods of encoding and rest. Throughout the encoding runs, participants learned triplets of images that were paired with semantically related sound cues. During two of the three rest periods, novel, irrelevant sounds were played. During one critical rest period, however, the sound cues learned in the preceding encoding period were played in an effort to preferentially increase reactivation of the associated visual images, a manipulation known as targeted memory reactivation. Representational similarity analyses were used to compare multi-voxel patterns of hippocampal activation across encoding and rest periods. Our index of reactivation was selectively enhanced for memory traces that were targeted for preferential reactivation during offline rest, both compared to information that was not targeted for preferential reactivation and compared to a baseline rest period. Importantly, this neural effect of targeted reactivation was related to the difference in delayed order memory for information that was cued versus uncued, suggesting that preferential replay may be a mechanism by which specific memory traces can be selectively strengthened for enhanced subsequent memory retrieval. We also found partial evidence of discrimination of unique temporal sequences within the hippocampus. Over time, multi-voxel patterns associated with a given triplet sequence became more dissimilar to the patterns associated with the other sequences. Furthermore, this neural marker of sequence preservation was correlated with the difference in delayed order memory for cued versus uncued triplets, signifying that the ability to reactivate particular temporal sequences within the hippocampus may be related to enhanced temporal order memory for the cued information. Taken together, these findings support the claim that awake replay can be biased towards preferential reactivation of particular memory traces and also suggest that this preferential reactivation, as well as representations of reactivated temporal sequences, can be detected within patterns of hippocampal activation. / Psychology

Komplexe Muster neuronaler Aktivität entstehen während der Sharp-wave Ripples (SWRs) im Hippocampus und während der Up States im Neokortex (Zuständen mit hoher Aktivität). Sequenzen von Verhalten, die in der Vergangenheit erlebt wurden, werden während des komplexen Musters abgespielt. Die zugrunde liegenden Mechanismen sind nicht gründlich erforscht: Wie können kleine synaptische Veränderungen die großflächige Netzwerkaktivität während des Gedächtnisabrufes und der Gedächtniskonsolidierung kontrollieren? Im ersten Teil dieser Abhandlung wird die Hypothese aufgestellt, dass eine schwache synaptische Konnektivität zwischen Hebbschen Assemblies von der bereits vorhandenen rekurrenten Konnektivität gefördert wird. Diese Hypothese wird auf folgende Weise geprüft: die vorwärts gekoppelten Assembly-Sequenzen werden in neuronale Netzwerke eingebettet, mit einem Gleichgewicht zwischen exzitatorischer und inhibitorischer Aktivität. Simulationen und analytische Berechnungen haben gezeigt, dass rekurrente Verbindungen innerhalb der Assemblies zu einer schnelleren Signalverstärkung führen, was eine Reduktion der notwendigen Verbindungen zwischen den Assemblies zur Folge hat. Diese Aktivität kann entweder von kleinen sensorisch ähnlichen Inputs hervorgerufen werden oder entsteht spontan infolge von Aktivitätsschwankungen. Globale -- möglicherweise neuromodulatorische -- Änderungen der neuronalen Erregbarkeit können daher die Netzwerkzustände steuern, die Gedächnisabruf und die Konsolidierung begünstigen. Der zweite Teil der Arbeit geht der Herkunft der SWRs nach, die in vitro beobachtet wurden. Neueste Studien haben gezeigt, dass SWR-ähnliche Erscheinungen durch optogenetische Stimulation der Subpopulationen von inhibitorischen Neuronen hervorgerufen werden können (Schlingloff et al., 2014). Um diese Ergebnisse zu erklären wird ein de-inhibierendes Schaltkreis-Modell diskutiert, das die beobachteten Populationsausbrüche generieren kann. Die Auswirkungen der pharmakologischen GABAergischen Modulatoren auf die SWR-Häufigkeit werden in vitro untersucht. Die gewonnenen Ergebnisse wurden in Rahmen des Schaltkreis-Modells analysiert. Insbesondere wird den folgenden Fragen nachgegangen: Wie unterdrückt Gabazine, ein GABA_A-Rezeptor-Antagonist, die Entwicklung von SWRs? Wird das Zeitintervall zwischen SWRs durch die Dynamik der GABA_B Rezeptoren moduliert? / Complex patterns of neural activity appear during up-states in the neocortex and sharp-wave ripples (SWRs) in the hippocampus, including sequences that resemble those during prior behavioral experience. The mechanisms underlying this replay are not well understood. How can small synaptic footprints engraved by experience control large-scale network activity during memory retrieval and consolidation? In the first part of this thesis, I hypothesise that sparse and weak synaptic connectivity between Hebbian assemblies are boosted by pre-existing recurrent connectivity within them. To investigate this idea, sequences of assemblies connected in a feedforward manner are embedded in random neural networks with a balance of excitation and inhibition. Simulations and analytical calculations show that recurrent connections within assemblies allow for a fast amplification of signals that indeed reduces the required number of inter-assembly connections. Replay can be evoked by small sensory-like cues or emerge spontaneously by activity fluctuations. Global--potentially neuromodulatory--alterations of neuronal excitability can switch between network states that favor retrieval and consolidation. The second part of this thesis investigates the origin of the SWRs observed in in-vitro models. Recent studies have demonstrated that SWR-like events can be evoked after optogenetic stimulation of subpopulations of inhibitory neurons (Schlingloff et al., 2014; Kohus et al., 2016). To explain these results, a 3-population model is discussed as a hypothetical disinhibitory circuit that could generate the observed population bursts. The effects of pharmacological GABAergic modulators on the SWR incidence in vitro are analysed. The results are discussed in the light of the proposed disinhibitory circuit. In particular, how does gabazine, a GABA_A receptor antagonist, suppress the generation of SWRs? Another explored question is whether the slow dynamics of GABA_B receptors is modulating the time scale of the inter-event intervals.