Amygdalar Modulation of Fear-Conditioned Changes in REM Sleep

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): 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.