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Stress is considered to be an important cause of disrupted sleep and insomnia. However, controlled and experimental studies in rodents indicate that effects of stress on sleep-wake regulation are complex and may strongly depend on the nature of the stressor. While most stressors are associated with at least a brief period of arousal and wakefulness, the subsequent amount and architecture of recovery sleep can vary dramatically across conditions even though classical markers of acute stress such as corticosterone are virtually the same. Sleep after stress appears to be highly influenced by situational variables including whether the stressor was controllable and/or predictable, whether the individual had the possibility to learn and adapt, and by the relative resilience and vulnerability of the individual experiencing stress. There are multiple brain regions and neurochemical systems linking stress and sleep, and the specific balance and interactions between these systems may ultimately determine the alterations in sleep-wake architecture. Factors that appear to play an important role in stress-induced wakefulness and sleep changes include various monominergic neurotransmitters, hypocretins, corticotropin releasing factor, and prolactin. In addition to the brain regions directly involved in stress responses such as the hypothalamus, the locus coeruleus, and the amygdala, differential effects of stressor controllability on behavior and sleep may be mediated by the medial prefrontal cortex. These various brain regions interact and influence each other and in turn affect the activity of sleep-wake controlling centers in the brain. Also, these regions likely play significant roles in memory processes and participate in the way stressful memories may affect arousal and sleep. Finally, stress-induced changes in sleep-architecture may affect sleep-related neuronal plasticity processes and thereby contribute to cognitive dysfunction and psychiatric disorders.
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Stress, Arousal, and Sleep
Larry D. Sanford, Deborah Suchecki and Peter Meerlo
Abstract Stress is considered to be an important cause of disrupted sleep and
insomnia. However, controlled and experimental studies in rodents indicate that
effects of stress on sleep–wake regulation are complex and may strongly depend on
the nature of the stressor. While most stressors are associated with at least a brief
period of arousal and wakefulness, the subsequent amount and architecture of
recovery sleep can vary dramatically across conditions even though classical
markers of acute stress such as corticosterone are virtually the same. Sleep after
stress appears to be highly influenced by situational variables including whether the
stressor was controllable and/or predictable, whether the individual had the possi-
bility to learn and adapt, and by the relative resilience and vulnerability of the
individual experiencing stress. There are multiple brain regions and neurochemical
systems linking stress and sleep, and the specific balance and interactions between
these systems may ultimately determine the alterations in sleep–wake architecture.
Factors that appear to play an important role in stress-induced wakefulness and sleep
changes include various monominergic neurotransmitters, hypocretins, corticotro-
pin releasing factor, and prolactin. In addition to the brain regions directly involved
in stress responses such as the hypothalamus, the locus coeruleus, and the amygdala,
differential effects of stressor controllability on behavior and sleep may be mediated
by the medial prefrontal cortex. These various brain regions interact and influence
each other and in turn affect the activity of sleep–wake controlling centers in the
brain. Also, these regions likely play significant roles in memory processes and
L. D. Sanford (&)
Department of Pathology and Anatomy, Eastern Virginia Medical School,
P.O. Box 1980, Norfolk, VA 23507, USA
e-mail: SanforLD@evms.edu
D. Suchecki
Departamento de Psicobiologia, Universidade Federal de Sao Paulo,
Sao Paulo, Brazil
P. Meerlo
Center for Behavior and Neurosciences, University of Groningen,
Groningen, The Netherlands
ÓSpringer-Verlag Berlin Heidelberg 2014 379
Curr Topics Behav Neurosci (2015) 25: 379–410
DOI 10.1007/7854_2014_314
Published Online: 23 May 2014
participate in the way stressful memories may affect arousal and sleep. Finally,
stress-induced changes in sleep-architecture may affect sleep-related neuronal
plasticity processes and thereby contribute to cognitive dysfunction and psychiatric
disorders.
