Threatening or aversive stimuli normally evoke healthy fear, in which the brain?s defensive motivational systems drive protective behaviors. When a person or animal learns that a particular sensory stimulus predicts future harm, that stimulus begins to evoke fearful reactions as well. This is called learned fear. Sensory stimuli that are physically similar or conceptually related to the threat-predictive stimulus normally also evoke fear because of the reasonable belief that they might also predict future harm. This is called generalization of learned fear, and it is a normal part of healthy fear. However, many Americans suffer from disordered fear, in which the feeling of acute threat (fear) or potential threat (anxiety) generalizes to inappropriate stimuli and situations that may resemble or be associated with traumatic events but do not actually indicate an impending threat. Figuring out how to limit generalization so that a patient is only fearful in appropriate situations is a key practical challenge for the treatment of anxiety disorders. Most research on the biological basis of anxiety disorders and learned fear has focused on the mechanisms by which the brain learns the initial fear and extrapolates fearful behavior across situations. However, evidence is accumulating that learned fear also evokes profound changes in the brain?s sensory systems. This includes becoming hyper-sensitive and hyper-responsive to threat-predictive stimuli in ways that may underlie common post-traumatic symptoms like hyper-vigilance and attentional bias toward threat-predictive stimuli. In the previous project period we used a mouse model to observe how the neurobiology of the olfactory system is changed during appropriate fear and observed that fear learning makes the olfactory system selectively hyper-responsive to threat-predictive odor, generating a neural ?alarm signal? as early as the sensory input to the brain. In contrast, in this project period we will explore the more clinically- relevant situation of fear generalization, where initial trauma evokes fear of new stimuli that may not actually predict a threat. In preliminary experiments we employed an experimental paradigm in which mice undergo a traumatic experience associated with a particular odor but then generalize their fear across many novel odors. We will test whether this experience causes the olfactory system to become non-selectively hyper-responsive to many dissimilar odors, which might drive downstream responding as if the new odors are dangerous. We will also investigate the neural circuitry by which information about the traumatic event reaches the olfactory system and induces change in the response to many different odors. Finally, we will evaluate multiple candidate approaches to reverse the behavioral and sensory consequences of fear generalization, including comparing conventional exposure (a.k.a. extinction) therapy using the original trauma-associated odor with new therapy paradigms intended to ?refine? the generalized fear either through repeated exposure to novel stimuli or through follow-up fear training in which the trauma is explicitly paired with actually predictive stimuli but not with non- threatening stimuli.

Public Health Relevance

Anxiety disorder, depression, and other mental health problems often include sensory symptoms, including changes in how stimuli are perceived, how they attract attention, and what reactions they evoke. This project uses mice that have been genetically engineered so that neurons in their brains fluoresce based on their activity as a model to visualize changes in the brain?s response to sensory stimuli when they become associated with traumatic experiences. The results should help to understand what goes on in the brain during and after traumatic experiences and provide new insights into possible ways to reverse or mitigate harmful changes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH101293-06A1
Application #
9686225
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Vicentic, Aleksandra
Project Start
2013-07-01
Project End
2023-11-30
Budget Start
2019-02-01
Budget End
2019-11-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Rutgers University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
001912864
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
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McIntyre, Jeremy C; Thiebaud, Nicolas; McGann, John P et al. (2017) Neuromodulation in Chemosensory Pathways. Chem Senses 42:375-379
Kass, Marley D; McGann, John P (2017) Persistent, generalized hypersensitivity of olfactory bulb interneurons after olfactory fear generalization. Neurobiol Learn Mem 146:47-57
McGann, John P (2017) Poor human olfaction is a 19th-century myth. Science 356:
Kass, Marley D; Czarnecki, Lindsey A; Moberly, Andrew H et al. (2017) Differences in peripheral sensory input to the olfactory bulb between male and female mice. Sci Rep 7:45851
Kass, Marley D; Guang, Stephanie A; Moberly, Andrew H et al. (2016) Changes in Olfactory Sensory Neuron Physiology and Olfactory Perceptual Learning After Odorant Exposure in Adult Mice. Chem Senses 41:123-33
McGann, John P (2015) Associative learning and sensory neuroplasticity: how does it happen and what is it good for? Learn Mem 22:567-76
Kass, Marley D; Rosenthal, Michelle C; Pottackal, Joseph et al. (2013) Fear learning enhances neural responses to threat-predictive sensory stimuli. Science 342:1389-1392