The coordinating influence of thalamic nucleus reuniens on sleep oscillations in cortical and hippocampal structures – relevance to memory consolidation and sleep structure

Sleep is a fascinating and a bit mysterious behavior. Not only do so called “higher” animals like mammals sleep but also simpler organisms like jellyfish display rhythmic periods of quiescence which are interpreted as sleep. Despite it being almost ubiquitous across the animal kingdom, the function of sleep is still not fully understood. However, we do know that especially the brain is important for the initiation and maintenance of that state and that it is highly active during sleep. There has been a special focus on electric neuro-oscillations where research over the last 90 years has revealed that the brain displays quite distinct oscillatory patterns during sleep and its specific functions are slowly being brought to light, such as memory consolidation and communication between different brain regions. For example, it has been argued that newly formed memories are either stored in the hippocampus or at least dependent on it for reactivation and are later transferred to the neocortex or become independent of the hippocampus while being stabilized in the cortex, with a portion of the thalamus, the nucleus reuniens thalami, being possibly involved in this process as it is an anatomical relay between cortex and hippocampus. The aim of my PhD project was to investigate the coupling of neuro-oscillations between prefrontal cortex, thalamus, and hippocampus in both a descriptive and manipulative way. Namely, we investigated the coupling between prelimbic cortex, nucleus reuniens of the thalamus and the CA1 portion of the hippocampus during unperturbed natural sleep, sleep after sleep deprivation and sleep with increased mnemonic demands after a learning task. Lastly, we optogenetically manipulated nucleus reuniens during sleep to assess its properties as a synchronizing link between prefrontal cortex and hippocampus. We described the coupling of corticothalamic slow waves and spindles with ripples in the hippocampus by quantifying the amount of co-occurrence of the aforementioned events, describing the phase-locking of ripples to slow waves and spindles, and determining which oscillations drives the other. Next we found that spiking behavior of nucleus reuniens is coupled to ripples and cortical slow waves. Lastly, optogenetic manipulation showed that nucleus reuniens is involved in the precise phase-event coupling, in the co-occurrence of the mentioned events, and oscillatory drive between cortex and hippocampus. However, the effects we found on the neuro-oscillatory coupling were not accompanied by a change in memory performance after a learning task

High-Performance Modelling and Simulation for Big Data Applications

This open access book was prepared as a Final Publication of the COST Action IC1406 “High-Performance Modelling and Simulation for Big Data Applications (cHiPSet)“ project. Long considered important pillars of the scientific method, Modelling and Simulation have evolved from traditional discrete numerical methods to complex data-intensive continuous analytical optimisations. Resolution, scale, and accuracy have become essential to predict and analyse natural and complex systems in science and engineering. When their level of abstraction raises to have a better discernment of the domain at hand, their representation gets increasingly demanding for computational and data resources. On the other hand, High Performance Computing typically entails the effective use of parallel and distributed processing units coupled with efficient storage, communication and visualisation systems to underpin complex data-intensive applications in distinct scientific and technical domains. It is then arguably required to have a seamless interaction of High Performance Computing with Modelling and Simulation in order to store, compute, analyse, and visualise large data sets in science and engineering. Funded by the European Commission, cHiPSet has provided a dynamic trans-European forum for their members and distinguished guests to openly discuss novel perspectives and topics of interests for these two communities. This cHiPSet compendium presents a set of selected case studies related to healthcare, biological data, computational advertising, multimedia, finance, bioinformatics, and telecommunications

High-Performance Modelling and Simulation for Big Data Applications

This open access book was prepared as a Final Publication of the COST Action IC1406 “High-Performance Modelling and Simulation for Big Data Applications (cHiPSet)“ project. Long considered important pillars of the scientific method, Modelling and Simulation have evolved from traditional discrete numerical methods to complex data-intensive continuous analytical optimisations. Resolution, scale, and accuracy have become essential to predict and analyse natural and complex systems in science and engineering. When their level of abstraction raises to have a better discernment of the domain at hand, their representation gets increasingly demanding for computational and data resources. On the other hand, High Performance Computing typically entails the effective use of parallel and distributed processing units coupled with efficient storage, communication and visualisation systems to underpin complex data-intensive applications in distinct scientific and technical domains. It is then arguably required to have a seamless interaction of High Performance Computing with Modelling and Simulation in order to store, compute, analyse, and visualise large data sets in science and engineering. Funded by the European Commission, cHiPSet has provided a dynamic trans-European forum for their members and distinguished guests to openly discuss novel perspectives and topics of interests for these two communities. This cHiPSet compendium presents a set of selected case studies related to healthcare, biological data, computational advertising, multimedia, finance, bioinformatics, and telecommunications