Keywords Stress Controllability Predictability Vulnerability Individual
differences Fear Arousal Sleep disturbance Insomnia Psychopathology
Contents
1 Introduction........................................................................................................................ 380
2 Complex Effects of Stress on Sleep Architecture............................................................ 381
2.1 Effects of Acute Stress ............................................................................................. 382
2.2 Repeated or Chronic Stress ...................................................................................... 383
3 Effects on Sleep May Vary with Specific Stress Parameters.......................................... 384
3.1 Stressor Controllability............................................................................................. 385
3.2 Stressor Predictability............................................................................................... 386
3.3 Stress-Related Learning and Sleep .......................................................................... 387
3.4 Fear Extinction and Sleep ........................................................................................ 388
3.5 Stressor Resilience and Vulnerability to Sleep Disturbance................................... 389
4 Stress Mediators as an Important Cause of Arousal and Sleep Disturbance.................. 390
4.1 Hypocretin/Orexin .................................................................................................... 390
4.2 Corticotropin Releasing Hormone............................................................................ 391
4.3 Prolactin .................................................................................................................... 393
4.4 Monoamines.............................................................................................................. 394
5 Brain Regions Linking Stress, Arousal and Sleep........................................................... 394
5.1 Amygdala and Stress-Induced Alterations in Arousal and Sleep........................... 395
5.2 REM Regulatory Regions, Medial Prefrontal Cortex and Stressor Control .......... 398
6 Stress, Sleep and Neuronal Plasticity: Implications for Stress-Related Disorders ......... 399
References................................................................................................................................ 401
1 Introduction
Stress is generally viewed as a major cause of disrupted sleep. Traumatic life events
often result in sleep disturbances that may include insomnia or subjective sleep
problems (Lavie 2001) and the persistence of these disturbances may be predictive
of the future development of emotional and cognitive disorders (Chang et al. 1997;
Koren et al. 2002; Neckelmann et al. 2007). Understandably, given the practical and
ethical concerns, few controlled and experimental studies on severe stress and its
effect on subsequent sleep have been done in human subjects. As such, most of the
available data on stress and sleep have come from studies in laboratory rodents
(Pawlyk et al. 2008). Importantly, the large body of animal studies based on a wide
variety of experimental stress models indicates that effects of stress on sleep may be
far more complex than a simple and prolonged increase of wakefulness. The impact
380 L. D. Sanford et al.
of stress on sleep may vary with specific characteristics of a stressor (e.g., duration,
intensity, controllability, and predictability) and with characteristics of the indi-
vidual experiencing stress (e.g., individual stress coping strategies, relative resil-
ience, and vulnerability). In addition, any stressful situation provides an opportunity
for learning, and the success or failure of an organism in developing an adaptive
coping strategy can influence post-stress sleep and behavior. Subsequently, evoking
stress-related memories can impact sleep and behavior in much the same fashion as
the original stress.
There are significant overlaps of the neural circuitry and neurochemistry
underlying the stress response and that regulating arousal and sleep. Thus, it is not
surprising that the interaction between stress and sleep is implicated in a variety of
disease processes and psychiatric disorders. However, it is important to note that
even significant stress can be experienced without producing permanent or path-
ological changes. The stress response engages the physiological and behavioral
resources needed to cope with a challenge followed by a return to normalcy when
the situation is resolved. Indeed, the purpose of the stress response is to restore
homeostasis (Johnson et al. 1992; Chrousos 2009).
In this review, we will discuss the complex effects of stress on sleep, the stress
parameters that appear to be important in determining post-stress sleep, and the
neurochemical and neuroanatomical substrates important in regulating the rela-
tionship between stress and sleep. Lastly, we will discuss factors linking stress and
sleep in the genesis of stress-related disorders.
2 Complex Effects of Stress on Sleep Architecture
Much of our knowledge of the relationship between stress and sleep is based on
animal models, which allow for controlled studies on the consequences of both acute
and chronic stress. A wide variety of experimental paradigms have been used to
assess effects of acute stress on sleep, including social defeat stress (Meerlo et al.
