The hippocampus is a brain structure that is critical for normal learning and memory functions. One of the first brain regions to deteriorate in Alzheimer's Disease is the entorhinal cortex, the key processing stage between the neocortex and the hippocampus. This degeneration correlates with the memory deficits that are among the first cognitive symptoms of the disease. To understand why hippocampal damage causes such severe memory deficits, it is necessary to understand the basic computational functions of this brain region. The entorhinal cortex is divided into two regions: the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC). A long-standing theory hypothesizes that the hippocampus supports the conscious recall of autobiographical events (?episodic memory?) by binding the different aspects of an experience?the sights, sounds, thoughts, emotions, etc., experienced at a moment in one's life?onto a framework that represents the spatial context in which that experienced occurred. The MEC is thought to provide the hippocampus with this spatial framework, whereas the LEC is thought to represent the ?item and events? of experience. Much is known about how the MEC represents space, but how the LEC represents experience is much less understood.
The specific aims of this project are to test the hypothesis that the LEC encodes the location of attended items in the external world relative to the individual (i.e., an egocentric framework), whereas the MEC encodes both the locations of attended external items and the location of the individual in a world-centered coordinate system (i.e., an allocentric framework). Furthermore, we will test the hypothesis that the hippocampus incorporates new information within the spatial framework by creating new place fields when the rat performs a discrete, attentive behavior known as head scanning, especially when that behavior is accompanied by a reward. Finally, we will test the hypothesis that the hippocampus explicitly encodes the identity of nonspatial, surface texture cues experienced at a given location by modulating the firing rate of the place cell at that location (so-called rate remapping). The results of these experiments will provide crucial knowledge about how the brain encodes and stores representations of events within their spatial contexts, which underlies our abilities to form conscious memories of our life experiences.

Public Health Relevance

Memory loss is a devastating consequence of a number of neurological disorders, including Alzheimer's disease, stroke, and epilepsy. The hippocampus is a brain structure that is critical for the ability to form new memories and is highly susceptible to damage from these disorders, but the exact neural circuits and mechanisms underlying the role of the hippocampus in memory are not well understood. The results from this project will provide insight into how the normal brain encodes memories, which may provide powerful new clues to understand why deficits in memory arise from these neurological disorders and how these crippling deficits may be ameliorated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039456-21
Application #
9959475
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Babcock, Debra J
Project Start
1999-12-01
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
21
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Wang, Cheng; Chen, Xiaojing; Lee, Heekyung et al. (2018) Egocentric coding of external items in the lateral entorhinal cortex. Science 362:945-949
Savelli, Francesco; Luck, J D; Knierim, James J (2017) Framing of grid cells within and beyond navigation boundaries. Elife 6:
Connor, Charles E; Knierim, James J (2017) Integration of objects and space in perception and memory. Nat Neurosci 20:1493-1503
Knierim, James J; Neunuebel, Joshua P (2016) Tracking the flow of hippocampal computation: Pattern separation, pattern completion, and attractor dynamics. Neurobiol Learn Mem 129:38-49
Lee, Heekyung; Wang, Cheng; Deshmukh, Sachin S et al. (2015) Neural Population Evidence of Functional Heterogeneity along the CA3 Transverse Axis: Pattern Completion versus Pattern Separation. Neuron 87:1093-105
Knierim, James J (2015) From the GPS to HM: Place cells, grid cells, and memory. Hippocampus 25:719-25
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

Showing the most recent 10 out of 35 publications