We aim to study how populations of neurons in the hippocampus and prefrontal cortex support navigational learning and decision-making. During awake behavior, hippocampal neurons are active in precise sequences that reflect trajectories taken in the past, and hypothetical trajectories to be taken in the future. This phenomenon is known as awake replay. The broad objective of this proposal is to investigate a possible role for awake replay in learning and decision making. Previous data together with a model suggest a framework in which replay sequences can be used to learn trajectories to reward locations, and also provide the ability to """"""""look ahead"""""""" along hypothetical future trajectories during decision-making. We make use of high-density tetrode electrophysiology techniques which allow simultaneous recording of hundreds of neurons in multiple brain regions, in freely behaving animals. We record single unit and wideband EEG activity during the learning and performance of navigational tasks. Our preliminary data show that replay undergoes learning-related changes, that replay in the hippocampus is closely coordinated with activity in prefrontal cortex which is an area strongly associated with decision-making, and that replay at choice points is predictive of navigational decisions. We will pursue these preliminary results in three specific aims. Understanding how replay relates to learning will provide novel insight into offline mechanisms of learning, which are increasingly thought to be important, both in normal cognition, and in diseases such as Alzheimer's disease, autism and schizophrenia. Understanding how the hippocampus interacts with prefrontal cortex during replay will shed further light on the importance of offline activity, and also provide novel insight into the way that the hippocampus conveys specific information to areas of the brain that influence behavior. Hence, we will investigate a novel and important link between hippocampal neural activity and behavioral outcomes. Finally, understanding how hippocampal replay is organized during decision-making will provide novel insight into hippocampal memory retrieval. Understanding how the hippocampus supports memory is a major goal in medicine, given the involvement of the hippocampus in memory problems in Alzheimer's disease, Korskoff's syndrome, normal aging, stroke and temporal lobe epilepsy. Further, this study may reveal novel prefrontal mechanisms of planning and decision making, which may shed light on those brain diseases that have been associated with degraded prefrontal function, such as schizophrenia and autism. Ultimately, the search for the neural basis of memory is a fundamental goal with profound implications for the development of therapeutic targets in brain disease.

Public Health Relevance

Despite the prevalence of memory disorders associated with damage to the hippocampus, from such conditions as Alzheimer's disease, aging, stroke and epilepsy, we lack a mechanistic understanding of how hippocampal neurons encode and retrieve memories, which could help us address these problems. However, recently developed techniques for recording from large numbers of neurons simultaneously in awake, freely behaving animals, have begun to reveal patterns of activity across hippocampal neurons that may provide a model of memory processing. This study will take these results further by asking how the retrieval of specific memories by the hippocampus drives the selection of appropriate behavior, thus shining light on the very processes that may go awry when memory fails.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085823-03
Application #
8266287
Study Section
Cognitive Neuroscience Study Section (COG)
Program Officer
Osborn, Bettina D
Project Start
2010-07-15
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$405,900
Indirect Cost
$158,400
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ambrose, R Ellen; Pfeiffer, Brad E; Foster, David J (2016) Reverse Replay of Hippocampal Place Cells Is Uniquely Modulated by Changing Reward. Neuron 91:1124-1136
Feng, Ting; Silva, Delia; Foster, David J (2015) Dissociation between the experience-dependent development of hippocampal theta sequences and single-trial phase precession. J Neurosci 35:4890-902
Altimus, Cara; Harrold, Jon; Jaaro-Peled, Hanna et al. (2015) Disordered ripples are a common feature of genetically distinct mouse models relevant to schizophrenia. Mol Neuropsychiatry 1:52-59
Pfeiffer, Brad E; Foster, David J (2015) Discovering the brain's cognitive map. JAMA Neurol 72:257-8
Wu, Xiaojing; Foster, David J (2014) Hippocampal replay captures the unique topological structure of a novel environment. J Neurosci 34:6459-69
Pfeiffer, Brad E; Foster, David J (2013) Hippocampal place-cell sequences depict future paths to remembered goals. Nature 497:74-9
Suh, Junghyup; Foster, David J; Davoudi, Heydar et al. (2013) Impaired hippocampal ripple-associated replay in a mouse model of schizophrenia. Neuron 80:484-93
Foster, David J; Knierim, James J (2012) Sequence learning and the role of the hippocampus in rodent navigation. Curr Opin Neurobiol 22:294-300