Leutgeb, Stefan - University of California, San Diego

研究领域

Life-long memories are formed at an instant, but considerably outlast the neuronal activity that instigated them or even the synaptic modifications that initially retained them. In addition to early processes at the cellular level, the long-term retention of memories therefore requires that entire populations of neurons in widely distributed neural systems are reorganized. Such reorganization at the systems level is not only needed to ensure that each distinct memory is retained for long time periods, but also to provide a framework that allows for the integration of individual learning events into an accumulating knowledge base. The main objective of research in our laboratory is to describe neuronal mechanisms of long-term memory storage at the systems level and to investigate how coordinated neuronal activity and synaptic plasticity in distributed cell assemblies can result in the formation of new cell assemblies. In addition, we are interested in the translational implications of this basic research and in understanding whether the neurodegenerative processes underlying dementia can result from a failure to appropriately organize neuronal activity and synaptic plasticity during our adult lives. This is addressed by recording from many single neurons (up to 100) in the brain simultaneously and by testing how their activity is coordinated before, during, and long after learning. The recording methods are complemented by computational and analytical approaches, and also by molecular techniques that allow us to manipulate the activity of neuronal networks and to test whether the identified mechanisms are necessary for memory formation. Using these methods, we previously discovered neuronal network mechanisms that combine spatial and nonspatial information in the mammalian hippocampus, and showed that orthogonal encoding of the two types of information is used to generate very different neuronal firing patterns for very similar sensory input. Such pattern separation is thought to be a prerequisite for storing a large number of separate memories. To test this hypothesis, we currently investigate how multiple memories are encoded in the hippocampus as well as in a more widely distributed cortical network. In complementary research program, we aim to investigate how memory processing is altered in the aged brain and when the brain is affected by neurodegenerative disorders. Since memory processing first appears relatively intact in degenerating neuronal networks, but then catastrophically fails, we aim to determine in which way and to what extent a cell assembly can be degraded before failing to support memory retrieval.

