A pervasive problem in many psychiatric disorders, including depression and post-traumatic stress disorder, is the failure to inhibit intense emotional reactions elicited by certain environmental cues. Behavioral interventions often attempt to eliminate these reactions through extinction techniques designed to weaken the ability of environmental cues to trigger problematic responses by severing the relation between the cues and responses. A challenge for the long-term success of this kind of intervention, however, is that the behavior that is suppressed during extinction spontaneously recovers with time, demonstrating that the original memory remains intact after extinction. The experiments outlined in this proposal are designed to examine some circumstances that may lead to the persistence of extinction, thereby weakening any spontaneous recovery effect. Specifically, the aims of the proposal are centered around the role of time in the development and long-term maintenance of extinction of fear in mice. First, we will examine the role of time between extinction experiences to examine the conditions under which different temporal patterns of extinction may suppress fearful memories. Second, we will examine extinction as a function of time since acquisition to see if there are intervals after acquisition in which the fearful memory is particularly vulnerable to the suppressive properties of extinction. Third, we will explore the effects of time since extinction on sensitivity to pharmacological manipulations. Our pharmacological studies will focus on protein kinase A and protein synthesis, two critical molecular processes involved in memory. These pharmacological studies will examine the contribution of the hippocampus to the formation of extinction memories after contextual fear conditioning. At a basic level, determining the course and persistence of extinction after these different treatments will have important implications for current theories of extinction and learning in general. At a clinical level, exploring the behavioral and pharmacological interventions that make the extinction memory long lasting will suggest treatment combinations that may be used to cause lasting suppression of debilitating environmentally triggered responses that underlie many psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH077111-04
Application #
7664637
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Vicentic, Aleksandra
Project Start
2006-09-30
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$260,189
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Bolkan, Scott S; Lattal, K Matthew (2014) Opposing effects of D-cycloserine on fear despite a common extinction duration: interactions between brain regions and behavior. Neurobiol Learn Mem 113:25-34
Raybuck, Jonathan D; Lattal, K Matthew (2014) Bridging the interval: theory and neurobiology of trace conditioning. Behav Processes 101:103-11
Raybuck, J D; Lattal, K M (2014) Differential effects of dorsal hippocampal inactivation on expression of recent and remote drug and fear memory. Neurosci Lett 569:1-5
Tipps, Megan E; Raybuck, Jonathan D; Lattal, K Matthew (2014) Substance abuse, memory, and post-traumatic stress disorder. Neurobiol Learn Mem 112:87-100
Abraham, Antony D; Neve, Kim A; Lattal, K Matthew (2014) Dopamine and extinction: a convergence of theory with fear and reward circuitry. Neurobiol Learn Mem 108:65-77
Stafford, James M; Maughan, DeeAnna K; Ilioi, Elena C et al. (2013) Exposure to a fearful context during periods of memory plasticity impairs extinction via hyperactivation of frontal-amygdalar circuits. Learn Mem 20:156-63
Lattal, K Matthew; Wood, Marcelo A (2013) Epigenetics and persistent memory: implications for reconsolidation and silent extinction beyond the zero. Nat Neurosci 16:124-9
Bernardi, Rick E; Lattal, K Matthew (2012) Prazosin differentially affects extinction of cocaine conditioned place preference on the basis of dose and initial preference. Neuroreport 23:1048-51
Lattal, K Matthew; Maughan, Deeanna K (2012) A parametric analysis of factors affecting acquisition and extinction of contextual fear in C57BL/6 and DBA/2 mice. Behav Processes 90:49-57
Lattal, K Matthew; Lattal, Kennon A (2012) Facets of Pavlovian and operant extinction. Behav Processes 90:1-8

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