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 #
5R01MH073689-07
Application #
8420336
Study Section
Special Emphasis Panel (ZRG1-IFCN-L (02))
Program Officer
Osborn, Bettina D
Project Start
2005-04-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
7
Fiscal Year
2013
Total Cost
$405,604
Indirect Cost
$165,604
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
Bahar, Amir S; Shapiro, Matthew L (2012) Remembering to learn: independent place and journey coding mechanisms contribute to memory transfer. J Neurosci 32:2191-203
Ferbinteanu, Janina; Shirvalkar, Prasad; Shapiro, Matthew L (2011) Memory modulates journey-dependent coding in the rat hippocampus. J Neurosci 31:9135-46
Young, James J; Shapiro, Matthew L (2011) Dynamic coding of goal-directed paths by orbital prefrontal cortex. J Neurosci 31:5989-6000
Bahar, Amir S; Shirvalkar, Prasad R; Shapiro, Matthew L (2011) Memory-guided learning: CA1 and CA3 neuronal ensembles differentially encode the commonalities and differences between situations. J Neurosci 31:12270-81
Shirvalkar, Prasad R; Rapp, Peter R; Shapiro, Matthew L (2010) Bidirectional changes to hippocampal theta-gamma comodulation predict memory for recent spatial episodes. Proc Natl Acad Sci U S A 107:7054-9
Shirvalkar, Prasad R; Shapiro, Mathew L (2010) Design and construction of a cost effective headstage for simultaneous neural stimulation and recording in the water maze. J Vis Exp :
Young, James J; Shapiro, Matthew L (2009) Double dissociation and hierarchical organization of strategy switches and reversals in the rat PFC. Behav Neurosci 123:1028-35
Kennedy, Pamela J; Shapiro, Matthew L (2009) Motivational states activate distinct hippocampal representations to guide goal-directed behaviors. Proc Natl Acad Sci U S A 106:10805-10
Rich, Erin L; Shapiro, Matthew (2009) Rat prefrontal cortical neurons selectively code strategy switches. J Neurosci 29:7208-19
Bozdagi, Ozlem; Rich, Erin; Tronel, Sophie et al. (2008) The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism. J Neurosci 28:9857-69

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