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)
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
Project End
Budget Start
Budget End
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; 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
Wellman, Laurie L; Yang, Linghui; Ambrozewicz, Marta A et al. (2013) Basolateral amygdala and the regulation of fear-conditioned changes in sleep: role of corticotropin-releasing factor. Sleep 36:471-80
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
Dong, Enheng; Wellman, Laurie L; Yang, Linghui et al. (2012) Effects of microinjections of Group II metabotropic glutamate agents into the amygdala on sleep. Brain Res 1452:85-95
Zeng, Tao; Mott, Christopher; Mollicone, Daniel et al. (2012) Automated determination of wakefulness and sleep in rats based on non-invasively acquired measures of movement and respiratory activity. J Neurosci Methods 204:276-87
Yang, L; Wellman, L L; Tang, X et al. (2011) Effects of corticotropin releasing factor (CRF) on sleep and body temperature following controllable footshock stress in mice. Physiol Behav 104:886-92
Liu, Xianling; Wellman, Laurie L; Yang, Linghui et al. (2011) Antagonizing corticotropin-releasing factor in the central nucleus of the amygdala attenuates fear-induced reductions in sleep but not freezing. Sleep 34:1539-49
Yang, Linghui; Wellman, Laurie L; Ambrozewicz, Marta A et al. (2011) Effects of stressor predictability and controllability on sleep, temperature, and fear behavior in mice. Sleep 34:759-71
Sanford, Larry D; Yang, Linghui; Wellman, Laurie L et al. (2010) Differential effects of controllable and uncontrollable footshock stress on sleep in mice. Sleep 33:621-30

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