Sensory system physiology in both higher order (Li et al. 2008; Edeline & Weinberger 1991; Gdalyahu et al. 2012) and early (Fletcher 2012) processing centers can be modified by emotional learning. Sensory pathologies are in fact a common element of many affective disorders, ranging from outright hallucinations in post traumatic stress disorder (Mueser & Butler 1987; Freeman & Fowler 2009) to more subtle changes in attentional processing (Desseilles et al. 2009; Adenauer et al. 2010) which may bias incoming sensory information to threat-predictive stimuli in anxiety disorders (Beck & Clark 1997; Buckley 2000). Anxiety disorders are routinely studied in animal models using associative fear conditioning paradigms, in which an animal learns that a neutral sensory stimulus, such as an odor (the CS+), predicts the occurrence of an aversive stimulus, such as a footshock. Such models provide a unique opportunity to investigate the role of sensory processing in emotional learning, and in preliminary studies we found that discriminative olfactory fear conditioning causes a surprising enhancement of CS+-evoked neurotransmitter release from olfactory sensory neurons (OSNs), the primary (first) sensory inputs to the brain. This enhancement may be beneficial in facilitating later detection of the CS+ or focusing attention towards similar sensory stimuli, or alternatively, may be maladaptive and contribute to anxiety. To further investigate the associations between early sensory processing and anxiety-like states, this study will perform longitudinal in vivo physiological and morphometric optical imaging procedures in mice that undergo discriminative olfactory fear conditioning. Odorant-evoked OSN synaptic output to olfactory bulb glomeruli will be visualized through a bilateral cranial window implanted above the dorsal olfactory bulbs at baseline, after fear learning, and again after extinction learning in individual mice expressing the synaptopHluorin (spH) exocytosis indicator in all mature OSN axon terminals (Bozza et al. 2004). Presynaptic sniff-locked Ca2+ signals in mice whose OSN axon terminals have been loaded with calcium-sensitive dye will be visualized before and after fear conditioning to assess how odorant-evoked response dynamics of CS+-responsive OSNs are modified by emotional learning. In vivo two-photon-based morphometric analyses will be performed on glomeruli identified during physiological imaging experiments to assess potential structural plasticity in OSN glomerular innervation (Jones et al. 2008). Our preliminary data suggest that the enhanced representation of the CS+ is mediated by changes in the olfactory bulb circuitry that gates incoming sensory information (i.e., emotional learning may cause the gate to open). To test this in vivo in mice that undergo fear conditioning, we will pharmacologically manipulate the intraglomerular circuit that presynaptically modulates OSN activity, electrically stimulate the olfactory nerve, and directly visualize odor- evoked activity n GABAergic interneurons that presynaptically inhibit neurotransmitter release from OSN axon terminals (in mice expressing the genetically-encoded Ca2+ indicator GCamP3 in GAD65-ergic interneurons).

Public Health Relevance

The proposed research explores how emotional learning about odors can alter the neural processing of olfactory stimuli as early as the input to the brain's olfactory bulb. Because the olfactory system is the only system in which the primary sensory representations of stimuli can be directly observed; this research will inform our understanding of how the brain encodes and responds to ecologically-important sensory stimuli more generally; with potential implications for the development of anxiety disorders (where symptoms are often triggered by sensory stimuli).

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-SRB-Y (52))
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Sklare, Dan
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Rutgers University
Schools of Arts and Sciences
New Brunswick
United States
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