1997,2001a; Meerlo and Turek 2001), restraint or immobilization (Rampin et al.
1991; Meerlo et al. 2001b), footshocks (Smith 1995; Palma et al. 2000; Sanford
et al. 2005), water immersion (Smith 1995), cold exposure (Palma et al. 2000; Tiba
et al. 2004,2008), ether exposure (Roky et al. 1995; Bodosi et al. 2000), cage changes
(Tang et al. 2004,2005b), exposure to novel environments (Tang et al. 2004,2005b),
and exposure to novel objects (Schiffelholz and Aldenhoff 2002; Tang et al. 2004,
2005b). Studies aimed at chronic stress are often based on repetition of a stressful
stimulus [i.e., intermittent footshock: (Kant et al. 1995)] or alternating presentations
of different noxious stimuli [i.e., tilted cage, wet cage, food deprivation, etc. (Cheeta
et al. 1997; Gronli et al. 2004)] over a prolonged period of time.
Despite the obvious variation in the nature of the stimuli applied, their use in
studies on stress is motivated by the assumption that these stimuli and conditions
are, to some degree, aversive to the animals. In many cases this assumption is
supported by data showing activation of the classical neuroendocrine stress
Stress, Arousal, and Sleep 381
systems, i.e., the sympatho-adrenal axis and the hypothalamic-pituitary-adrenal
(HPA) axis. Indeed the major similarity between these models in terms of stress
appears to be an increase in the plasma levels of the stress hormones adrenaline
and corticosterone, although one has to keep in mind that such elevations occur in
response to virtually any kind of challenge and not exclusively to aversive stimuli
(Koolhaas et al. 2011). Importantly, though the outcome in many studies on stress
and sleep is discussed in terms of general stress effects, the experimental para-
digms that are used may have stimulus-specific effects as well.
2.1 Effects of Acute Stress
Stress is generally considered to be a functional response of the brain and the body
to challenges that humans and other animals may face. Coping with environmental
challenges requires alertness and, since stress is a state of physiological activation
and arousal, by definition, it inhibits sleep. Indeed, exposing animals to stressors is
invariably associated with at least a short-lasting increase in wakefulness. Con-
sistent with this aspect of the stress response, several of the classical neuropeptides
and hormones involved in the stress response are known to promote wakefulness
(see Sect. 4).
After the initial phase of arousal, sleep architecture is often altered; but in ways
that may vary among stressors. In addition to inhibiting all sleep, some stressors may
have a more pronounced and prolonged inhibiting effect on rapid eye movement
(REM) sleep, that is, once the animals fall asleep there may be a prolonged period of
time with non-REM (NREM) sleep but little or no REM sleep. This has been shown,
for example, in rodents after exposure to severe social stress (Meerlo and Turek
2001) and exposure to multiple presentations of inescapable footshock stress
(Adrien et al. 1991; Liu et al. 2003; Sanford et al. 2003a,b,c).
The initial period of stress-induced wakefulness and sleep disruption is most
often followed by a rebound to compensate for the NREM and/or REM sleep that
was lost. However, how much of the lost sleep is compensated and which sleep
state varies widely between studies and stressors. For example, in rodents exposed
to acute social stress, the initial loss of REM sleep is largely compensated during
the subsequent recovery period (Meerlo and Turek 2001). However, such a REM
sleep rebound may not occur after exposure to inescapable footshock stress in fear
conditioning paradigms (Sanford et al. 2003a,b,c,2010) or learned helplessness
paradigms (Adrien et al. 1991).
