Comprehensive computational model for memory processing in the hippocampus and entorhinal cortex circuitry

Size: px

Start display at page:

Download "Comprehensive computational model for memory processing in the hippocampus and entorhinal cortex circuitry"

Charlene Hardy
5 years ago
Views:

injury, temporal lobe epilepsy, posttraumatic stress disorder, schizophrenia, and Alzheimer s disease are associated with a dysfunction of brain regions in the medial temporal lobe, including the

1 Comprehensive computational model for memory processing in the hippocampus and entorhinal cortex circuitry A. Project Scope (1) Describe the relevance of the scientific problem within the biological and medical sciences Many neurological, psychiatric, and neurodegenerative diseases, including traumatic brain injury, temporal lobe epilepsy, posttraumatic stress disorder, schizophrenia, and Alzheimer s disease are associated with a dysfunction of brain regions in the medial temporal lobe, including the hippocampus and entorhinal cortex. Because the dysfunctional brain regions are critical for memory formation, in particular for autobiographical memories, patients with these diseases frequently suffer from memory impairments, and treatments to restore memory function in disorders with neural circuit dysfunction could be better designed to be disease modifying or to reversing the disease if we gain a better understanding of how neural networks support memory function. Evidence from humans and from animal models indicates that the hippocampus and entorhinal cortex are particularly critical for the learning and memory. The hippocampus was first described as a trisynaptic circuit in which information is serially processed from the entorhinal cortex to the dentate gyrus, from the dentate to CA3 and from CA3 to CA1. Subsequent network models have then added the finding that the subregions are not only serially connected but that each also receives direct entorhinal projections and form multiple parallel loops through the hippocampus. These circuit diagrams have nonetheless not included the CA2 subregion as a separate processing stage, while recent data indicate that CA2 shows major differences in its connectivity, plasticity, and neuronal firing patterns compared to other subregions (Fig. 1). In particular, CA2 may code to a lesser extent than other hippocampal subregions for spatial context and to a larger extent for temporal and social aspects of behavior (Fig. 2). The integration of these functions may complement the hippocampal circuit such that it supports multisensory integration rather than a more specialized processing of space. In the current PhD project we will take advantage of data recorded with state-of-the-art electrophysiology and in vivo imaging in order to develop mathematical models to dissect the contributions of different hippocampal regions on spatial memory processing. In particular, the function of the connection between entorhinal cortex and particular hippocampal subregions will be investigated. The aims of the projects are: (a) Develop hippocampal models that include processing by different subregions and functional cell types layers (b) Develop models to understand how the loops between hippocampal subregions and entorhinal cortex support memory processing

2 (2) Describe how computational approaches will be used to address this problem and extend prior work in this field Most current computational models of the hippocampus have been limited to the dentate, CA1 and CA3 subregion, but anatomical data and physiological recordings show a large diversity in that more diverse functional cell types are found in the CA2 regions and in the entorhinal cortex. A comprehensive model of neural networks that support memory processing needs to take the diversity of these subregions and functional cell types into account. We aim to develop a comprehensive model on the integration of sensory, social, and spatial inputs and on how these representations change over time to support episodic memory. B. Inter-Institutional Collaboration (1) This project will be based primarily at Simula. (2) List the contributing faculty at Simula and/or UiO, and their roles (e.g. Primary advisor, etc.) Primary advisor: Marianne Fyhn, Department of Biosciences, UiO Co-supervisors: Aslak Tveito, Simula, Anders Malthe-Sørenssen, Department of Physics, UiO, and Torkel Hafting, Department of Basic Medical Sciences, UiO. (3) List the contributing faculty at UCSD, and their roles (e.g. Primary advisor, etc.) Primary advisor: Jill Leutgeb, UCSD Co-supervisor: Sefan Leutgeb, UCSD (4) Describe how the project will foster collaboration between the UCSD and Oslo groups, and how the major scientific and training objectives of the proposal will be distributed between Oslo and San Diego. Hafting, Fyhn and the Leutgebs are former colleagues at the Kavli Institute for Systems Neuroscience, NTNU, where they were key contributors of the discoveries of the grid cells and the computational uniqueness of specific sub-regions of the hippocampus for memory processing and navigation (work for which M-B and E Moser were awarded the Nobel Prize in Physiology or Medicine, 2014). A collaboration exploiting the complementary expertise of their research groups at UiO and UCSD holds great potential for novel discoveries and understanding of fundamental principles of brain function. The close interaction between experimental neuroscience (Fyhn, Hafting, Leutgeb) with expertise in computational physics (Malthe- Sørenssen (cinpla.org) and Tveito) will bring fundamental insights into the mechanisms memory processing. The current project will enable this collaboration which will be the start of a unique research training environment for the PhD student as well as for the research groups at Simula, UiO and UCSD. The candidate, being located at Simula, will analyze large data sets and develop the computational models and will work closely with experimentalist at both places; large scale extracellular recordings are being collected at UCSD and in vivo Ca2+ imaging will be conducted at the UiO. The student will attend experiments as we believe it is essential to become familiar with experimental neuroscience. C. International and Local Training (1) List any courses to be taken at UiO: PhD courses in computer programming (IFI), computational physics (FI) and neurobiology (e.g. MBV9340-Advanced Neurobiology (10 ERCT)) (2) Describe additional professional/research training activities at UiO/Simula Simula-UCSD Summer School in Computational Biology, part of the training program in the Norwegian Research School in Neuroscience, activities in CINPLA ( (3) Describe additional professional/research training activities at UCSD (4) Describe how advisors at both institutions will monitor the student s progress and development At both places, the primary supervisors (Tveito and Leutgeb) will meet with the student several times a week. Moreover, the student will be part of the respective research groups and attend all activities. Regular skype meetings will be used for overseas follow-up.

