Associative fear learning, the underlying cause of disorders such as Post-Traumatic Stress Disorder (PTSD), involves the pairing of a stimulus with an aversive outcome. This pairing produces robust fear responses to the conditioned stimulus. Odor memories, such as those formed during olfactory fear learning are acquired quickly, are long lasting, and are apparent as early as the olfactory bulb (OB) glomeruli, which constitutes the first site of central nervous system olfactory sensory processing. This makes the OB an ideal place to investigate mechanisms underlying sensory processing and plasticity as they relate to fear learning. Herein, we present pilot data establishing that pairing odor presentations with foot shock induces behavioral fear and enhances glomerular responses to the conditioned stimulus (CS) in awake, behaving transgenic mice expressing a fluorescent calcium indicator. Similarly, odor-foot shock experience induces fear and enhances glomerular responses to neutral, unconditioned odor stimuli, a process known as stimulus generalization in which fear is transferred from the CS to neutral, unconditioned stimuli. Furthermore, sensory representations of the CS and neutral odors undergo transformations increasing the representational similarities, possibly leading to behavioral generalization. However, the time course of learning-induced transformations in sensory processing and the neural networks underlying generalized behavior and glomerular alterations is still unknown. By combining behavioral methods with awake, behaving wide-field calcium imaging, we will elucidate when associative olfactory fear learning modulates the processing of sensory information at the glomerular layer of the olfactory bulb and the role of the neural networks responsible for encoding the stimulus-fear association in these transformations, as well as how this relates to generalization of olfactory fear at the behavioral level. We will test the hypothesis that glomerular enhancement to the CS begins during acquisition, while generalized enhancements to odors not paired with shock occur during consolidation, and that activity in the basolateral amygdala (BLA), the putative center of fear learning, is responsible for generalization. To characterize the time course of sensory transformations following learning, mice will be subjected to imaging trials during olfactory fear conditioning and comparisons of the CS and neutral odor-evoked glomerular responses will be made before and at different time points after training. Then a separate cohort of mice will undergo fear conditioning while the BLA is inactivated and both behavioral expressions of fear and training-induced glomerular response alterations will be quantified to assess the impact of BLA activity on behavioral and physiological generalization. Together, these experiments will characterize the biobehavioral adaptations of the OB throughout acquisition and consolidation of associative fear learning. Furthermore, these experiments will provide insights into underlying mechanism of behavioral fear generalization with potential clinical implications in PTSD as well as other sensory processing mechanisms.

Public Health Relevance

A major symptom of anxiety disorders, such as Post-Traumatic Stress Disorder (PTSD), is fear generalization, in which individuals exhibit strong fear responses to neutral stimuli that are similar to the fear-inducing stimulus. The underlying mechanisms of generalization are not well understood; however, the olfactory bulb (OB) presents a unique model system in which to investigate how learned fear alters sensory processing of the fear-inducing stimulus as well as similar, neutral stimuli at the neuronal level. Understanding the mechanisms of learning-induced sensory processing alterations as they relate to behavior will make a significant contribution to the understanding of fear generalization and have the immense potential to translate to the treatment of PTSD.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZDC1)
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Rivera-Rentas, Alberto L
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University of Tennessee Health Science Center
Anatomy/Cell Biology
Schools of Medicine
United States
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