The hippocampus is a brain structure that is critical for forming and retaining long-term, episodic memories. Damage to the hippocampus from Alzheimer's Disease, stroke, epilepsy, or traumatic brain injury causes a profound amnesic syndrome in which patients are unable to form lasting memories of the everyday events of their lives. Converging evidence from humans and animal models suggests that the hippocampus integrates information from two parallel processing streams, which convey information about spatial location (context) and about individual objects or items, to create conjunctive representations of objects in place (or events in context). This proposal will investigate the organization of the flow of information through these parallel processing streams into the hippocampus, as well as the interaction of these streams with intrahippocampal processing of the CA3 and CA1 regions. Prior work on hippocampal place cells of rats has demonstrated a dissociation between the hippocampal CA3 and CA1 fields in terms of the coherence of ensemble spatial representations when local cues and global landmarks are pitted against each other. CA3 demonstrated a more coherent representation than CA1, in that the place fields tended to be controlled coherently by the local cues, whereas CA1 representations split into local- and global-landmark dominated ensembles. This proposal will test a series of hypotheses regarding the anatomical flow of information into the CA3 and CA1 regions that may account for the different responses of these regions. Multi-electrode techniques will be used to record the activity of neurons in different parts of the CA3 and CA1 regions and their input structures, including the entorhinal cortex and subicular complex (parasubiculum and presubiculum) in freely behaving rats. Local and global cues sets will be altered to test whether different parts of the hippocampal formation are preferentially bound to local or global frames of reference, and whether the known anatomical projections among these areas can account for the differential responses of CA3 and CA1 ensembles to these manipulations. These experiments will generate great insight into the nature of information processing and the organization of information flow into and through the hippocampal system, information that is critical toward understanding the computations performed by the hippocampus in the service of episodic memory. Such fundamental knowledge may be crucial for devising treatment strategies to ameliorate the devastating symptoms of hippocampal amnesia and to target selective sites for potential pharmaceutical or surgical therapies for these disorders. Profound memory loss is a hallmark of such degenerative brain disorders as Alzheimer's Disease, which originates in an area called the entorhinal cortex, progresses into the hippocampus, and eventually progresses throughout the brain's cortical regions. The experiments in this proposal will address fundamental issues regarding the nature of information processing and functions in the entorhinal cortex and hippocampus, generating insight into how these brain regions work normally and how they may go awry when the regions are damaged by Alzheimer's epilepsy, stroke, or traumatic injury.

Public Health Relevance

Profound memory loss is a hallmark of such degenerative brain disorders as Alzheimer's Disease, which originates in an area called the entorhinal cortex, progresses into the hippocampus, and eventually progresses throughout the brain's cortical regions. The experiments in this proposal will address fundamental issues regarding the nature of information processing and functions in the entorhinal cortex and hippocampus, generating insight into how these brain regions work normally and how they may go awry when the regions are damaged by Alzheimer's epilepsy, stroke, or traumatic injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039456-13
Application #
8215671
Study Section
Special Emphasis Panel (ZRG1-IFCN-L (03))
Program Officer
Babcock, Debra J
Project Start
1999-12-01
Project End
2013-08-14
Budget Start
2012-02-01
Budget End
2013-08-14
Support Year
13
Fiscal Year
2012
Total Cost
$349,302
Indirect Cost
$134,927
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Knierim, James J; Neunuebel, Joshua P; Deshmukh, Sachin S (2014) Functional correlates of the lateral and medial entorhinal cortex: objects, path integration and local-global reference frames. Philos Trans R Soc Lond B Biol Sci 369:20130369
Neunuebel, Joshua P; Knierim, James J (2014) CA3 retrieves coherent representations from degraded input: direct evidence for CA3 pattern completion and dentate gyrus pattern separation. Neuron 81:416-27
Monaco, Joseph D; Rao, Geeta; Roth, Eric D et al. (2014) Attentive scanning behavior drives one-trial potentiation of hippocampal place fields. Nat Neurosci 17:725-31
Deshmukh, Sachin S; Knierim, James J (2013) Influence of local objects on hippocampal representations: Landmark vectors and memory. Hippocampus 23:253-67
Neunuebel, Joshua P; Yoganarasimha, D; Rao, Geeta et al. (2013) Conflicts between local and global spatial frameworks dissociate neural representations of the lateral and medial entorhinal cortex. J Neurosci 33:9246-58
Foster, David J; Knierim, James J (2012) Sequence learning and the role of the hippocampus in rodent navigation. Curr Opin Neurobiol 22:294-300
Neunuebel, Joshua P; Knierim, James J (2012) Spatial firing correlates of physiologically distinct cell types of the rat dentate gyrus. J Neurosci 32:3848-58
Monaco, Joseph D; Knierim, James J; Zhang, Kechen (2011) Sensory feedback, error correction, and remapping in a multiple oscillator model of place-cell activity. Front Comput Neurosci 5:39
Knierim, James J; Hamilton, Derek A (2011) Framing spatial cognition: neural representations of proximal and distal frames of reference and their roles in navigation. Physiol Rev 91:1245-79
Deshmukh, Sachin S; Knierim, James J (2011) Representation of non-spatial and spatial information in the lateral entorhinal cortex. Front Behav Neurosci 5:69

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