Periodic Reporting for period 2 - M-GATE (Memory research: Ground-breaking, Applied, and Technological Exchanges) Reporting period: 2019-10-01 to 2022-03-31 Summary of the context and overall objectives of the project In relation to its limited volume, the hippocampus is probably the most sophisticated piece of technology human beings carry along. The hippocampus is a small structure tucked deep inside the temporal lobes of our brain, which is critical to our ability to form memories for the events of our lives. Understanding the hippocampus is socially and economically important because when damaged, the hippocampus contributes to making life miserable in several pathologies. After migraine, epilepsies and Alzheimer disease are the most common neurological disorders. Temporal Lobe Epilepsy is the most common form of epilepsy in adults, is drug-resistant in 30% of the cases and is associated with co-morbidities, including cognitive deficits. Both disorders represent a huge cost to society estimated at 1.2% of world GDP. Hence, there is a clear need for further knowledge and treatment options for disorders affecting the functioning of the hippocampus. In line with this assessment, there is a great need for future experts in the field that have been trained and have developed unique multidisciplinary skills combining physiology, molecular biology, computational skills and micro-engineering in an interdisciplinary setting. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The M-GATE project has recruited 14 ESRs, all enrolled in PhD programs at their host institutions. Three of them had purely computational projects, while the remaining 11 had experimental projects. The main focus of the experimental work was the exploration of the neural circuits in the hippocampus and connected brain structures, and their relationship with cognition and behavior, with special emphasis on memory. Most of the work required high-resolution, advanced invasive techniques that can only be applied to animal models (rats and mice), except for one student who worked on a cognitive neuroscience project on humans using functional neuroimaging and computational methods. The questions, approaches, in this project were as close as possible to those other fellows applied to animals so that we could transfer some of the knowledge acquired with detailed work in the animal model to humans. All experimental students received training in their respective technique, involving electrophysiology, that is, the recording of the electrical activity of many neurons as well as optical imaging, where neural activity is monitored via fluorescent indicators that are inserted in neurons with genetic methods. All projects attained significant advances of our understanding of the neural basis of memory, from the level of single neurons, to the level of global brain networks. To cite just a few examples, in the hippocampus and other cortical areas involved in memory, such as the anterior cingulate cortex, we shed light on how information is encoded in the timing of neural impulses, and how different types of neuronal cells contribute to the information encoding process. At a very different level of analysis, we looked at the activation of brain areas or the brain as a whole, and we discovered new laws of interaction (for example between the hippocampus and the cerebral cortex during sleep), and we developed new mathematical methods to characterize the brain "state" (a very complex complex and multi-dimensional entity) in terms of a few dimensions that are relevant for brain dynamics and information processing. We have applied these methods to the healthy and the epileptic brain, generating a new way to classify epileptic seizures. Epileptic-like activity was also studied in mouse models of Alzheimer's disease, In humans, we have identified the brain circuit supporting the planning of sophisticated actions such as routes through a city like London.The theoretical work has provided a computational framework to understand our data, with a good collaboration between theoretical and experimental fellows. Notably, we devised a scaling law for the behavior of human memory capacity, derived from first principles of statistics and statistical physics, which fits experimental data very well. Furthermore, we calculated quantitative estimates of the information that may be stored in neural networks exhibiting the well-known "grid" response pattern, observed in the medial entorhinal cortex, keeping the details of hippocampal anatomy into account.In addition to the research and training that all ESRs received at their host institutions, training events featuring world class speakers and instructors from within and from outside the network were organized in Trieste (Italy), Nijmegen (Netherlands), Tromso (Norway) and Rehovot (Israel). The Trieste and Tromso events – the latter in collaboration with the Norwegian Neuroscience Society – also had a public component and were open to students from outside the network. During the COVID pandemics, training and networking continued online. Despite the delays that some ESRs encountered as a result of the COVID pandemic, the M-GATE project generated 18 publications as well as 10 manuscripts already submitted for review and some 17 manuscripts in preparation, 5 ESRs have already obtained their PhD degree, 7 ESRs will complete their PhD this year and another 2 ESRs are scheduled to defend their PhD thesis in 2023. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) All M-GATE ESR-projects are at the forefront of the research on neuroscience of memory. We have generated a large amount of data and new findings, on the dynamics of neural networks, from the scale of a single hippocampal subfield, or cortical layer, to the global activity of the medial temporal lobe and the cortex as a whole. This open data will represent a boon for future theoretical and experimental research by the partner groups and other researchers. In summary: - We characterized how inhibitory interneurons coalesce their activity to influence hippocampal activity- We overhauled key notions about how information is encoded in the timing of hippocampal neurons, using novel genetic methods to probe neural circuits- We characterized correlates of memory for objects in the anterior cingulate cortex- We studied the brain-wide neural circuits supporting planning of complex actions in humans and mice, using innovative behavioral tasks- We characterized the link between spontaneous brain activity in cerebral cortex networks and oscillations in the hippocampus during sleep, which support memory consolidation- In computational models, we studied the theoretical efficiency of biologically plausible synaptic plasticity models in storing information - We also characterized the memory storage efficiency for memory of spatial trajectories vs. disjoint spatial locations and digits- We produced a first-principle model for short-term memory - We defined a novel notion of brain state based on dynamical and information-theoretical parameters- We provided a new characterization of epileptic seizures based on multi-dimensional measurements - We studied neural dynamic in a novel mouse model of Alzheimer's disease enabling a more realistic modeling of tau and amyloid pathologyThe results represent a major advance in our understanding of the circuits of memory in the brain. The interactions between experimentalists and theoreticians will help providing a theoretical framework for the new data. Importantly, we are applying the same cutting-edge experimental techniques that are in use in fundamental research for animal models of disease, providing new possibilities for translational research. M-GATE logo
