Amygdalar Modulation of Fear-Conditioned Changes in REM Sleep

Summary

Principal Investigator: ADRIAN MORRISON
Affiliation: University of Pennsylvania
Country: USA
Abstract: The overall objective of this project is to understand the manner in which amygdalar processing of sensory inputs modulates basic sleep-wake mechanisms. We propose to use cued fear conditioning (CFC) as an experimental paradigm for studying the more general role of the amygdala (AMY) in determining an organism's responsiveness to its environment. Specifically, we shall study changes in REM sleep (REM) after fear conditioning in rats, and related behavioral changes during wakefulness (W). In the current proposal, we focus on the lateral nucleus (LA) of AMY. As a first aim, we shall study a group of rats according to a standard CFC protocol. We shall expand our neurobehavioral assessment of these animals to include REM phasic activity during sleep and ultrasonic vocalizations (USV), novelty detection and freezing behavior during W. As a second aim, we shall study the same measures during sleep and W in a group of rats with complete bilateral electrolytic lesions of LA. We shall repeat the lesion study by making cytotoxic lesions with ibotenic acid in order to determine whether the changes observed with the former lesions originate from cellular destruction and not fiber damage. To demonstrate that LA lesions interfere with the fear conditioning of sleep-wake specifically by interrupting conditioned stimulus (CS)-unconditioned stimulus (US) associations during training, we shall, in another group of rats, make temporary bilateral lesions of LA using a local anesthetic, lidocaine, immediately before training in the CFC protocol. There is evidence that serotonin (5-HT) plays an important role in mechanisms of LA activation and inhibition, possibly by exciting GABAergic interneurons that synapse on LA principal cells. As a third aim we shall explore the modulatory role of 5-HT in the CS-US association process that occurs during training in the CFC protocol and alters sleep-wake behavior. In 1 experiment, we will inject 5-HT into LA bilaterally immediately before training a group of rats. In a second experiment, we shall inject 5-HT together with a nonspecific serotonergic antagonist. In order to begin to delineate the cellular mechanisms of 5-HT's actions, we will, in a third experiment, inject 5-HT together with a GABAA antagonist. This proposal has particular relevance to human mental disorders that arise in the aftermath of a psychologically stressful experience and involve significant abnormalities in sleep-wake behavior and the microarchitecture of sleep. In particular, we expect to gain insight into the sleep disturbance in posttraumatic stress disorder (PTSD), which is often intractable to currently available psychotherapeutic and pharmacological treatments. Primary insomnia also may be a sequel to a stressful experience, and REM interruption insomnia may occur in some individuals with PTSD. It is very important to investigate the serotonergic modulation of CFC in animals because drugs that influence 5-HT function have widespread acceptance for treating PTSD yet little is known about their actions in related animal models.
Funding Period: 2005-09-01 - 2010-08-31
more information: NIH RePORT

Top Publications

  1. pmc The α1 adrenoceptor antagonist prazosin enhances sleep continuity in fear-conditioned Wistar-Kyoto rats
    Benjamin M Laitman
    Department of Animal Biology, School of Veterinary Medicine, Philadelphia, PA, United States Electronic address
    Prog Neuropsychopharmacol Biol Psychiatry 49:7-15. 2014
  2. pmc Fear conditioning fragments REM sleep in stress-sensitive Wistar-Kyoto, but not Wistar, rats
    Jamie K Dasilva
    Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, Box 80, 600 South 43rd Street, Philadelphia, PA 19104, USA
    Prog Neuropsychopharmacol Biol Psychiatry 35:67-73. 2011
  3. pmc Reduced γ range activity at REM sleep onset and termination in fear-conditioned Wistar-Kyoto rats
    Benjamin M Laitman
    University of Pennsylvania School of Veterinary Medicine, Department of Animal Biology, 3800 Spruce Street, Philadelphia, PA 19104, USA
    Neurosci Lett 493:14-7. 2011
  4. doi Social partnering significantly reduced rapid eye movement sleep fragmentation in fear-conditioned, stress-sensitive Wistar-Kyoto rats
    J K Dasilva
    Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, 600 South 43rd Street, Philadelphia, PA 19104, USA
    Neuroscience 199:193-204. 2011
  5. pmc Stress-induced changes in sleep in rodents: models and mechanisms
    Aaron C Pawlyk
    Women s Health and Musculoskeletal Biology, Wyeth Research, Collegeville, PA 19426, USA
    Neurosci Biobehav Rev 32:99-117. 2008
  6. pmc Long-term effect of cued fear conditioning on REM sleep microarchitecture in rats
    Vibha Madan
    Laboratory for Study of the Brain in Sleep, Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104 6045, USA
    Sleep 31:497-503. 2008

Scientific Experts

Detail Information

Publications7

  1. pmc The α1 adrenoceptor antagonist prazosin enhances sleep continuity in fear-conditioned Wistar-Kyoto rats
    Benjamin M Laitman
    Department of Animal Biology, School of Veterinary Medicine, Philadelphia, PA, United States Electronic address
    Prog Neuropsychopharmacol Biol Psychiatry 49:7-15. 2014
    ..They also had a shorter non-REMS latency and fewer non-REMS arousals at baseline and on Days 1 and 7 after FC. Thus, in FC rats, prazosin reduced both REMS fragmentation and non-REMS discontinuity. ..
  2. pmc Fear conditioning fragments REM sleep in stress-sensitive Wistar-Kyoto, but not Wistar, rats
    Jamie K Dasilva
    Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, Box 80, 600 South 43rd Street, Philadelphia, PA 19104, USA
    Prog Neuropsychopharmacol Biol Psychiatry 35:67-73. 2011
    ..The shift toward sequential REMS in fear-conditioned WKY rats may represent REMS fragmentation, and may provide a model for investigating the neurobiological mechanisms of sleep disturbances reported in posttraumatic stress disorder...
  3. pmc Reduced γ range activity at REM sleep onset and termination in fear-conditioned Wistar-Kyoto rats
    Benjamin M Laitman
    University of Pennsylvania School of Veterinary Medicine, Department of Animal Biology, 3800 Spruce Street, Philadelphia, PA 19104, USA
    Neurosci Lett 493:14-7. 2011
    ..Gamma range activity may indicate neural activity underlying maintenance of REMS continuity. Low relative gamma power at REMS transitions may be associated with increased REMS fragmentation in WKY after FC...
  4. doi Social partnering significantly reduced rapid eye movement sleep fragmentation in fear-conditioned, stress-sensitive Wistar-Kyoto rats
    J K Dasilva
    Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, 600 South 43rd Street, Philadelphia, PA 19104, USA
    Neuroscience 199:193-204. 2011
    ..Our findings suggest that social partnering may protect WKY rats from the REMS fragmentation that is observed following CFC in isolation...
  5. pmc Stress-induced changes in sleep in rodents: models and mechanisms
    Aaron C Pawlyk
    Women s Health and Musculoskeletal Biology, Wyeth Research, Collegeville, PA 19426, USA
    Neurosci Biobehav Rev 32:99-117. 2008
    ..A complete understanding of the neural correlates of stress-induced sleep alterations may lead to novel treatments for a variety of debilitating sleep disorders...
  6. pmc Long-term effect of cued fear conditioning on REM sleep microarchitecture in rats
    Vibha Madan
    Laboratory for Study of the Brain in Sleep, Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104 6045, USA
    Sleep 31:497-503. 2008
    ..To study long-term effects of conditioned fear on REM sleep (REMS) parameters in albino rats...