Curriculum Vitae Marianne Fyhn, PhD Sex: Female Born: 11.10.1973 Nationality: Norwegian Family: Married, three children (2004, 2007 and 2010). E-mail: marianne.fyhn@ibv.uio.

3 Curriculum Vitae Marianne Fyhn, PhD Sex: Female Born: Nationality: Norwegian Family: Married, three children (2004, 2007 and 2010). Current position: Associate Professor, Department of Biosciences, University of Oslo, Norway. Tel: Associate Professor at University of Oslo, Norway. In my own lab, I combine the techniques I have acquired during my research career to understand the mechanisms of cortical plasticity and processing. I find the new role of research leadership challenging and rewarding and I am confident that my group will have success to conduct edge-cutting research with results that will contribute significantly to our understanding of brain function. I was recently appointed as head of Section for Physiology and Cell Biology at the IBV. I also spearheaded and is now the leader of a research initiative at the Faculty of Mathematics and Natural Sciences, UiO, called Centre of Integrative Neuroplasticity Head of Center for Integrative Neuroplasticity (CINPLA, a novel interdisciplinary strategic research initiative at the Faculty of Mathematics and Natural Sciences, UiO, with the aim to converge experimental biology with computational physics and mathematics in order to leap forward our understand mechanisms of brain plasticity. A key strategy of CINPLA is also to implement a computational foundation in the education of future neuroscientists and students in Life Sciences in general Head of Section for Physiology and Cell Biology at the Department of Biosciences where I have the personal responsibility for 65 employees consisting of professors, temporary employed and technical support staff. In this position I am also responsible for development of research strategy and teaching resources in the section. Education: Ph.D. in Neuroscience, Norwegian University of Science and Technology (NTNU), Norway. PhD supervisors: professor May-Britt Moser and professor Edvard Moser Master of Science in Physiology, University of Tromsø, Norway Bachelor in Arctic Biology, The University Courses on Svalbard, Norway Bachelor in Biology, University of Bergen and University of Oslo, Norway. Supervision: Since 2012 I have been the main supervisor of seven MSc students (three completed and four currently working on their thesis) and 7 PhD students (three as main supervisor and four as co-supervisor in experimental neuroscience and computational neuroscience, the first one will defend early 2016).

