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)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-T (02)M)
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Rossi, Andrew
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Boston University
Schools of Arts and Sciences
United States
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Hasselmo, Michael E; Stern, Chantal E (2018) A network model of behavioural performance in a rule learning task. Philos Trans R Soc Lond B Biol Sci 373:
Hinman, James R; Dannenberg, Holger; Alexander, Andrew S et al. (2018) Neural mechanisms of navigation involving interactions of cortical and subcortical structures. J Neurophysiol 119:2007-2029
Záborszky, Laszlo; Gombkoto, Peter; Varsanyi, Peter et al. (2018) Specific Basal Forebrain-Cortical Cholinergic Circuits Coordinate Cognitive Operations. J Neurosci 38:9446-9458
Ferrante, Michele; Shay, Christopher F; Tsuno, Yusuke et al. (2017) Post-Inhibitory Rebound Spikes in Rat Medial Entorhinal Layer II/III Principal Cells: In Vivo, In Vitro, and Computational Modeling Characterization. Cereb Cortex 27:2111-2125
Hasselmo, Michael E; Hinman, James R; Dannenberg, Holger et al. (2017) Models of spatial and temporal dimensions of memory. Curr Opin Behav Sci 17:27-33
Dannenberg, Holger; Young, Kimberly; Hasselmo, Michael (2017) Modulation of Hippocampal Circuits by Muscarinic and Nicotinic Receptors. Front Neural Circuits 11:102
Ferrante, Michele; Tahvildari, Babak; Duque, Alvaro et al. (2017) Distinct Functional Groups Emerge from the Intrinsic Properties of Molecularly Identified Entorhinal Interneurons and Principal Cells. Cereb Cortex 27:3186-3207
Monaghan, Caitlin K; Chapman 4th, G William; Hasselmo, Michael E (2017) Systemic administration of two different anxiolytic drugs decreases local field potential theta frequency in the medial entorhinal cortex without affecting grid cell firing fields. Neuroscience 364:60-70
Newman, Ehren L; Venditto, Sarah Jo C; Climer, Jason R et al. (2017) Precise spike timing dynamics of hippocampal place cell activity sensitive to cholinergic disruption. Hippocampus 27:1069-1082
Dannenberg, Holger; Hinman, James R; Hasselmo, Michael E (2016) Potential roles of cholinergic modulation in the neural coding of location and movement speed. J Physiol Paris 110:52-64

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