Exposure therapy is the most widely used treatment for excessive fear caused by post-traumatic stress disorder and phobias. During exposure therapy the patient repeatedly confronts the fear-inducing situation or the memory of a traumatic event in a safe environment, which over time results in decreased fear in most patients. However, exposure therapy in its current form rarely leads to a permanent suppression of fear. A better understanding of how exposure therapy, also known as fear extinction, works is therefore needed. A brain region called the basolateral amygdala (BLA) can cause increased fear in both humans and other mammals. We found that the BLA of mice undergoes changes during fear extinction that might help to suppress fear. Specifically, fear extinction silenced BLA fear neurons, while changing the inhibitory synapses that are located around these fear neurons. To test if these changes in perisomatic inhibitory synapses contribute to fear suppression, we silenced the parvalbumin-positive (PV+) interneurons that make these perisomatic inhibitory synapses. This increased the activation of BLA fear neurons and the expression of fear. Furthermore, it changed the activation of neurons in a brain region outside of the BLA called the medial prefrontal cortex (mPFC). Finally, silencing PV+ interneurons in the BLA altered the frequency distribution of local field potential (LFP) oscillations in both the BLA and mPFC, indicating broad changes in the activation of neuronal circuits that connect these two brain regions. Based on these results, we formulated a model in which extinction decreases fear by increasing the ability of PV+ perisomatic synapses to inhibit BLA fear neurons, thereby giving fear-suppressing circuits a competitive advantage over fear-promoting circuits. The three aims of this proposal will test if this model is correct.
Aim 1 is to determine the contribution of PV+ perisomatic synapse remodeling in the BLA to extinction-induced fear suppression. To achieve this, we will monitor the strength of PV+ perisomatic synapses under conditions when fear suppression stops working, and by manipulating brain-derived neurotrophic factor signaling during fear extinction, which is predicted to interfere with extinction-induced perisomatic synapse remodeling.
Aim 2 is to localize and manipulate functionally opposed LFP oscillations in the BLA during extinction-induced fear suppression. To achieve this, we will manipulate the activation state of three types of BLA neurons (PV+ interneurons, fear neurons, extinction neurons), while measuring both LFP oscillations and fear behavior.
Aim 3 is to identify downstream neural circuits that mediate the contribution of BLA PV+ interneurons to extinction-induced fear suppression. This will be achieved by analyzing and manipulating BLA projection pathways to two subdivisions of the mPFC. Completion of this proposal can identify a critical role for BLA PV+ interneurons in tuning the balance between a fear-promoting circuit and a fear-suppressing circuit following fear extinction, which would aid the rationale design of new and more effective treatments for patients suffering from excessive fear.

Public Health Relevance

Exposure therapy is the most widely used treatment for excessive fear caused by post-traumatic stress disorder and phobias, but it rarely leads to a permanent suppression of fear. This proposal will determine if exposure therapy reduces fear by changing a specific connection between brain cells, thereby giving fear-suppressing brain circuits a competitive advantage over fear-promoting brain circuits. Increased understanding of the neurobiological mechanisms of exposure therapy generated by this proposal will aid the development of better treatment options for patients suffering from excessive fear.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH104589-04
Application #
9929638
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Vicentic, Aleksandra
Project Start
2017-08-05
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Tufts University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Davis, Patrick; Reijmers, Leon G (2018) The dynamic nature of fear engrams in the basolateral amygdala. Brain Res Bull 141:44-49
Davis, Patrick; Zaki, Yosif; Maguire, Jamie et al. (2017) Cellular and oscillatory substrates of fear extinction learning. Nat Neurosci 20:1624-1633