Intellectual Merit: Although considerable progress has been made in understanding how episodic memory is stored in the brain, fundamental questions remain. We will use a combination of experimental and computational approaches to study two major questions.
Aim 1 : Network mechanisms of sequence recall in the hippocampus: Our ability to recall a sequence of events is a core component of episodic memory. The hippocampus is necessary for episodic memory, and electrophysiological recordings from this structure have begun to reveal some of the processes involved. After a rat experiences a spatial path, it recalls sequences of places along that path during brief events called sharp waves. Recent experiments show that these waves are necessary for memory consolidation. Sharp waves are generated intrahippocampally, but the specific hippocampal subregions that produce them are not known. According to one hypothesis, CA3 alone generates the sharp wave. Another hypothesis (the ping-pong hypothesis) posits that sharp waves are generated by the combined action of the dentate gyrus (DG) and CA3.This hypothesis has its origins in the work of Sompolinsky and Kleinfeld, who argued that each cycle in sequence recall requires two substeps: a) a chaining substep in which cells representing one item stimulate the cells representing the next item in the sequence and b) an autoassociative substep that corrects minor errors produced in each chaining step, thereby avoiding concatenation of error. Lisman proposed how this could be mapped onto hippocampal circuitry: CA3 cells that represent the nth item in the sequence excite the n+1 item in the DG (by the known backprojections);then, the n+1 item in DG is sent to CA3 for error correction (pattern completion). This, in turn, initiates te next cycle. To distinguish between the ping-pong and CA3-alone hypotheses, J. Leutgeb will record simultaneously from dentate and CA3. She will determine whether both dentate and CA3 cells fire during sharp waves and whether they fire at a different phase of gamma oscillations, as would be expected from a ping-pong process. To test whether accurate sequence recall in CA3 requires the dentate, Leutgeb will use optogenetic methods. If the dentate is required, accurate sequence recall should be disrupted by artificially inducing activity in the dentate or by blocking activity in the dentate. The data analysis will be done in the Lisman laboratory.
Aim 2 : Neural coding in the hippocampus: Two key experiments have provided insight into how spatial and sensory information are encoded in the hippocampus. O'Keefe showed that different spatial positions in a sequence are represented in different phases of a theta cycle. The Moser lab demonstrated that sensory information is encoded by """"""""rate remapping"""""""": sensory information associated with a place is encoded by a change in the firing RATE of the place cells that encode that position. It is unclear whether these major ideas are compatible: the increased number of spikes during rate remapping might smear theta phase and thereby compromise phase coding. To determine whether this is the case, Lisman will analyze an existing data set and a new data set to be obtained by Leutgeb. Our working hypothesis is that rate remapping increases the number of spikes in a brief burst;since the spikes in a burst have nearly the same theta phase, phase coding would not be significantly degraded. Broader Impact: Understanding memory is a major goal of neuroscience because of the increasing incidence of memory problems in an aging population. The proposed experiment will identify a key component of the neural circuitry that underlies episodic memory. This may enable more targeted therapeutic strategies. A second contribution will be a MATLAB tutorial for the Summer Program in Neuroscience, Ethics and Survival (SPINES). This is an NIMH-sponsored course aimed at helping grad students and postdocs from under-represented minority and disadvantaged groups to develop knowledge and skills. Lisman and Leutgeb will lecture on major advances in episodic memory and describe how computation is important in this endeavor. This will be followed by a one-month tutorial on the computational platform MATLAB.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-B (50))
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Glanzman, Dennis L
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Brandeis University
Schools of Arts and Sciences
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Sasaki, Takuya; Piatti, Verónica C; Hwaun, Ernie et al. (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 21:258-269
Sanders, Honi; Ji, Daoyun; Sasaki, Takuya et al. (2018) Temporal coding and rate remapping: Representation of nonspatial information in the hippocampus. Hippocampus :
Lisman, John (2017) Glutamatergic synapses are structurally and biochemically complex because of multiple plasticity processes: long-term potentiation, long-term depression, short-term potentiation and scaling. Philos Trans R Soc Lond B Biol Sci 372:
Diehl, Geoffrey W; Hon, Olivia J; Leutgeb, Stefan et al. (2017) Grid and Nongrid Cells in Medial Entorhinal Cortex Represent Spatial Location and Environmental Features with Complementary Coding Schemes. Neuron 94:83-92.e6
Otmakhov, Nikolai; Regmi, Shaurav; Lisman, John E (2015) Fast Decay of CaMKII FRET Sensor Signal in Spines after LTP Induction Is Not Due to Its Dephosphorylation. PLoS One 10:e0130457
Sanders, Honi; Rennó-Costa, César; Idiart, Marco et al. (2015) Grid Cells and Place Cells: An Integrated View of their Navigational and Memory Function. Trends Neurosci 38:763-775
Lisman, John (2015) The challenge of understanding the brain: where we stand in 2015. Neuron 86:864-882
Sasaki, Takuya; Leutgeb, Stefan; Leutgeb, Jill K (2015) Spatial and memory circuits in the medial entorhinal cortex. Curr Opin Neurobiol 32:16-23
Lisman, John (2014) Two-phase model of the basal ganglia: implications for discontinuous control of the motor system. Philos Trans R Soc Lond B Biol Sci 369:
Lisman, John (2014) Gamma frequency feedback inhibition accounts for key aspects of orientation selectivity in V1. Network 25:63-71

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