Intriguingly, after some stressors, animals appear to gain more sleep than was
actually lost during and immediately following the stress. For example, controlled
studies in laboratory rats and mice showed that exposure to acute social stress, i.e.,
a 1 h interaction with an aggressive male conspecific, is followed by deeper or
longer NREM sleep than a similar period of non-stressful sleep deprivation
(Meerlo et al. 1997; Meerlo and Turek 2001). On the other hand, other studies
have shown that acute immobilization or restraint stress is often followed by a
382 L. D. Sanford et al.
selective increase in REM sleep (Rampin et al. 1991; Meerlo et al. 2001b). The
latter has long been the basis for the widely held belief that stress causes an
increase in REM sleep, which we now know is clearly not a general feature of all
stressors. It has not been established whether the stressor-specific increases in one
sleep state or another reflect disturbances in sleep regulation or perhaps functional
adaptations that evolved to deal with and recover from different stress conditions.
Indeed, it has been argued that acute social stress may represent a form of intense
wakefulness associated with increased brain activity, which would require a higher
than normal need for recovery sleep (Meerlo et al. 1997). Similarly, the increase in
REM sleep after e.g., immobilization stress has been suggested to be an adaptive
coping response that may also serve the purpose of recovery (Suchecki et al.
2012). However, it remains unknown why some stressors are not followed by a
complete compensation for the sleep that was lost, whereas other stressors are
followed by more sleep than was lost. Nor is it understood why some stressors
seem to promote NREM sleep whereas others are followed by an increase in REM
sleep. This complex variation in the effects of different stressors on sleep may
depend on the nature of the stressors and the specific effects they have on phys-
iology and brain function. The variation in outcome may also be modulated by the
way stressors are perceived by the individual, e.g., in terms of controllability and
predictability see (Sects. 3.1 and 3.2), and whether or not a successful coping
strategy is developed (Sect. 3.3).
Overall, the finding that, in most animal models of acute stress, the arousing and
sleep-inhibiting effects of stressors are rapidly overcome and are sometimes fol-
lowed by increased sleep during the recovery phase may seem at odds with the
general notion that stress is a major cause of sleep disturbance and insomnia in
humans. One explanation for this apparent inconsistency is that in laboratory
rodents the physiological activation and arousal disappear quite rapidly upon ter-
mination of the stressor and return to the home cage, whereas human beings may
carry their problems and stress with them. That is, the ‘‘stress’’ responsible for
prolonged sleep disruption in humans may be a cognitive and emotional phe-
nomenon that is not necessarily always associated with an acute challenge. Humans
may suffer from stress based on memories of past events as well as worries and
expectations about the future. In that respect, compared to some animals, the human
brain may be more capable of turning a single acute stressor or life event that
occurred in the past, or even one pending in the future, into a persistent and chronic
stress state.
2.2 Repeated or Chronic Stress
With chronic stress, prolonged activation of the same behavioral, physiological,
and metabolic processes beneficial for coping with an acute stressor can become
detrimental (Chrousos 1998). Chronic stress has been reported to be a factor in the
Stress, Arousal, and Sleep 383
disruption of sleep in a variety of situations including individuals lacking social
support in the work environment (Gadinger et al. 2009; Nomura et al. 2009),
children and adolescents exposed to traumatic events (Charuvastra and Cloitre
2009), and burnout patients (Armon et al. 2008). Chronic stress has also been
viewed as a risk factor for the development of insomnia (Cartwright and Wood
1991).
A number of experimental studies in laboratory rats have applied a model of
so-called chronic mild stress, which consists of exposing animals to a mixture of
noxious stimuli, once or twice a day, for periods up to 3 or 4 weeks (e.g. Cheeta
et al. 1997, Gronli et al. 2004). The stimuli include tilting of the cage, temporary
exposure to a wet or soiled cage, food and water deprivation, exposure to pro-
longed periods of continuous lighting, and even stroboscopic lighting in one of the
studies (Cheeta et al. 1997). The most significant finding in these studies was an
increase in the amount of REM sleep the day after 3 or 4 weeks of treatment. The
overall amount of sleep tended to be somewhat increased as well, which may in
part reflect a rebound due to sleep loss during the actual stress exposure. Unfor-
tunately, some of the stimuli applied, in particular the continuous or stroboscopic
lighting, may have effects on sleep that have little to do with stress per se, for
example through alterations in circadian function.