An introduction to Musical Interactions

The article presents a contextual survey of eight contributions in the special issue Musical Interactions (Volume I) in Multimodal Technologies and Interaction. The presentation includes (1) a critical examination of what it means to be musical, to devise the concept of music proper to MTI as well as multicultural proximity, and (2) a conceptual framework for instrumentation, design, and assessment of musical interaction research through five enabling dimensions: Affordance; Design Alignment; Adaptive Learning; Second-Order Feedback; Temporal Integration. Each dimension is discussed and applied in the survey. The results demonstrate how the framework provides an interdisciplinary scope required for musical interaction, and how this approach may offer a coherent way to describe and assess approaches to research and design as well as implementations of interactive musical systems. Musical interaction stipulates musical liveness for experiencing both music and technologies. While music may be considered ontologically incomplete without a listener, musical interaction is defined as ontological completion of a state of music and listening through a listener’s active engagement with musical resources in multimodal information flow

Active provenance for data intensive research

The role of provenance information in data-intensive research is a significant topic of discussion among technical experts and scientists. Typical use cases addressing traceability, versioning and reproducibility of the research findings are extended with more interactive scenarios in support, for instance, of computational steering and results management. In this thesis we investigate the impact that lineage records can have on the early phases of the analysis, for instance performed through near-real-time systems and Virtual Research Environments (VREs) tailored to the requirements of a specific community. By positioning provenance at the centre of the computational research cycle, we highlight the importance of having mechanisms at the data-scientists’ side that, by integrating with the abstractions offered by the processing technologies, such as scientific workflows and data-intensive tools, facilitate the experts’ contribution to the lineage at runtime. Ultimately, by encouraging tuning and use of provenance for rapid feedback, the thesis aims at improving the synergy between different user groups to increase productivity and understanding of their processes. We present a model of provenance, called S-PROV, that uses and further extends PROV and ProvONE. The relationships and properties characterising the workflow’s abstractions and their concrete executions are re-elaborated to include aspects related to delegation, distribution and steering of stateful streaming operators. The model is supported by the Active framework for tuneable and actionable lineage ensuring the user’s engagement by fostering rapid exploitation. Here, concepts such as provenance types, configuration and explicit state management allow users to capture complex provenance scenarios and activate selective controls based on domain and user-defined metadata. We outline how the traces are recorded in a new comprehensive system, called S-ProvFlow, enabling different classes of consumers to explore the provenance data with services and tools for monitoring, in-depth validation and comprehensive visual-analytics. The work of this thesis will be discussed in the context of an existing computational framework and the experience matured in implementing provenance-aware tools for seismology and climate VREs. It will continue to evolve through newly funded projects, thereby providing generic and user-centred solutions for data-intensive research

REGULATION OF GABA RELEASE BY PRESYNAPTIC CAV2.2 IN THE BASOLATERAL AMYGDALA AND INFRALIMBIC CORTEX

Anxiety is linked to dysregulation of neuronal activity in several brain regions including the infralimbic (IL) area of the medial prefrontal cortex (mPFC) and the basolateral nucleus of the amygdala (BLA). Disruptions to the balance of excitatory and inhibitory signaling in these regions are implicated in anxiety-like behaviors in animals and anxiety disorders in humans. The neuronal circuitry between excitatory neurons, known as pyramidal cells (P-cells), and inhibitory neurons, known as interneurons (INs), is a primary target for anxiety modulation at the cellular level. INs, particularly the subtype that contain the neuropeptide cholecystokinin (CCK+INs), form inhibitory synapses around P-cells. Through GABAergic neurotransmitter release, CCK+INs regulate P-cell activity and subsequent anxiety-related neuronal output. Two protein complexes, the N-type calcium channel (CaV2.2) and the type-1 cannabinoid receptor (CB1), are expressed in the presynaptic terminal of CCK+INs. CaV2.2 and CB1 have been shown to regulate neurotransmitter release from CCK+INs in the hippocampus, but it is not known if this role is conserved in the anxiety-related neuronal circuits of the BLA and IL. CaV2.2 has also been shown to regulate the intrinsic firing properties of P-cells in the hippocampus and deep cerebellar nuclei, but this role has not been demonstrated in the IL. To investigate these neuronal circuits, I used a combination of transgenic mouse models, confocal microscopy, patch-clamp electrophysiology, optogenetics, and pharmacology. In the first chapter of my thesis, I investigated the role of CaV2.2 in CCK+IN/P-cell synapses in the BLA. In the second chapter of my thesis, I investigated the role of CB1 in regulating GABA release from CCK+INs in the BLA. In the third chapter of my thesis, I assessed the regulation of GABA release and intrinsic firing by CaV2.2 in the IL. I present electrophysiology data which demonstrate GABA release from CCK+INs is partially CaV2.2-dependent in the BLA. I obtained preliminary electrophysiology recordings which suggest CB1 receptors modulate GABA release in CCK+IN/P-cell synapses in the BLA. I found that neurotransmitter release from GABAergic INs is partially CaV2.2-dependent in the IL. I found that GABA release from CCK+INs is not CaV2.2-dependent in this region. Lastly, I observed that CaV2.2 plays a minimal role in the intrinsic firing properties of P-cells in the IL. My findings suggest that CaV2.2 differentially regulates GABA release and intrinsic firing properties across brain regions, suggesting there are region-specific implications of CaV2.2 modulation in anxiety-related neuronal output

Understanding Episodic Memory in Animals and Humans: A Methodological Approach.