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Sasaki T, Piatti VC, Hwaun E, Ahmadi S, Lisman JE, Leutgeb S, Leutgeb JK (2018). Dentate network activity is necessary for spatial working memory by supporting CA3 sharp-wave ripple generation and prospective firing of CA3 neurons. Nat Neurosci. doi: 10.1038/s41593-017-0061-5. Zutshi I, Leutgeb JK, Leutgeb S (2017). Theta sequences of grid cell populations can provide a movement-direction signal. Curr Opin Behav Sci. 17:147-154. Diehl GW, Hon OJ, Leutgeb S, Leutgeb JK (2017) Grid and non-grid cells in medial entorhinal cortex represent spatial location and environmental features with complementary coding schemes. Neuron 94, 83-92. Ewell LA, Liang L, Armstrong C, Soltész I, Leutgeb S, Leutgeb JK (2015) Brain state is a major factor in preseizure hippocampal network activity and influences success of seizure intervention. J Neurosci 35, 15635-48. Schiller D, Eichenbaum H, Buffalo EA, Davachi L, Foster DJ, Leutgeb S, Ranganath C (2015) Memory and Space: Towards an Understanding of the Cognitive Map. J Neurosci 35:13904-13911. Schlesiger MI*, Cannova CC*, Boublil BL, Hales JB, Mankin EA, Brandon MP, Leutgeb JK, Leibold C, Leutgeb S (2015). The medial entorhinal cortex is necessary for temporal organization of hippocampal neuronal activity. Nat Neurosci 18, 1123-1132. *These authors contributed equally Mankin EA, Diehl GW, Sparks FT, Leutgeb S, Leutgeb JK (2015) Hippocampal CA2 activity patterns change over time to a larger extent than between spatial contexts. Neuron 85 190-201. Ewell LA, Leutgeb S. Replay to remember: a boost from dopamine (2014) Nat Neurosci 17, 1629-31. News and Views. Sasaki T, Leutgeb S, Leutgeb, JK (2014) Spatial and memory circuits in the medial entorhinal cortex. Curr Opin Neurobiol 32C, 16-23. Hales JB*, Schlesiger MI*, Leutgeb JK, Squire LR, Leutgeb S**, Clark RE** (2014) Medial entorhinal cortex lesions only partially disrupt hippocampal place cells and hippocampus-dependent place memory. Cell Reports 9, 893-901. *These authors contributed equally. **These authors contributed equally. Brandon, MP, Koenig J, Leutgeb JK, and Leutgeb S (2014) New and distinct hippocampal place codes are generated in a new environment during septal inactivation. Neuron 82, 789-96. Brandon MP, Koenig J, Leutgeb S (2014) Parallel and convergent processing in grid cell, head-direction cell, boundary cell, and place cell networks. Wiley Interdiscip Rev Cogn Sci 5, 207-219. Lu L*, Leutgeb JK*, Tsao A, Henriksen EJ, Leutgeb S, Barnes CA, Witter MP, Moser MB, Moser EI (2013) Impaired hippocampal rate coding after lesions of the lateral entorhinal cortex. Nature Neuroscience 16, 1085-1093. *These authors contributed equally. Dulcis D, Jamshidi P, Leutgeb S, Spitzer NC (2013) Neurotransmitter switching in the adult brain regulates behavior. Science 340, 449-453. Schlesiger MI, Cressey JC, Boublil B, Julie Koenig J, Neal R. Melvin NR, Leutgeb JK, Leutgeb S (2013) Hippocampal activation during the recall of remote spatial memories in radial maze tasks. Neurobiol Learn Mem 106, 324-333. Schlesiger MI, Cressey JC, Boublil B, Julie Koenig J, Neal R. Melvin NR, Leutgeb JK, Leutgeb S (2013) Hippocampal activation during the recall of remote spatial memories in radial maze tasks. Neurobiol Learn Mem 106, 324-333. Mankin EA, Sparks FT, Slayyeh B, Sutherland RJ, Leutgeb S, Leutgeb JK (2012) A neuronal code for extended time in the hippocampus. Proc Natl Acad Sci U S A 109, 19462-19467. Koenig J, Linder AN, Leutgeb JK, Leutgeb S (2011). The spatial periodicity of grid cells is not sustained during reduced theta oscillations. Science 332, 592-595. Download reprint. Colgin LL*, Leutgeb S*, Jezek K, Leutgeb JK, Moser EI, McNaughton BL, Moser MB (2010). Attractor-map versus autoassociation based attractor dynamics in the hippocampal network. J. Neurophysiol. 104, 35-50. *These authors contributed equally. Alme CB, Buzzetti RA, Marrone DF, Leutgeb JK, Chawla MK, Schaner MJ, Bohanick JD, Khoboko T, Leutgeb S, Moser EI, Moser MB, McNaughton BL (2010) Barnes CA. Hippocampal granule cells opt for early retirement. Hippocampus 20, 1109-1123. Kjelstrup KB, Solstad T, Brun VH, Hafting T, Leutgeb S, Witter MP, Moser EI, Moser MB (2008). Finite scale of spatial representation in the hippocampus. Science 321, 140-143. Leutgeb S (2008). Neuroscience. Detailed differences. Science 319, 1623-1624. Brun VH, Leutgeb S, Wu H-Q, Schwarcz R, Witter MP, Moser EI and Moser M-B (2008). Impaired spatial representation in CA1 after lesion of direct input from entorhinal cortex. Neuron 57, 290-302. Leutgeb S, Leutgeb JK (2007). Pattern separation, pattern completion, and new neuronal codes in a continuous CA3 map. Learn. Mem. 14, 745-757. Leutgeb JK, Leutgeb S, Moser M-B, Moser EI (2007). Distinct mechanisms for pattern separation in dentate gyrus and CA3 of the hippocampal formation. Science 315, 961-966.