Learning reorganizes brain activity to encode long-lasting memories of emotional events. These memories enhance survival by guiding adaptive behaviors like pursuit of food and avoidance of threats. However, in 6.8% of Americans, and as high as 14-16% of U.S. military service members, the experience of trauma leads to severe and recurrent anxiety and fear, exacerbated by reminders of the traumatic event. This syndrome, known as post-traumatic stress disorder (PTSD), shares commonalities with fear-related disorders like panic and phobia, and is characterized by persistent re-experiencing of traumatic emotion. Current treatments for PTSD confer some remission of symptoms, but do not work in some individuals, and frequently become ineffective over time due to relapse. Acquisition and attenuation of emotional responses can be modeled in the laboratory by Pavlovian fear conditioning and extinction. These studies have suggested that one factor impeding recovery from PTSD may be exposure to stress-related neurotransmitters. The goal of this study is to define which cells and brain pathways mediate adverse effects of the neurotransmitter noradrenaline. In preliminary experiments, we determined that noradrenaline signals through the a1 adrenoreceptor subtype to activate inhibitory neurons and increase their transmission in the amygdala, a critical brain region in fear conditioning and a site of abnormal activity in PTSD. Furthermore, we show that these receptors promote formation of fear memories that are resistant to extinction, a process for inhibiting fear that is analogous to exposure-based emotional therapies. The objective of this proposal is to define the specific circuit mechanisms that, when activated by noradrenaline, impede extinction.
Our specific aims are 1. To establish the role of specific inhibitory cell types in noradrenaline-dependent circuit modifications, 2. To test the impact of these inhibitory neurons on behavioral flexibility, and 3. To establish circuit determinants of extinction success and failure. We will rely on transgenic mice, patch-clamp electrophysiology, optogenetics and chemicogenetics to accomplish these goals. The results of these experiments will define cell types as well as synaptic pathways at which improved therapies for attenuating emotion can be directed.

Public Health Relevance

The goal of this proposal is to define specific circuit and neuronal mechanisms of emotional flexibility in fear learning. The results of these studies will identify cells and brain pathways that may be instrumental in recovery from severe emotional experiences in conditions like post-traumatic stress disorder (PTSD).

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH105414-04
Application #
9384758
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Vicentic, Aleksandra
Project Start
2014-12-15
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
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
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Lucas, Elizabeth K; Wu, Wan-Chen; Roman-Ortiz, Ciorana et al. (2018) Prazosin during fear conditioning facilitates subsequent extinction in male C57Bl/6N mice. Psychopharmacology (Berl) :
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Lucas, Elizabeth K; Jegarl, Anita M; Morishita, Hirofumi et al. (2016) Multimodal and Site-Specific Plasticity of Amygdala Parvalbumin Interneurons after Fear Learning. Neuron 91:629-43
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Arruda-Carvalho, Maithe; Clem, Roger L (2014) Pathway-selective adjustment of prefrontal-amygdala transmission during fear encoding. J Neurosci 34:15601-9