ReviewStress-induced changes in sleep in rodents: Models and mechanisms
Introduction
Stress, although a potentially confusing term (see Day, 2005), is believed to be a significant factor in a variety of health problems (Korte et al., 2005). A reasonable definition of stress is a stimulus or situation that challenges homeostasis and induces a multi-system response (Day, 2005). Stress research historically has focused on physiological changes in an organism after exposure to some stress-inducing procedure. Levels of corticosterone, the major adrenocortical glucocorticoid hormone in rodents, are often used as an index of acute stress (Brennan et al., 2000; Ottenweller et al., 1989), as are plasma levels of epinephrine (Lundberg, 2005). Exposure to stress in humans is related to increased incidences of a number of psychiatric illnesses, including posttraumatic stress disorder (PTSD) (Brady and Sinha, 2005) and other anxiety disorders, mood disorders, and substance-related disorders.
While other anxiety disorders and depression may be induced or exacerbated by stress, PTSD by definition only occurs after exposure to a severe stressor (DSM-IV, 1994). This is not to say that stress alone leads to the development of psychiatric disorders. For example, approximately only one-third of patients who have been exposed to a traumatic stressor develop long-term PTSD (Zatzick et al., 1997). Animal models can provide an understanding of how organisms respond to stress, and the nature of inter-individual differences in the stress response. Given the importance of sleep disturbances in the PTSD symptom complex, both animal and pre-clinical studies of the effects of stress on sleep may have particular relevance to this disorder.
PTSD is an Axis I anxiety disorder that can develop after exposure to a traumatic event (Schnurr and Green, 2004). It has a number of clinical features, and it can be severely debilitating. The Diagnostic and Statistical Manual of the American Psychiatric Association, 4th Edition-Revised (1994) lists a number of major diagnostic criteria, which include autonomic, behavioral, and somatic symptoms. Of all the chronic symptoms associated with PTSD, the changes in sleep may be the most debilitating. We have previously argued that the sleep disturbance in PTSD is, in fact, the hallmark of the disorder (Ross et al., 1989). This is based on several related pieces of evidence; first, the prevalence of anxiety dreams in patients with PTSD is high (Harvey et al., 2003). Second, no other psychiatric disorder is characterized by repetitive, stereotypical anxiety dreams. Since dreams with the highest emotional and aggressive content occur during rapid eye movement (REM) sleep (McNamara et al., 2005), it is logical to look for REM sleep abnormalities in PTSD patients, and these have been reported by our group (Ross et al., 1994) and others (e.g., Mellman et al., 1997). It should be noted that the sleep disturbances in PTSD are not limited to REM sleep (see Neylan et al., 2006).
A report from Mellman and colleagues (1995) is particularly interesting in that PTSD patients showed reductions in REM sleep time, while patients with major depression did not. This suggests that REM sleep changes may be a divergent marker for these two disorders, which otherwise have many overlapping features. Apart from a reduction in the total amount of REM sleep, there have been reports of other changes in REM sleep. Mellman et al. (1995) and Ross et al. (1994) reported an increase in REM density (number of rapid eye movements/REM sleep time) in combat-related PTSD. Interestingly, REM density appears to be related to the intensity of mental activity during sleep (Smith et al., 2004). A decrease in average REM sleep episode length within a month of psychological traumatization has been shown to predict the severity of symptoms of PTSD at follow-up in one study (Mellman et al., 2002). This suggests that understanding the changes in sleep that occur early in the pathogenesis of the disorder may lead to prevention strategies and perhaps improved therapies.
Our plan in the current paper is to review the literature on stress-induced changes in sleep in rats and mice. We will first review studies using immobilization, a common stress procedure, before considering studies that utilized electric shock. Next we will describe some of our work and the work of others on how conditioned stimuli associated with stressors produce changes in sleep similar to the stressors themselves. Finally, we will review some potential physiological mechanisms that may mediate the sleep changes.
Section snippets
Rodent models of stress-induced changes in sleep
In recent years there have been a number of studies of the effects of stress on sleep in rats and mice. We have chosen to review the studies by stressor type, before drawing global conclusions. Further, we have chosen not to address the significant number of studies that have used either total sleep or REM sleep deprivation as a stressor (see McEwen, 2006, for a review). This is because a sleep or REM sleep rebound could confound the direct effect of stress. In fact, investigations of the
Immobilization stress
A common procedure for inducing stress in rodents is immobilization (Table 1). Immobilization is considered primarily as a “psychological” stressor because there is no pain involved; it is the inability to escape that induces psychological stress. In the initial report (Rampin et al., 1991), 2 h of immobilization at the beginning of the dark phase produced an increase in REM sleep. A subsequent study replicated this finding, with 1 h of immobilization leading to increases in both slow-wave sleep
Shock stress
Exposure to electric shock is another very common method for inducing stress in rodents (Table 1). Exposure to shock has typically been associated with a decrease in subsequent REM sleep (Kant et al., 1995; Palma et al., 2000; Vazquez-Palacios and Velazquez-Moctezuma, 2000). Kant and colleagues (1995) carried out a long-term study of the effects of chronic stress on physiology and behavior. Their animals lived for two weeks in operant chambers and were required to pull a chain to escape or
Fear-conditioned changes in sleep
Although it is interesting that the stress of mild electric footshock transiently suppresses REM sleep, a viable animal model of the sleep changes after stress should also address the long-term changes that can persist for years after exposure to traumatic stress in humans. PTSD symptoms appear to be maintained at least in part by classical conditioning (see Mineka and Zinbarg, 2006, for a review). To that end, we have utilized a fear conditioning procedure to study the effect of cues
Neural and pharmacological mechanisms of S/W changes
Elucidation of the neural and pharmacological mechanisms responsible for the observed changes in sleep following stress is clearly a way to develop treatments for the myriad sleep disorders that are influenced by stress. We will, therefore, attempt to synthesize information from studies of the neurobiology of the stress-sleep relationship.
The standard index of the stress response in animals is activation of the HPA axis, as indicated by plasma CORT level. CORT levels have been measured during
Summary and conclusions
Stress can modulate sleep, both directly as well as by contributing to the development of depressive and anxiety disorders. The development of animal models of stress-induced changes in sleep is critical to both fully understand the disorders, as well as to pre-clinically evaluate potential treatments. Of particular interest to our group has been the etiology of PTSD as a consequence of exposure to intense stress in humans (Brady and Sinha, 2005). Of all the chronic symptoms associated with
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Supported by RO1-MH072897 (ARM, PI).