Memory's purpose is to guide adaptive behavior: we recall the past to inform the present, to anticipate the outcome of choices, and thereby guide goal-directed responses. To be useful, memory retrieval must be selective, directed by the salient features of situations, and flexible to adapt to changing internal goals, environmental opportunities, and potential actions. The hippocampus and the orbital prefrontal cortex (OFC) are crucial for different aspects of adaptive behavior, and dysfunction of either of these brain regions can contribute to neuropsychiatric disorders including Alzheimer's disease, PTSD, and schizophrenia. This proposal will investigate how the OFC and the hippocampus contribute to flexible, goal-directed, memory guided behavior. The experiments, part of a larger research program on how prefrontal cortex contributes to memory, will test the general hypothesis that bidirectional interactions between OFC and hippocampal circuits provide key mechanisms for selective retrieval of goal-related representations by integrating reward history and memory for episodes.
The specific aims will investigate these mechanisms by combining behavior analysis, temporary inactivation, simultaneous recording of neuronal activity in both structures, and deep brain stimulation (DBS).
Aim 1 will assess the functional interactions between the two structures during learning and memory retrieval. Rats will be trained in a + maze task that either requires one structure, the other, both, or neither. Interactions between the structures will be tested by temporarily disrupting one, the other, or both on opposite sides of the brain. If OFC-hippocampal interactions are required for flexible memory retrieval, then the crossed inactivation should produce similar impairments as bilateral inactivation.
Aim 2 will record neuronal activity in both structures simultaneously to determine how activity within and between the OFC and hippocampus predict learning and memory performance. We recently identified EEG patterns in the hippocampus that predicted memory retrieval, and discovered that DBS could both mimic these patterns and restore memory in otherwise amnestic animals.
Aim 3 will therefore test the causal relationships between the OFC and hippocampus by combining temporary inactivation, dual recordings, and DBS. Recording one structure while disrupting activity in the other will determine the extent to which normal coding in each structure depends on the other,and how these interactions influence learning and memory. Targetted patterns of DBS will be used to mimic identified signals within and between hippocampal and OFC circuits to determine if the effects of inactivation can be overcome, or normal performance enhanced. The outcome will advance neuroscience by revealing how the OFC and hippocampus interact to guide flexible and selective use of memory, and will inform emerging treatments for behavioral and neuropsychiatric disorders that involve disintegration of prefrontal cortex and hippocampal functions, including schizophrenia and Alzheimer's disease.

Public Health Relevance

Memory for recent experience is impaired early in Alzheimer's disease, and associated with damage to neurons in the cortex and hippocampus. The organization of behavior and memory depend upon the prefrontal cortex. The proposed experiments will investigate how prefrontal and hippocampal neurons interact to contribute to memory, a fundamental issue to neuroscience, neurology, and psychiatry.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
4R01MH073689-10
Application #
8974442
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Buhring, Bettina D
Project Start
2005-04-01
Project End
2016-11-30
Budget Start
2016-02-17
Budget End
2016-11-30
Support Year
10
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Riceberg, Justin S; Shapiro, Matthew L (2017) Orbitofrontal Cortex Signals Expected Outcomes with Predictive Codes When Stable Contingencies Promote the Integration of Reward History. J Neurosci 37:2010-2021
Seip-Cammack, Katharine M; Young, James J; Young, Megan E et al. (2017) Partial lesion of the nigrostriatal dopamine pathway in rats impairs egocentric learning but not spatial learning or behavioral flexibility. Behav Neurosci 131:135-42
Guise, Kevin G; Shapiro, Matthew L (2017) Medial Prefrontal Cortex Reduces Memory Interference by Modifying Hippocampal Encoding. Neuron 94:183-192.e8
Harony-Nicolas, Hala; Kay, Maya; Hoffmann, Johann du et al. (2017) Oxytocin improves behavioral and electrophysiological deficits in a novel Shank3-deficient rat. Elife 6:
Golden, Sam A; Heshmati, Mitra; Flanigan, Meghan et al. (2016) Basal forebrain projections to the lateral habenula modulate aggression reward. Nature 534:688-92
Shapiro, Matthew (2015) A limited positioning system for memory. Hippocampus 25:690-6
Christoffel, Daniel J; Golden, Sam A; Walsh, Jessica J et al. (2015) Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress. Nat Neurosci 18:962-4
Tavares, Rita Morais; Mendelsohn, Avi; Grossman, Yael et al. (2015) A Map for Social Navigation in the Human Brain. Neuron 87:231-43
Fletcher, Bonnie R; Hill, Gordon S; Long, Jeffrey M et al. (2014) A fine balance: Regulation of hippocampal Arc/Arg3.1 transcription, translation and degradation in a rat model of normal cognitive aging. Neurobiol Learn Mem 115:58-67
Seip-Cammack, Katharine M; Shapiro, Matthew L (2014) Behavioral flexibility and response selection are impaired after limited exposure to oxycodone. Learn Mem 21:686-95

Showing the most recent 10 out of 26 publications