Every year at least 18% of all Americans are afflicted with an anxiety disorder. Current treatment strategies for many anxiety disorders focus on ways to lessen the ability of environmental stimuli to evoke mental, emotional and physical anguish. One treatment is extinction - exposure to fear-evoking environmental stimuli in the absence of the aversive outcome can weaken the ability of those stimuli to elicit anxiety responses. Extinction results in the formation of a new inhibitory extinction memory that prevents the stimuli from reactivating such powerful affective responses and is thus an active process requiring accompanying changes in underlying neural networks. Recent research indicates that chromatin (DNA packaging complexes) modifications via histone acetylation (HA) results in networks of molecular changes (e.g., gene expression) underlying memory formation. Although many studies have shown that increasing HA with histone deacetylase inhibitors (HDACi) enhances learning, we know surprisingly little about how HDACi and changes in HA modulate fear memory extinction and reactivation. The major goals of this proposal are to bridge this gap in knowledge by (1) addressing how pharmacologically manipulating HA within neural networks alters fear reactivation and extinction, and (2) to assess how systems-wide changes in HA dependent gene expression map into behavioral expression of fear extinction and reactivation in mice. To establish a fearful memory, mice will receive contextual fear conditioning, in which exposure to a novel context will be paired with a shock. The memory will be reactivated at different post-conditioning time points by exposing mice to the context (memory retrieval). During these reactivation episodes, extinction will develop as the mice learn that the context is no longer associated with the shock (fear extinction).
In Aim 1, we will evaluate how the time course of HDACi prior to memory retrieval affects 1) subsequent expression of the fear memory in behavior and 2) time-dependent regional changes in HA following memory retrieval.
In Aim 2, we will examine the effects of HDACi infusion into different brain regions prior to a memory retrieval trial on (1) enhancements and extinction of behavior, and (2) effects on transcriptional control of regional gene expression following memory retrieval. By combining molecular, neuropharmacological and behavioral approaches, the proposed study aims to provide insight into molecular and neural systems that are potential therapeutic targets for decreasing the impact of traumatic and anxiety-inducing stimuli.

Public Health Relevance

Many anxiety disorders, including post-traumatic stress disorder, are characterized by a failure to inhibit the powerful mental, emotional and physical anguish evoked by environmental stimuli. The proposed research aims to understand how brain region specific networks of genes are activated in response to these anxiety- inducing stimuli. By examining how these molecular changes map into fear-related behavior, this study will guide future research in devising pharmaceutical interventions for anxiety disorders that dampen the emotional impact of anxiety-inducing stimuli by targeting these gene networks.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F02A-J (20))
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Desmond, Nancy L
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Oregon Health and Science University
Other Basic Sciences
Schools of Medicine
United States
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Stafford, James M; Jarrett, Benjamin R; Miranda-Dominguez, Oscar et al. (2014) Large-scale topology and the default mode network in the mouse connectome. Proc Natl Acad Sci U S A 111:18745-50
Stafford, James M; Maughan, DeeAnna K; Ilioi, Elena C et al. (2013) Exposure to a fearful context during periods of memory plasticity impairs extinction via hyperactivation of frontal-amygdalar circuits. Learn Mem 20:156-63
Stafford, James M; Raybuck, Jonathan D; Ryabinin, Andrey E et al. (2012) Increasing histone acetylation in the hippocampus-infralimbic network enhances fear extinction. Biol Psychiatry 72:25-33
Stafford, James M; Lattal, K Matthew (2011) Is an epigenetic switch the key to persistent extinction? Neurobiol Learn Mem 96:35-40