Chronic stress as discussed here partly relies on direct stimulation of the
animals, which may explain some of the changes in sleep, whereas stress-related
sleep disturbances in humans often appear to be of a more psychological nature.
It may very well be that the physiological and neurobiological mechanisms
resulting in disrupted sleep due to repeated presentations of actual stressors are
quite different from those involved in psychological stress in humans. Although,
these studies are important first steps toward developing relevant models for
stress-related sleep disturbances and insomnia, perhaps research on the rela-
tionship between stress and sleep would gain by models that are based more on
psychological factors; for instance, conditioned fear and arousal in which animals
anticipate the occurrence of adverse events. Such an approach may have more
resemblance with the psychological stress in humans, and may allow us to study
central mechanisms by which sleep is disrupted and how such disturbances could
best be treated.
3 Effects on Sleep May Vary with Specific Stress
Parameters
While the importance of specific stress parameters and individual differences in
stress sensitivity is generally well established, there has been very limited
research on these issues with respect to their influence on sleep. Indeed, to date,
much of the work on stress and sleep has been primarily descriptive and focused
on effects of different types of stressors. The variable outcomes in terms of sleep
384 L. D. Sanford et al.
produced by different stressors clearly indicate that the observed changes are not
simply a generalizable stress effect. One should thus be careful with the inter-
pretation and extrapolation of findings from these types of studies and perhaps
even not refer to the sleep changes as simple stress effects, as sleep after a
stressful event can be modified as a consequence of specific stimuli or conditions.
Indeed, in our view, experimental paradigms that manipulate specific stress
parameters (e.g., duration, intensity, controllability, and predictability) and par-
adigms that consider organismal variables (e.g., learning and memory, resilience,
and vulnerability) have considerably more potential for providing actual insight
into the complex relationship between stress and sleep. In this section, we will
provide an overview of how a number of these factors can modulate the stress-
induced changes in sleep.
3.1 Stressor Controllability
Recent work has examined changes in sleep after controllable and uncontrollable
stress, and of memories associated with each parameter, using a simple yoked
control paradigm. In this paradigm, animals receive equal amounts of footshock,
but one of the yoked pair can terminate the footshock simply by moving to the safe
side of the shuttlebox. The actions of the yoked animal cannot alter shock pre-
sentation. Even though both animals receive equal shock, sleep in the post-shock
period can be dramatically different. As demonstrated in Fig. 1, animals trained
with controllable stress [escapable shock (ES)] can show significant enhancements
of REM sleep, whereas their yoked controls that receive uncontrollable stress
[inescapable shock (IS)] show significant reductions in REM sleep (Sanford et al.
2010). Returning the animals to the shock context without presenting footshock is
also followed by increased REM in the controllable stress condition and decreased
REM in the uncontrollable stress condition. Importantly, upon return to the shock
context, both groups of mice show enhanced freezing, the primary behavioral
indicator of fear memory (e.g. Blanchard and Blanchard 1969; Phillips and
LeDoux 1992; Paylor et al. 1994). Training with ES and IS also elicits similar
acute physiological stress responses as indicated by increased levels of plasma
corticosterone (Shors et al. 1989) and increased body temperature (stress-induced
hyperthermia) (Yang et al. 2011a). Thus, in this model, controllable and uncon-
trollable stress (and reminders of controllable and uncontrollable stress) result in
similar activation of the acute stress response and behavioral indices of fear but
directionally different alterations in REM. Controllability over a stressor does not
simply dampen the changes in sleep but rather, it may result in qualitatively
different changes. This work extends the findings based on the standard condi-
tioned fear paradigm and further demonstrates that post-stress changes in sleep are
not a simple function of the physical stress that an animal receives.
