Clinical disorders of fear and anxiety, including trauma- and stressor-related disorders, represent an enormous public health burden. Cognitive-behavioral therapies, such as prolonged exposure therapy, have proven to be remarkably effective in reducing pathological fear in patients with these disorders. Nonetheless, there are a number of factors that limit the efficacy of exposure therapy. In particular, stress undermines exposure-based therapies by impairing extinction learning and promoting fear relapse. Despite years of work elucidating the neural circuitry for extinction, the neural mechanisms responsible for stress-induced extinction impairments remain poorly understood. One possibility is that stress dysregulates neuronal activity in the medial prefrontal cortex (mPFC), a brain area that is critical for extinction learning. In support of this possibility, we have recently shown that footshock stress causes lasting decreases in the spontaneous firing of neurons in the infralimbic (IL) division of the mPFC in rats. Decreases in IL firing were associated with an ?immediate extinction deficit? (IED), an extinction impairment that occurs when extinction is performed soon after fear conditioning (a stressor). Importantly, systemic administration of propranolol, a -noradrenergic receptor antagonist, prevented both the stress-induced depression of IL firing and the IED, suggesting a role for locus coeruleus norepinephrine (LC-NE) in this phenomenon. Although these data reveal that noradrenergic transmission is involved in the stress-induced depression of mPFC firing, the neural circuit by which stress perturbs mPFC firing is unknown. Interestingly, we have found that propranolol rescues the IED when delivered to the basolateral amygdala (BLA), but not the IL. Based on this work, we propose a novel hypothesis that stress-induced NE release from the LC recruits an inhibitory BLA->IL circuit that dampens activity in IL principal neurons to impair the acquisition and retention of long-term extinction memories. We propose three specific aims to test this hypothesis using a combination of in vivo electrophysiology, functional circuit tracing, and pharmacogenetic manipulations (e.g., `designer receptors exclusively activated by designer drugs' or DREADDs). The first specific aim of the project examines whether LC-NE projections to the IL or BLA are necessary and sufficient for stress-induced changes in mPFC firing and extinction learning deficits. The second specific aim examines explores whether BLA neurons projecting to the IL or PL mediate these effects. The third specific aim determines whether parvalbumin interneurons (PV-INs) in the mPFC are recruited by LC- NE activation and mediate the immediate extinction deficit through feed forward inhibition by BLA afferents. The outcomes of these aims will advance a novel circuit mechanism for stress-induced extinction impairments. Understanding this mechanism will facilitate the development of novel pharmacotherapeutic approaches that optimally engage mPFC circuits to facilitate extinction learning under stress.

Public Health Relevance

Stress undermines behavioral interventions after trauma by impairing extinction learning and promoting fear relapse. Despite years of work elucidating the neural circuitry for extinction, the neural mechanisms responsible for stress-induced extinction impairments remain poorly understood. In this project, we seek to uncover the brain circuits involved in stress-impaired extinction learning.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH117852-01
Application #
9609605
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Vicentic, Aleksandra
Project Start
2018-06-11
Project End
2023-03-31
Budget Start
2018-06-11
Budget End
2019-03-31
Support Year
1
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
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Ressler, Reed L; Maren, Stephen (2018) Synaptic encoding of fear memories in the amygdala. Curr Opin Neurobiol 54:54-59
Ramanathan, Karthik R; Jin, Jingji; Giustino, Thomas F et al. (2018) Prefrontal projections to the thalamic nucleus reuniens mediate fear extinction. Nat Commun 9:4527
Ramanathan, Karthik R; Ressler, Reed L; Jin, Jingji et al. (2018) Nucleus Reuniens Is Required for Encoding and Retrieving Precise, Hippocampal-Dependent Contextual Fear Memories in Rats. J Neurosci 38:9925-9933