The dendritic trees of neurons in the brain's cortex conduct elemental brain functions such as information processing and learning. Research in brain slices has provided a wealth of information about the dendritic mechanisms that could be operating in behaving animals to integrate, and alter the strength of, synaptic inputs from presynaptic sources. Key among these mechanisms are back-propagating action potentials and nonlinear integration of synaptic inputs leading to dendritic spiking, which confer to the dendriti tree a host of local and global signaling possibilities. Numerous alluring models of information processing and learning have arisen as a result of these in vitro findings, but currently almost nothing is known about which of these mechanisms are at work in awake, behaving animals. The present proposal leverages recent technical advances developed by the PI that enable functional imaging of calcium transients with sub-cellular resolution in the hippocampus of head-restrained mice performing spatial behaviors in a virtual-reality interface. Using these methods, the research proposed in this grant application will allow us to bridge two disconnected areas of neuroscience research: studies that characterize the firing patterns of hippocampal neurons in behaving rodents, and experiments that study the mechanisms underlying firing and plasticity in these cells in reduced preparations. Specifically, we aim to determine the behavioral relevance of the fundamental dendritic mechanisms of bAPs and dSpikes in the hippocampus. This will allow testing of models of plasticity which have been developed based on in vitro data, across a wide range of parameter space, to finally establish which learning mechanisms are behaviorally relevant.

Public Health Relevance

The hippocampus is a brain structure critically involved in learning, memory and spatial navigation, and its dysfunction is associated with amnesia, Alzheimer's disease, and epilepsy. It is not known how the neurons of the hippocampus change their connections to other neurons to facilitate the learning of a new task or the memory of a specific life episode, although several candidate mechanisms have been suggested by experiments in brain slices. In the present application, we propose to establish the behavioral relevance of basic neuronal mechanisms that can be used in the brains of awake animals in order to provide a framework for understanding information processing and memory formation and retrieval in normal brain functioning and in disease states.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Asanuma, Chiiko
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Northwestern University at Chicago
Schools of Arts and Sciences
United States
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Heys, James G; Dombeck, Daniel A (2018) Evidence for a subcircuit in medial entorhinal cortex representing elapsed time during immobility. Nat Neurosci 21:1574-1582
Radvansky, Brad A; Dombeck, Daniel A (2018) An olfactory virtual reality system for mice. Nat Commun 9:839
Sheffield, Mark E J; Adoff, Michael D; Dombeck, Daniel A (2017) Increased Prevalence of Calcium Transients across the Dendritic Arbor during Place Field Formation. Neuron 96:490-504.e5
Howe, M W; Dombeck, D A (2016) Rapid signalling in distinct dopaminergic axons during locomotion and reward. Nature 535:505-10
Sheffield, Mark E J; Dombeck, Daniel A (2015) Calcium transient prevalence across the dendritic arbour predicts place field properties. Nature 517:200-4
Heys, James G; Rangarajan, Krsna V; Dombeck, Daniel A (2014) The functional micro-organization of grid cells revealed by cellular-resolution imaging. Neuron 84:1079-90