Stress, Arousal, and Sleep 385
3.2 Stressor Predictability
Predictability is an important factor in the effects of stress and a preference for
predictability has been repeatedly demonstrated (French et al. 1972; Gliner 1972;
Miller et al. 1974). For example, animals given the opportunity to determine
whether shocks delivered to them will be signaled or unsignaled typically choose
to spend their time in the signaled conditions regardless of whether the shock is
escapable or inescapable [reviewed in (Badia et al. 1979)]. The strong behavioral
effects suggest that predictability may also have a role in the modulating effects of
stress on sleep. In fact, stressor predictability is a significant component in shock
avoidance training in a shuttlebox, a paradigm in which laboratory rats are sig-
naled of imminent shock and can learn to prevent shock from being delivered.
Variants of this paradigm have often been used in studies of learning and sleep and
have typically found increases in the amount of REM sleep at various latencies
after training that have been interpreted as indicating a role for REM sleep in
memory consolidation (e.g. Smith and Lapp 1986; Datta 2000). Unfortunately, the
REM Episodes
Counts
0
40
80
120
Base ST1 ST2 Con
**** **** ****
REM Episode dur ation
Minutes
0
0.4
0.8
1.2
Base ST1 ST2 Con
***
** ***
Total REM
Minutes
0
30
60
90
**** **** ****
REM/ TST
Percent
0
5
10
15
**** **** ****
ES
IS
(a) (b)
(c) (d)
Fig. 1 REM sleep parameters plotted as 20 h totals for baseline (Base), two shock training days
(ST1,ST2), and context (Con) in a study comparing the effects of controllable (modeled by
escapable shock or ES) and uncontrollable (modeled by inescapable shock or IS) stress. aTotal
REM sleep. bREM sleep percentage (total REM sleep time/total sleep time). cNumber of REM
sleep episodes. dREM sleep episode duration. Significant differences between ES and IS: **,
p\0.01; ***, p\0.001; ****, p\0.0001 (Tukey test). Significant differences compared to
Base (open symbols) are indicated by dark circles or squares for the ES and IS groups. Reprinted
with permission from (Sanford et al. 2010)
386 L. D. Sanford et al.
potential role of predictability in modulating sleep after stress has received very
little attention.
One study of stressor predictability in mice examined sleep after training with
signaled escapable shock (SES) and signaled inescapable shock (SIS) (Yang et al.
2011a). Compared to mice experiencing SIS, those experiencing SES showed
significantly increased REM sleep after each of two shock training sessions
whereas compared to mice experiencing SES, those experiencing SIS showed
significantly increased NREM sleep after both shock sessions. Interestingly,
groups receiving either SES or SIS showed reduced REM sleep in response to cue
presentation alone. In another study, mice exposed to either predictive or non-
predictive auditory cues during training with ES also showed post-stress increases
in REM sleep (Machida et al. 2013). However, a subgroup of mice (around 35 %)
trained with the predictive auditory cue failed to improve their escape performance
from the first to second day of training. Those mice that did not improve also did
not show enhanced REM on either shock training day, suggesting a learning
component in the alterations in REM sleep.
It is useful to compare these results to those obtained using non-signaled
escapable and IS used to model controllable and uncontrollable stress as described
above (Sanford et al. 2010). Without predictive cues, the relative differences in
post-stress REM after escapable and IS were more pronounced. Contexts associ-
ated with non-signaled escapable and IS also produced directionally different
changes in REM similar to those seen when shock was presented (Sanford et al.
2010), whereas predictive cues associated with either escapable or IS produced
similar reductions in REM sleep.
While at this point the data are limited, these findings suggest that contexts and
auditory cues associated with different shock training conditions may carry dif-
ferent, and potentially competing, types of information regarding the stressful
situations. This difference is more pronounced in training with ESs as both con-
textual and cued fear associated with uncontrollable stress have similar effects on
sleep in mice and both reduce REM (Sanford et al. 2003a,c). Thus, competing
cued and contextual information associated with ESs may have interacted during
training resulting in competing influences on REM, thereby suggesting that
stressor predictability and controllability may interact in complex ways to mod-
ulate the changes in subsequent sleep.