4 Teaching: Course organizer of undergraduate course in physiology (MBV ERCT), master/phd course in Experimental animal research (MBV ERCT) and a master/phd course in Advanced Neurobiology (MBV ERCT) in addition to lectures in other courses. I am also in change of organizing a summer school in neuroscience (Aug 2015) Understanding Measurements in Neuroscience supported by the Norwegian Research School in Neuroscience. Furthermore, I am engaged in reforming the undergraduate education in biosciences with particular focus on implementing Computing in Science Education. Portfolio of experimental techniques: Two-photon laser-scanning microscopy and chronic spine imaging in vivo. Single-cell electroporation by shadow-patching in vivo. Gene delivery by in utero electroporation and viral vectors. Optogenetic manipulation of neural networks in vivo. Intrinsic optical imaging of visual cortex. Two-photon spine- and Ca 2+ -imaging of awake head-restrained mice. Chronic large-scale single unit recordings of behaving rats & mice. Pharmacological manipulations, lesions and behavioural studies of rats. Anatomical tracing and histology. Work experience: Research assistant at Norwegian Polar Institute and at Institute of Medical Biology, University of Tromsø, Norway Lecturer in undergraduate courses in biological psychology, NTNU, Norway Graduate research fellow at KI-CBM, NTNU, Norway. In the lab of Drs. May-Britt and Edvard Moser I performed electrophysiological recordings of cell ensembles with single unit resolution in entorhinal cortex and hippocampal subfields in behaving rats. I did hippocampal lesions and recorded from hippocamectomized rats. I developed the technique of extracellular recordings in medial entorhinal cortex leading to my discovery of grid cells Postdoctoral researcher at KI-CBM, NTNU, Norway. I followed up my PhD work with large-scale electrophysiological recordings in entorhinal cortex and hippocampus in free-roaming rats and mice. I recorded for the first time grid cells in mice. I developed methods for simultaneous recordings of cell ensembles from two brain areas in combination with intrahippocampal infusions of pharmaca Post doctoral researcher at University of California San Francisco (UCSF), USA. In the lab of Dr. Michael P. Stryker I studied the effects of activity-dependent plasticity in visual cortex of mice by intrinsic optical imaging and two-photon laser-scanning microscopy (2PLSM). I performed genetic labelling of subclasses of neurons with fluorescent markers and genetically encoded Ca 2+ sensors using in utero electroporation, single-cell electroporation, and viral vectors. I implemented the technique and built equipment for in vivo 2PLSM imaging of identified neurons in head-restrained mice running on a styro-foam ball floating on air. I established the technique of shadow-patch for single-cell electroporation in the lab for chronic 2PLSM of sub-cellular structures. Boards Board of the Department of Biosciences, University of Oslo Board of the Norwegian Research School in Neuroscience Board of the Norwegian Neuroscience Society.

