Problems with fear memory and fear extinction (new learning that reduces fear) are core elements of a variety of psychiatric disorders. Fear-related learning is thought to play a significant role in the development of emotional disorders and fear conditioning (usually employing footshock as the fear-inducing stimulus) is a key research model used in this work. After conditioning, memories of the fearful experience produce virtually identical behavioral and physiological responses to those elicited by footshock. Fear also has a significant impact on sleep. One prominent effect of fear on sleep is reduced rapid eye movement (REM) sleep that occurs in the period after certain fearful experiences. However, fear behavior and subsequent sleep can dissociate depending on the conditions in which fear occurs. Fear learning associated with uncontrollable stress produces overt fear behavior in wakefulness (freezing in rodents) and decreases REM sleep whereas fear learning associated with controllable stress produces similar fear behavior in wakefulness but can increase REM sleep. Sleep disturbances occur in essentially all psychiatric disorders;therefore, understanding the neurobiological processes by which stressful and fearful events can alter the impact of emotional memory on sleep can provide insight needed to improve treatments in disorders in which sleep is impacted. We recently found that the basolateral amygdala (BLA) plays a critical role in determining whether fear memory alters sleep. In this project, we will establish the role o BLA in mediating the impact of fear on sleep by determining its role in fear learning, fear memory consolidation and fear extinction. We will determine the effects of global inactivation of BLA on sleep, fear behavior and the stress response during fear learning, fear memory consolidation and fear extinction. We will determine how clinically relevant systems (i.e., corticotropin releasing factor and metabotropic glutamate) alter fear learning, fear memory consolidation and fear extinction, and their effects on sleep, fear behavior and the stress response. We will use biosensors to assess in near real time how glutamate changes in BLA in association with fear learning, fear memory consolidation and fear extinction and with spontaneous changes in arousal state. Lastly, we will use optogenetics to activate and inhibit glutamate neurons in BLA to delineate which specific fear processes (fear learning, fear memory and fear extinction) the BLA regulates. These studies will fill in a significant knowledge gap by increasing our understanding of the association between fear, sleep, and stress, and the neurobiological processes by which fearful memories come to affect sleep.

Public Health Relevance

Fear-related learning is implicated in the genesis of psychiatric disorders including anxiety and mood disorders. Fearful memories can also significantly impact sleep and disturbed sleep is found in essentially all psychiatric disorders. We will assess the neurobiological mechanisms by which fear-related memories come to impact sleep which will provide insight needed to improve interventions for treating disorders linked to fear and diseases which are associated with disturbed sleep.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH064827-12
Application #
8743265
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Vicentic, Aleksandra
Project Start
2001-09-28
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Eastern Virginia Medical School
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Norfolk
State
VA
Country
United States
Zip Code
23507
Wellman, Laurie L; Fitzpatrick, Mairen E; Sutton, Amy M et al. (2018) Antagonism of corticotropin releasing factor in the basolateral amygdala of resilient and vulnerable rats: Effects on fear-conditioned sleep, temperature and freezing. Horm Behav 100:20-28
Machida, Mayumi; Lonart, Gy├Ârgy; Sanford, Larry D (2018) Effects of stressor controllability on transcriptional levels of c-fos, Arc, and brain-derived neurotrophic factor in mouse amygdala and medial prefrontal cortex. Neuroreport 29:112-117
Tang, Xiangdong; Sanford, Larry D (2017) Ceiling effects of sedatives should be considered in the management of chronic insomnia. Sleep Med 32:266
Machida, Mayumi; Wellman, Laurie L; Fitzpatrick Bs, Mairen E et al. (2017) Effects of Optogenetic inhibition of BLA on Sleep Brief Optogenetic Inhibition of the Basolateral Amygdala in Mice Alters Effects of Stressful Experiences on Rapid Eye Movement Sleep. Sleep 40:
Wellman, Laurie L; Fitzpatrick, Mairen E; Hallum, Olga Y et al. (2017) The basolateral amygdala can mediate the effects of fear memory on sleep independently of fear behavior and the peripheral stress response. Neurobiol Learn Mem 137:27-35
Wellman, Laurie L; Fitzpatrick, Mairen E; Hallum, Olga Y et al. (2016) Individual Differences in Animal Stress Models: Considering Resilience, Vulnerability, and the Amygdala in Mediating the Effects of Stress and Conditioned Fear on Sleep. Sleep 39:1293-303
Sanford, Larry D; Suchecki, Deborah; Meerlo, Peter (2015) Stress, arousal, and sleep. Curr Top Behav Neurosci 25:379-410
Wellman, Laurie L; Fitzpatrick, Mairen E; Machida, Mayumi et al. (2014) The basolateral amygdala determines the effects of fear memory on sleep in an animal model of PTSD. Exp Brain Res 232:1555-65
Britten, Richard A; Davis, Leslie K; Jewell, Jessica S et al. (2014) Exposure to mission relevant doses of 1 GeV/Nucleon (56)Fe particles leads to impairment of attentional set-shifting performance in socially mature rats. Radiat Res 182:292-8
Machida, Mayumi; Yang, Linghui; Wellman, Laurie L et al. (2013) Effects of stressor predictability on escape learning and sleep in mice. Sleep 36:421-30

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