This is a request to the NIH/NIMH for an Individual NRSA Postdoctoral Fellowship (F32) Award for Dr. Katherina Hauner, Research Fellow in the laboratory of Dr. Jay Gottfried, at Northwestern University Feinberg School of Medicine. Of all mental illnesses, anxiety disorders are the most prevalent. Treatment involves remodeling fear memories via a process of consolidation. The most critical period for memory consolidation is during sleep- particularly for emotional memory, such as fear. Moreover, symptoms of anxiety disorders (such as PTSD) predict impaired fear memory consolidation during sleep. Thus, the goal of the proposed research is to determine how consolidation of fear memories can be selectively modulated during sleep. This objective marks a novel extension of the applicant's previous work on the neural substrates of fear after exposure therapy. The proposed research will incorporate groundbreaking techniques that use olfactory contextual cues to modulate memory during sleep. While sleep is known to promote consolidation of fear memories, it is unknown if consolidation can be selectively manipulated to modulate fear memories. Critically, the decision to use odor stimuli as memory modulators is based on the intimate anatomical and functional connections between olfactory and limbic systems-olfactory sensory neurons are only two synapses removed from brain areas involved in emotion and learning. Prior research from the sponsor's lab has highlighted involvement of amygdala and orbitofrontal cortex (OFC) in olfactory-based fear conditioning. Moreover, there is recent evidence to suggest that odors have privileged access to brain networks during sleep, and that non-emotional, episodic memories can be manipulated by using odors as contextual cues. The central hypothesis of the proposed project is that an odor cue originally presented in the context of a feared stimulus-then continuously re-presented during sleep by itself-will destabilize the strength of the fear memory. This effect will be compared to a control condition in which the contextual odor cue is not re- presented during sleep. Fear responses will be measured using physiological recordings and fMRI. Using pattern-based (multivariate) imaging analyses, we predict that fMRI signatures of fear responses in amygdala and OFC at retrieval will show reduced pattern coherence to fear responses established at training, for feared stimuli in the odorant context that was also re-presented during sleep. Findings will have broad clinical relevance, as the proposed methods could serve to complement and accelerate existing therapy. The proposed research will require the applicant to complete new training in classical conditioning, physiological assessment of fear, olfaction, and advanced fMRI analysis-all highly relevant for her future research endeavors. The translational nature of this project will put the applicant firmly on the path toward becoming an independent investigator who applies neuroscience approaches to inspire novel clinical interventions.
This research is intended to discover how the consolidation of fear memories can be selectively manipulated during sleep. Given that treatment for anxiety disorders also involves the regulation of fear memory, information on how fear memory can be modulated during sleep may present an opportunity for enhanced therapy. Thus, the proposed study could lead to accelerated anxiety treatments that might attract and serve a greater number of affected individuals.
| Hauner, Katherina K; Howard, James D; Zelano, Christina et al. (2013) Stimulus-specific enhancement of fear extinction during slow-wave sleep. Nat Neurosci 16:1553-5 |
