Anxiety disorders such as post-traumatic stress disorder (PTSD) are characterized by deficient regulation of emotional responses to environmental cues. An emerging animal model of emotional regulation is extinction of Pavlovian fear conditioning, in which a tone that had been previously paired with a shock is repeatedly presented in the absence of the shock. Impaired extinction of fear is thought to contribute to PTSD and other anxiety disorders. It is now generally accepted that extinction is new learning that, like other forms of learning, proceeds through acquisition, consolidation and retrieval phases. Studies performed in the previous cycle of this grant show that the infralimbic prefrontal cortex (IL) plays a key role in the consolidation of extinction in rats. Neurons in IL exhibit NMDA receptor-dependent bursting immediately after extinction, and this bursting is correlated with the strength of extinction memory. Extinction-related bursting in IL likely reflects activation of specific inputs necessary for the consolidation of extinction. The overall goal of this grant is to understand how inputs to IL modulate bursting and excitability of IL neurons, thereby facilitating consolidation of extinction.
In Aim 1, we will evaluate the contribution of candidate inputs to IL (from the hippocampus, basolateral amygdala, or mediodorsal thalamus) in the consolidation of fear extinction, using post-training pharmacological inactivation.
In Aim 2, we will evaluate the contribution of candidate inputs to extinction-related bursting in IL neurons. This will be done by: 1) pharmacologically inactivating inputs while recording from single IL neurons, 2) recording simultaneously from input neurons and IL neurons, 3) microstimulating input neurons to strengthen extinction consolidation.
In Aim 3, we will evaluate the effect of extinction on the intrinsic excitability of IL neurons, using whole cell patch clamp recording. We will assess the timecourse of extinction-induced changes in IL excitability, as evidenced by the number of spikes evoked by injected current and the tendency to burst. We will then determine the extent to which this process depends on NMDA receptors and inputs to IL. Understanding the mechanisms by which the IL consolidates extinction could explain why a minority of individuals develop PTSD after a traumatic experience. Relevance This research will explore the physiological mechanisms of consolidation of extinction learning. Understanding the mechanisms by which the prefrontal cortex consolidates extinction of fear could explain why a minority of individuals develop post-traumatic stress disorder after a traumatic experience. This information could also lead to new ways to increase the effectiveness of extinction-based therapies for treatment of PTSD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH058883-16
Application #
8292235
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Vicentic, Aleksandra
Project Start
1998-08-01
Project End
2013-07-31
Budget Start
2012-06-01
Budget End
2013-07-31
Support Year
16
Fiscal Year
2012
Total Cost
$302,109
Indirect Cost
$100,703
Name
University of Puerto Rico Med Sciences
Department
Psychiatry
Type
Schools of Medicine
DUNS #
948108063
City
San Juan
State
PR
Country
United States
Zip Code
00936
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Pendyam, Sandeep; Bravo-Rivera, Christian; Burgos-Robles, Anthony et al. (2013) Fear signaling in the prelimbic-amygdala circuit: a computational modeling and recording study. J Neurophysiol 110:844-61
Burgos-Robles, Anthony; Bravo-Rivera, Hector; Quirk, Gregory J (2013) Prelimbic and infralimbic neurons signal distinct aspects of appetitive instrumental behavior. PLoS One 8:e57575
Padilla-Coreano, Nancy; Do-Monte, Fabricio H; Quirk, Gregory J (2012) A time-dependent role of midline thalamic nuclei in the retrieval of fear memory. Neuropharmacology 62:457-63
Rodriguez-Romaguera, Jose; Do Monte, Fabricio H M; Quirk, Gregory J (2012) Deep brain stimulation of the ventral striatum enhances extinction of conditioned fear. Proc Natl Acad Sci U S A 109:8764-9

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