5 Publications Three of my publications (Fyhn et al., 2004; Hafting, Fyhn et al., 2005; Sargolini, Fyhn et al., 2006) were put forward by the Nobel Committee to be the fundament for why May-Britt and Edvard Moser was awarded the Nobel Prize in Medicine or Physiology for As of Dec 2013 my publications had 1550 citations (ISI base, average citations per publication is 80). H-index Hagen E, Ness TV, Khosrowshahi A, Sørensen C, Fyhn M, Hafting T, Franke F, Einevoll GT (2015) Computational Neuroscience 245( ). 2. Bonnevie T, Dunn B, Fyhn M, Hafting T, Derdikman D, Kubie JL, Roudi Y, Moser EI, Moser MB (2013) Nature Neuroscience 16(3): (29). 3. Welcker J, Moe B, Bech C, Fyhn M, Schultner J, Speakman JR, Gabrielsen GW (2010) Evidence for an intrinsic energetic ceiling in free-ranging kittiwakes Rissa tridactyla. Journal of Animal Ecology 79: (19) 4. Colgin LL, Denninger T, Fyhn M, Hafting T, Bonnevie T, Jensen O, Moser M-B, Moser EI (2009) Frequency of gamma oscillations routes flow of information in the hippocampus. Nature 462(7271): (211) 5. Derdikman D, Whitlock JR, Tsao A, Fyhn M, Hafting T, Moser M-B, Moser EI (2009) Fragmentation of grid-cell maps in a multicompartment environment. Nature Neuroscience 12(10): (52) 6. Fyhn M, Hafting T, Witter MP, Moser EI, Moser M-B (2008a) Grid cells in mice. Hippocampus 18: (32) 7. Brun V, Solstad T, Kjelstrup KB, Fyhn M, Witter MP, Moser EI, Moser M-B (2008) Progressive increase in grid scale from dorsal to ventral medial entorhinal cortex. Hippocampus 18(12): (84) 8. Fyhn M, Solstad T, Hafting T (2008b) Entorhinal Grid Cells and the Neural Basis of Navigation. In Hippocampal Place Fields: Relevance to Learning and Memory. Editor Sheri Jane Mizumori, Oxford University Press US, ISBN Hafting T, Fyhn M, Bonnevie T, Moser M-B, Moser EI (2008) Hippocampus-independent phase precession in entorhinal grid cells. Nature 453: (136) 10. Fyhn M (2007) The grid map in the brain. Essay for the runner-up winner of Eppendorf Prize in Neurobiology. Published online in Science 26 October Fyhn M, Hafting T, Treves A, Moser M-B, Moser EI (2007) Hippocampal remapping and grid realignment in entorhinal cortex. Nature 446: (173) 12. Sargolini F, Fyhn M, Hafting T, Witter MP, Moser M-B, Moser EI (2006) Conjunctive representation of position, direction and velocity in the medial entorhinal cortex. Science May 5: (317) 13. Fyhn M (2005) Spatial Maps in the Entorhinal Cortex. Doctoral thesis, Centre for the Biology of Memory, Faculty of Medicine, Norwegian University of Science and Technology. Hafting T, Fyhn M, Molden S, Moser M-B, Moser EI (2005) Microstructure of a spatial map in the entorhinal cortex. Nature 436: (718) 14. Fyhn M, Molden S, Witter M P, Moser E I, Moser M-B (2004) Spatial representation in the entorhinal cortex. Science 305: (371) 15. Fyhn M, Molden S, Hollup S, Moser M-B, Moser EI (2002) Hippocampal neurons responding to first-time dislocation of a target object. Neuron 35: (91) 16. Bech C, Langseth I, Moe B, Fyhn M, Gabrielsen GW (2002) The energy economy of the Arctic-breeding Kittiwake (Rissa tridactyla): A review. Comparative Biochemestry and Physiology 133A, (23) 17. Moe B, Langseth I, Fyhn M, Gabrielsen GW, Bech C (2002) Changes in body condition in breeding Kittiwakes Rissa tridactyla. Journal of Avian Biology 33: (47) 18. Fyhn M, Gabrielsen GW, Nordøy ES, Moe B, Langseth I, Bech C (2001) Individual variation in field metabolic rate of Kittiwakes (Rissa tridactyla) during the chick-rearing period. Physiological and Biochemical Zoology 74: (32) 19. Langseth I, Moe B, Fyhn M, Gabrielsen GW, Bech C (2000) Flexibility of basal metabolic rate in arctic breeding kittiwakes (Rissa tridactyla). In: Heldmaier, G. and Klingenspor, M. (eds.): Life in the Cold. Springer-Verlag: pp

6 2. Invited presentations I am regularly invited to give seminars and talks at national as well as international Universities and Congresses. During the last 5 years I have given more than 30 such talks. I am also very much involved in science communication to the public giving numerous lectures and seminars for the public (schools, organizations, industry, public events, radio shows and so on). 3. Prizes and Awards 2012: Ranked as Top ten researcher in Norway under 40 years of age in all scientific fields. Presented in Morgenbladet, September 2012: : Post doctoral fellowship from the Norwegian Research Council (Grant No ). 2008: Award for outstanding contribution to behavioural neuroscience, European Brain and Behaviour Society. 2007: Runner-up winner for the Eppendorf-Science prize in Neurobiology. 2007: Norwegian Academy of Sciences and Letters for young researchers (Nansen award). 2006: Donald B. Lindsley s Prize in Behavioural Neuroscience. Award for the best PhD thesis in behavioural neuroscience in 2005.

7 Please refer to Professor Jill Leutgeb s UCSD profile for further details of her research program and interests: tab

EDVARD MOSER AND THE GRID CELLS MICROSTRUCTURE OF A SPATIAL MAP IN THE ENTORHINAL CORTEX

FAMOUS RESEARCHERS EDVARD MOSER AND THE GRID CELLS MICROSTRUCTURE OF A SPATIAL MAP IN THE ENTORHINAL CORTEX Y. TSENKINA EDVARD I. MOSER is a professor of neuroscience and a director of the Norwegian Centre