This competing renewal application focuses on the influence of cellular mechanisms on the coding of space by grid cells, head direction cells and conjunctive grid-by-head-direction cells in the rat medial entorhinal cortex.
Specific Aim #1 : In this aim, the properties of grid cells, conjunctive grid-by-head-direction cells and head direction cells will be analyzed with recordings of multiple single units in medial entorhinal cortex. The dynamical properties of firing will be analyzed for theta cycle skipping and theta phase precession relative to entorhinal theta rhythm oscillations, for the interaction of entorhinal rhythmic activity with hippocampal rhythmic activity in the field potential, and for the effects of local infusions of pharmacological agents. Computational biophysical network models based on recent anatomical data will combine features of oscillatory dynamics and attractor dynamics to address how the neural properties observed in recordings before and during pharmacological manipulations could arise from interactions of intrinsic properties with excitatory and inhibitory synaptic input.
Specific Aim #2 : In this aim, experiments will analyze specific cellular properties of entorhinal neurons that could contribute to the dynamical properties of grid cell firing. Experiments will include testing the phase of spiking dynamics relative to rhythmic synaptic input to analyze potential cellular mechanisms of grid cell firing properties. Experiments will als address the resonance properties of entorhinal interneurons and the influence of modulatory receptors on entorhinal interneuron firing properties. In vitro intracellular recordings will be compared with in vivo intracellular recordings during local infusions of pharmacological agents to determine how the intracellular properties extend to the intact circuits. Experiments will be guided by multicompartmental biophysical simulations analyzing how intrinsic membrane currents influence the response to synaptic input and how this could lead to the generation of spiking patterns in entorhinal grid cells, head direction cells and conjunctive grid-by-head-direction cells. The results of these experimental and computational studies can elucidate cellular and network mechanisms for generation of grid cells and their spiking relative to field potential oscillations. Investigating these cellular mechanisms may help understanding how events within an episode are encoded into memory. The analysis of effects of modulatory influences will provide insight into the dynamics underlying grid cell firing properties and into how drugs affect memory function. This influence on memory function could be part of the therapeutic effect of drugs used for treatment of anxiety disorders and depression. This analysis of entorhinal mechanisms for memory is also relevant to understanding the memory deficits associated with disorders that reduce the volume of hippocampus and entorhinal cortex, including Alzheimer's disease, depression and schizophrenia.

Public Health Relevance

This grant focuses on the brain rhythms involved in storing the location where events in an episode take place. This work includes experiments testing the activity of individual brain cells in relation to brain rhythms and location during behavior, and testing the effects of drugs on the rhythms of brain circuits and single cells. These tests could b relevant to understanding how drugs could influence the distortions of memory involved in mental disorders such as depression, which causes memory impairments and a negative bias in memories, as well as schizophrenia, which involves impairments and distortions in memory function.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Glanzman, Dennis L
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Boston University
Schools of Arts and Sciences
United States
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Newman, Ehren L; Climer, Jason R; Hasselmo, Michael E (2014) Grid cell spatial tuning reduced following systemic muscarinic receptor blockade. Hippocampus 24:643-55
Gupta, Kishan; Beer, Nathan J; Keller, Lauren A et al. (2014) Medial entorhinal grid cells and head direction cells rotate with a T-maze more often during less recently experienced rotations. Cereb Cortex 24:1630-44
Hasselmo, Michael E; Stern, Chantal E (2014) Theta rhythm and the encoding and retrieval of space and time. Neuroimage 85 Pt 2:656-66
Newman, Ehren L; Hasselmo, Michael E (2014) CA3 sees the big picture while dentate gyrus splits hairs. Neuron 81:226-8
Hasselmo, Michael E (2014) Neuronal rebound spiking, resonance frequency and theta cycle skipping may contribute to grid cell firing in medial entorhinal cortex. Philos Trans R Soc Lond B Biol Sci 369:20120523
Climer, Jason R; Newman, Ehren L; Hasselmo, Michael E (2013) Phase coding by grid cells in unconstrained environments: two-dimensional phase precession. Eur J Neurosci 38:2526-41
Tigerholm, Jenny; Migliore, Michele; Fransen, Erik (2013) Integration of synchronous synaptic input in CA1 pyramidal neuron depends on spatial and temporal distributions of the input. Hippocampus 23:87-99
Yoshida, Motoharu; Jochems, Arthur; Hasselmo, Michael E (2013) Comparison of properties of medial entorhinal cortex layer II neurons in two anatomical dimensions with and without cholinergic activation. PLoS One 8:e73904
Engelbrecht, Jan R; Loncich, Kristen; Mirollo, Renato et al. (2013) Rhythm-induced spike-timing patterns characterized by 1D firing maps. J Comput Neurosci 34:59-71
Gupta, K; Erdem, U M; Hasselmo, M E (2013) Modeling of grid cell activity demonstrates in vivo entorhinal 'look-ahead' properties. Neuroscience 247:395-411

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