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theses

Associative neuroplasticity permits the brain’s sensory systems to tune their sensitivity to ecologically critical stimuli and optimize discrimination between threat-predictive and neutral stimuli. However, dysfunctional plasticity leading to generalization of fear could underlie maladaptive fear learning such as in PTSD and Generalized Anxiety Disorder. Mechanistic studies in animals have demonstrated a suggestive linkage between sensory discrimination and associative-learning related discrimination, where animals that tend to generalize their fear responses across sensory stimuli also exhibit generalized changes in the sensorineural processing of those stimuli. In Part I, this dissertation explores aversive learning-induced sensory processing changes in humans. We found that after odor-cued aversive conditioning participants exhibiting normal levels of trait anxiety developed a larger skin conductance response (SCR) to the shock-predictive odor and substantial improvement in their perceptual discrimination between the two odors. Repeated exposure to the odors without shock partially extinguished the SCRs evoked by the threat-predictive odor but the improved olfactory discrimination persisted. By contrast, participants with high levels of trait anxiety developed comparably sized SCRs to both odors and displayed no improvement in their perceptual discrimination between them. Learning-induced perceptual plasticity is thus a normal part of sensory function that can be impaired in people with high levels of trait anxiety. In Part II, this dissertation uses neurophysiological experiments in a mouse model to explore the neural mechanisms by which odor-cued aversive conditioning can induce plasticity in early olfactory processing in the nervous system. This includes three main questions: a) when a mouse undergoes behaviorally generalizing olfactory fear conditioning, does the olfactory input from the nose to brain show enhancements that parallel this generalization, b) when the odor no longer predicts a shock, does the learning-related neuroplasticity reverse, and c) whether exposure to novel stimuli can “refine” otherwise generalizing fear into discriminative fear. Using an odor-cued fear conditioning paradigm designed to induce behavioral generalization of fear, we found that odor-evoked synaptic output from olfactory nerve into the brain’s olfactory bulb was greatly increased not only for the actually threat-predictive odor but also for novel odors that evoked generalized fear, even under anesthesia. This increase was equivalent in olfactory sensory neuron populations that respond to the threat-predictive odor and in those that did not, ruling out a classic explanation of generalization through overlapping neural representations between the stimuli. Conventional extinction training in which the threat-predictive odor was presented repeatedly without shocks reversed both the behavioral fear and the increased olfactory nerve output evoked by all odors. An alternative extinction paradigm using a panel of odorants similarly reversed neurophysiological enhancements and extinguished behavioral fear. Taken together the increased olfactory signaling to fear-evoking odors and the reversal of this increase when the mouse is no longer afraid of an odor suggests that the olfactory nerve plasticity follows the mouse’s perception of threat, even for olfactory stimuli and neuronal populations that have never actually been paired with shock. It is surprising that such beliefs about odor-shock contingencies would manifest as early as the synaptic input from the nose to the brain. Taken together, Part I and Part II demonstrate the fundamental linkage between learning, sensory processing, and perceptual plasticity and suggest that disruption of neurosensory plasticity may be part of the etiology or maintenance of anxiety.

http://dissertations.umi.com/gsnb.rutgers:12352

doi:10.7282/t3-8dt4-x891

Ph.D.

Includes bibliographical references

Part I. Is a manuscript published in 2022 by Elsevier, in Biological Psychology: High trait anxiety blocks olfactory plasticity induced by aversive learning by Michelle C. Rosenthal, Michael A. Bacallao, Adam T. Garcia and John P. McGann. Citation below.
Rosenthal MC, Bacallao MA, Garcia AT, McGann JP. High trait anxiety blocks olfactory plasticity induced by aversive learning. Biol Psychol. 2022 Apr;170:108324. doi: 10.1016/j.biopsycho.2022.108324. Epub 2022 Mar 25. PMID: 35346792; PMCID: PMC9038709.
Part II. Will comprise a manuscript to be submitted with anticipated and authorship to be: Michelle. C. Rosenthal and John P. McGann.

The author owns the copyright to this work.