Therapeutic interventions, such as exposure therapy, reduce pathological fear in patients with anxiety disorders-but this fear reduction is often transient and bound to the place or context in which therapy occurs. When patients confront phobic objects or reminders of trauma outside of the clinic, their fear often relapses-a phenomenon termed renewal. The loss of inhibitory control that underlies relapse phenomena, including fear renewal, is a major challenge to clinical interventions for a host of disorders, including anxiety and post- traumatic stress disorder. Therefore, the long-term goal of this project is to understand the neural substrates of fear relapse, particularly the specific brain circuits involved in the contextual control of renewal. To this end, we use Pavlovian fear conditioning and extinction procedures in rats. After fear conditioning, a conditioned stimulus (CS) that predicts an aversive unconditioned stimulus produces conditioned fear responses, including freezing, in any context the CS is encountered. These learned fear responses can be suppressed by repeated CS-alone presentations, a procedure termed extinction. Unlike fear memories, extinction memories are labile and context-dependent. That is, fear to an extinguished CS is suppressed in the extinction context, but renews in any other context. The context-dependence of extinction has major implications for the efficacy of behavioral interventions in humans, such as exposure therapy, that are mediated by extinction learning. Work in previous years of the project has identified a critical role for the hippocampus, medial prefrontal cortex, and amygdala in regulating when and where fear to an extinguished CS, however the nature of the functional interactions amongst these brain areas is not clear. Here we test a novel hypothesis that renewal is mediated by an active dampening of the inhibition that accrues to an extinguished CS. Specifically, we propose that the ventral hippocampus dampens prefrontal circuits that inhibit amygdala neurons involved in fear expression. We will test this hypothesis by using novel circuit tracing and manipulation methods (e.g., `designer receptors exclusively activated by designer drugs' or DREADDs and single-unit recordings in awake, behaving animals. The first specific aim of the project examines whether ventral hippocampal projections to the infralimbic cortex mediate fear renewal. The second specific aim examines whether ventral hippocampal neurons regulate behaviorally relevant spike firing in the mPFC. The third specific aim determines whether inhibition of the infralimbic cortex and its projections to the amygdala are necessary for fear relapse after extinction. This work has broad significance for understanding emotional regulation in the brain and the development of effective behavioral therapies for fear and anxiety disorders.

Public Health Relevance

Therapeutic interventions, such as exposure therapy, reduce pathological fear in patients with anxiety disorders-but this fear reduction is often transient and bound to the place or context in which therapy occurs. When patients confront phobic objects or reminders of trauma outside of the clinic, their fear often relapses-a phenomenon termed 'renewal'. The loss of inhibitory control that underlies relapse phenomena, including fear renewal, is a major challenge to clinical interventions for a host of disorders, including anxiety and post- traumatic stress disorder. Therefore, the long-term goal of this project is to understand the neural substrates of fear relapse, particularly the specific brain circuits involved in the contextual control of renewal. We have found that the fear renewal involves the ventral hippocampus, medial prefrontal cortex and amygdala. We hypothesize that renewal occurs as a result of an active dampening of extinction-related inhibition, which is mediated by ventral hippocampal projections to the medial prefrontal cortex. The goal of the present proposal is to test this model using functional tracing techniques, selective circuit manipulations using `designer receptors exclusively activated by designer drugs' (DREADDs), and single-unit recordings in awake, behaving animals. This work has important implications for understanding the brain mechanisms that contribute to the relapse of fear after therapeutic interventions in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH065961-15
Application #
9407162
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Vicentic, Aleksandra
Project Start
2002-09-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
15
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Texas A&M University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
020271826
City
College Station
State
TX
Country
United States
Zip Code
77845
Goode, Travis D; Maren, Stephen (2017) Role of the bed nucleus of the stria terminalis in aversive learning and memory. Learn Mem 24:480-491
Goode, Travis D; Holloway-Erickson, Crystal M; Maren, Stephen (2017) Extinction after fear memory reactivation fails to eliminate renewal in rats. Neurobiol Learn Mem 142:41-47
Giustino, Thomas F; Maren, Stephen (2017) Chandelier Cells Illuminate Inhibitory Control of Prefrontal-Amygdala Outputs. Trends Neurosci 40:640-642
Acca, Gillian M; Mathew, Abel S; Jin, Jingji et al. (2017) Allopregnanolone induces state-dependent fear via the bed nucleus of the stria terminalis. Horm Behav 89:137-144
Prater, Katherine E; Aurbach, Elyse L; Larcinese, Hanna K et al. (2017) Selectively Bred Rats Provide a Unique Model of Vulnerability to PTSD-Like Behavior and Respond Differentially to FGF2 Augmentation Early in Life. Neuropsychopharmacology 42:1706-1714
Maren, Stephen (2016) Parsing Reward and Aversion in the Amygdala. Neuron 90:209-11
Giustino, Thomas F; Fitzgerald, Paul J; Maren, Stephen (2016) Fear Expression Suppresses Medial Prefrontal Cortical Firing in Rats. PLoS One 11:e0165256
Maren, Stephen; Holmes, Andrew (2016) Stress and Fear Extinction. Neuropsychopharmacology 41:58-79
Giustino, Thomas F; Fitzgerald, Paul J; Maren, Stephen (2016) Revisiting propranolol and PTSD: Memory erasure or extinction enhancement? Neurobiol Learn Mem 130:26-33
Wang, Qian; Jin, Jingji; Maren, Stephen (2016) Renewal of extinguished fear activates ventral hippocampal neurons projecting to the prelimbic and infralimbic cortices in rats. Neurobiol Learn Mem 134 Pt A:38-43

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