3.3 Stress-Related Learning and Sleep
In addition to producing direct physiological effects, stressful situations provide an
opportunity for learning as the individual responds to the stressor and seeks to use
available information to cope with the ongoing challenge the stressor imposes.
While in humans this could involve a variety of activities, including higher order
cognitive processing; in rodents, the simplest behavioral responses to a stressor
may be avoidance or escape attempts. In this case, stress-related parameters such
Stress, Arousal, and Sleep 387
as controllability and predictability may provide useful information that shapes
avoidance and escape behaviors thereby facilitating successful coping. By com-
parison, stressors that are uncontrollable or occur unpredictably do not provide
information that can guide the animal to learn successful avoidance or escape
behaviors. In these situations, the animal may still engage in escape attempts, but
its behavior will not alter the presentation of the stressor or facilitate coping.
The impact of stressor controllability and predictability on behavior are central
to a number of well-established learning paradigms that are motivated by stressful
events. Of these, fear conditioning and related paradigms are beginning to dem-
onstrate that the learning options an animal has in a stressful situation play a
significant role in determining the impact of stress.
Experimental fear conditioning is a learning paradigm in which an animal makes
an association between an uncontrollable stressor (usually footshock) and previ-
ously neutral cues (typically auditory) or contextual information (the test box and
experimental room). Afterwards, presenting the fearful cues and contexts alone
elicit physiological and behavioral fear responses similar to those produced by the
initial uncontrollable stressor. Fear conditioned alterations in sleep are now also
established though these can vary with the amount of training and with the strain of
rats or mice that is studied. In agreement with the data in previous sections showing
that uncontrollable footshocks reduce REM sleep, the primary and most consistent
effect of extensive training with inescapable footshock is a marked reduction in
REM sleep that occurs both after the shock training and after presentation of shock
associated fearful cues and contexts (Sanford et al. 2003a,c; Tang et al. 2005d).
This reduction in REM sleep has been reported across species and across strains
(Sanford et al. 2001,2003a,c) and can occur without the rebound or recovery REM
sleep that has been reported for most stressors (Sanford et al. 2003a,c). Changes in
NREM sleep in fear conditioning studies appear to be less consistent. Some studies
have reported increases in (light) NREM sleep (Adrien et al. 1991), whereas others
have shown strain-dependent reductions in NREM sleep after shock training and
fearful contexts (Sanford et al. 2003a). There also may be relatively less NREM
sleep EEG delta power (slow wave activity) in animals that show greater fear
conditioned changes in sleep (Tang et al. 2006). Critically, these studies demon-
strate that fear conditioned memories of stressful events can produce mostly the
same changes in sleep as those produced by the stressful event itself and indicate
the importance of learning in both the immediate and lasting effects that stress can
have on sleep.
3.4 Fear Extinction and Sleep
Fear extinction is another important type of stress-related learning. While fear
conditioning can be involved in the long term, negative effects of stress, it also can
underlie adaptive behavior that occurs only so long as the fear-inducing stimulus
is predictive of, or associated with, an aversive event (Kishimoto et al. 2000;
388 L. D. Sanford et al.
Pitman et al. 2001). Repeated presentation of a fearful cue or context without
shock results in fear extinction, a type of new learning that inhibits subsequent fear
behavior without erasing the original memory for fear conditioning (Bouton 2004).
It is the failure of extinction that has been linked to stress-related psychopathology,
particularly posttraumatic stress disorder (PTSD) (Myers and Davis 2007).
The processes that make fear behaviors resistant to extinction remain mostly
unknown though there appears to be a relationship between fear extinction and
post-training REM sleep. Post-training REM sleep deprivation has been reported
to impair extinction (as indicated by freezing) for light cues (Silvestri 2005), but
not for auditory cues (Fu et al. 2007) previously paired with shock. REM sleep-
deprived rats did show greater spontaneous recovery of freezing on a second day
with presentation of the fearful auditory cue alone. Neither of these studies found
that post-training REM sleep deprivation significantly altered contextual fear
extinction learning or spontaneous recovery of freezing on a second day of testing
(Silvestri 2005; Fu et al. 2007). However, sleep (both NREM and REM) following
extinction of contextual fear does return to normal, whereas rats that continued to
show fear exhibited reductions in REM sleep (Wellman et al. 2008).
