This competing continuation application focuses on increasing our understanding of the cellular mechanisms in entorhinal cortex for active maintenance of spatial and non-spatial information and for encoding of episodic memory. This includes analysis of cellular mechanisms underlying the grid cell firing properties of entorhinal neurons, and analysis of the cellular mechanisms underlying persistent firing activity which could be involved in working memory and representation of continuous dimensions of sensory input. This work will enhance our understanding of memory-related neurological disorders such as Alzheimer's disease, which is associated with extensive pathology in entorhinal cortex, and understanding of memory components of mental disorders including schizophrenia, anxiety disorders and depression. Research in Aim #1 will use current clamp and voltage clamp techniques to analyze differences in frequency of subthreshold oscillations along the dorsal-ventral axis of entorhinal cortex building on data shown in PRELIMINARY DATA and accepted for publication in Science. These experiments test predictions from computational models showing how differences in temporal frequency could underlie differences in spatial periodicity of grid cell unit responses along the dorsal-ventral axis of the entorhinal cortex in recordings from awake, behaving rats. Research in Aim #2 will extend previous detailed models of single cell mechanisms for persistent spiking in layers V, III and II of entorhinal cortex, developing models for the induction of this persistent spiking with synaptic stimulation, and determining the role of metabotropic glutamate receptors in this induction process as demonstrated in preliminary experiments shown in the PRELIMINARY DATA section. Research in Aim #3 will focus on the role of oscillatory and persistent firing mechanisms in the maintenance of sequences of neural activity, testing the role of cellular mechanisms of persistent spiking in maintaining sequences of neural spiking activity across a population of neurons. Together these studies will assist in understanding the dynamic role of entorhinal cortex in representing environmental stimuli for active maintenance and encoding into episodic memory.

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National Institute of Mental Health (NIMH)
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Neurobiology of Learning and Memory Study Section (LAM)
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Glanzman, Dennis L
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Boston University
Schools of Arts and Sciences
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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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