This thesis sought to explore two different methodological approaches to episodic memory, namely episodic memory as demonstrated in humans and episodic-like memory as demonstrated in animals. The results of Chapter 2 were successful in demonstrating episodic-like memory in the rat using recollection alone, despite the fact that performance in this study was significantly poorer compared to the original (Eacott, Easton, & Zinkivskay, 2005). Subsequent experiments within this chapter highlighted potential methodological issues (e.g. interference of odour cues, stability of performance over lengthy testing periods) that impact on such spontaneous tasks. Chapter 3 investigated the effect of bilateral lesions to the hippocampus on episodic-like memory. The results of Chapter 3 were not in agreement with previous findings as none of the three groups (Sham Group/Partial Hippocampal Group/Hippocampal Group) showed evidence of episodic-like memory. In depth analyses of the three groups lead the author to the conclusion that this was not due to an ineffective task but due to extraneous factors impacting upon the performance of the animals. Analyses of D2 scores and raw exploration times in both phases of the experiment also highlighted the importance of D2 scores in determining object familiarity. Chapter 4 further investigated the effect of bilateral lesions to the hippocampus on episodic-like memory in animals using an Open Field arena. The addition of landmarks to the testing room resulted in the Sham group successfully demonstrating episodic-like memory whilst the Hippocampal lesion group remained at chance levels. As there was no significant difference between the two groups it was not possible to conclude that this was as a result of the lesions to the hippocampus. The control task showed neither group demonstrating memory for the more simple ‘what-where’ task, therefore it was concluded that a problem with the methodology still remained. Subsequent experiments within this chapter investigated cleaning methodology, the stability of performance over time, and the effect of task change on performance. The clear variability in the data over lengthy testing periods emphasised the sensitivity of such tasks. Chapter 5 aimed to investigate whether applying comparable ‘What-Where-When’ and ‘What-Where-Which’ tasks to human investigations of episodic memory would result in similar patterns of data with regard to recollection and familiarity. Analysis of the results revealed the use of other strategies to solve the episodic ‘What-Where-When’ questions. Subsequent experiments within this chapter aimed to confirm the use of strength of memory trace as a strategy for solving these episodic questions. Results from the final experiment suggested that other strategies were also being employed in addition to strength of memory trace. Conclusions were drawn regarding the individual components of episodic memory and their susceptibility to interference from other strategies. Overall conclusions focused on the definition of episodic memory and the potential implications of alternative strategies impacting on such tasks

Schema and memory consolidation

The traditional view of systems memory consolidation is that it is a gradual process that takes place over days or weeks. Within this approach, the hippocampus (HPC) is thought to be involved in the rapid encoding of specific events, whilst neocortex is thought to be involved in slow learning. An idea posited recently is that systems consolidation can occur rapidly if an appropriate “schema” into which the new information can be incorporated has been previously created. Using a hippocampaldependent paradigm, rats were trained to learn a schema involving 6 flavour-place paired-associates (PAs). Once the schema was acquired, relevant new information then became assimilated into extra-hippocampal regions and rapidly became hippocampal-independent. Building upon this foundation and the PAs schema paradigm, this thesis has explored several aspects of the neurobiology of schemas in animals. The first part of the thesis examined the importance of a relevant schema in new information processing. Rats were trained in both a consistent and inconsistent schema. In the consistent schema, rats could learn new PAs in a single trial; however, in the inconsistent schema, rats failed to learn the new PAs as they had not established an appropriate schema that could facilitate rapid learning. The second part of the thesis investigated the role of hippocampal NMDA receptors and dopamine receptors during encoding of new PAs. Bilateral hippocampal infusion of either the NMDA receptor antagonist D-AP5 or the D1/D5 dopamine receptor antagonist SCH23390 before encoding of new PAs resulted in impaired memory tested at 24 hr. This result suggests that the encoding of new PAs is dependent upon NMDA receptors in the HPC and also that dopamine is involved in the modulation of encoding new PAs. The final chapters of the thesis attempted to identify the extrahippocampal regions in which these new PAs are integrated with the schema during encoding. To identify the regions that may be involved, immediate early genes (Zif268 and Arc) were used. In a group of cortical structures, including the prelimbic cortex, there was significantly higher Zif268 and Arc expression when encoding 2 new PAs compared to the reactivation of previously learned (original) PAs or the encoding of 6 new PAs. These findings indicate that the prelimbic cortex may be critical for rapid assimilation of new information into a pre-existing schema. Finally, the last experiment in the thesis investigated this finding using bilateral microinfusions of either the AMPA receptor antagonist CNQX or the NMDA receptor antagonist D-AP5 into the prelimbic cortex. Infusions of CNQX and D-AP5 resulted in poor learning of the new PAs in the schema task. This indicates that parallel encoding of new PAs occurred in the prelimbic cortex and the HPC. The experimental results presented in this thesis suggest that the prelimbic cortex, in particular, plays a crucial role along with the HPC during encoding of new information in rapid memory formation