3.5 Stressor Resilience and Vulnerability to Sleep
Disturbance
Genetic differences in vulnerability and resilience are recognized as important
factors in the development of stress-related pathology. For example, approximately
20–30 % of individuals who experience traumatic events may develop PTSD
whereas others do not appear to suffer significant long-lasting effects (Cohen et al.
2003; Kerns et al. 2004). Attempts to develop animal models that better represent
individual differences in clinical populations have included the selection of low and
high responders to stressors in outbred rat strains (Cohen et al. 2003; Kerns et al.
2004). There is also evidence that differences in vulnerability are a factor in the
impact of stress on sleep, but the significance of individual differences has not been
fully appreciated in either studies of stress or in studies of sleep in general (Irmis
et al. 1971,1974; Tang et al. 2007).
Some of the best evidence for the role in resilience and vulnerability in the
impact of stress on sleep comes from studies comparing inbred strains of rodents,
which are genetically identical within strain but which vary genetically and phe-
notypically across strain. Work in mice and rats has demonstrated that strains that
exhibited greater anxiety-like behaviors in response to challenges in wakefulness
exhibited correspondingly greater and longer duration alterations in sleep after
training with IS and after fearful cues (Sanford et al. 2003c) and contexts (Sanford
et al. 2003a) associated with IS. In general, vulnerable mouse strains (e.g., BALB/
cJ mice compared to more resilient C57BL/6 J mice) also showed greater decreases
in sleep after stressful situations with unlearned responses, including exposure to an
Stress, Arousal, and Sleep 389
open field (Tang et al. 2004), cage change, and novel objects placed in the home
cage (Tang et al. 2005b). Moreover, BALB/cJ mice also do not show a significant
REM sleep increase during recovery from restraint stress, whereas C57BL/6 J mice
do (Meerlo et al. 2001b).
In addition to genetic determinants of individual resilience and vulnerability,
environmental factors and prior experiences with stress also play a major role in
shaping future responses to stressful challenges. One such factor is neonatal stress
that can be induced by disruptions of mother–infant relationship and that can have
repercussions for adult behavior (Levine 2005) though the specific effects of
maternal separation on sleep have varied across studies. For exampl e, 3 h of maternal
separation from postnatal days 2–14 in rats has been reported to increase both
spontaneous baseline REM sleep and cold-stress-induced changes in REM sleep in
males (Tiba et al. 2004) and females (Tiba et al. 2008). Similarly, neonatal rats
maternally separated for 3 h and exposed to chronic mild stress as adults were
reported to show longer sleep time, more episodes of REM sleep, and more episodes
of NREM sleep transitioning to REM sleep (Mrdalj et al. 2013). By comparison, 6 h
of neonatal maternal deprivation reduced the time spent in REM, without changes in
NREM sleep when the rats attained adulthood (Feng et al. 2012). In addition to
differences in experimental procedure, another important aspect that may differen-
tiate these studies is the strain of rats used. While Feng and co-workers used Sprague-
Dawley rats, the other studies used Wistar rats, which display more maternal
behavior upon reunion with their litters (Lehmann and Feldon 2000), possibly buf-
fering potential harmful effects of the separation procedure.
4 Stress Mediators as an Important Cause of Arousal
and Sleep Disturbance
The regulation of sleep and arousal involves multiple neurotransmitter systems as
well as excitatory and inhibitory amino acids, peptides, purines, and neuronal and
non-neuronal humoral (i.e., cytokines and prostaglandins) modulators (Steiger and
Holsboer 1997; Steiger et al. 1998; Jones 2005; Steiger 2007; Luppi 2010; Espana
and Scammell 2011). Many of these same neurotransmitters and neuromodulators
are also influenced by and/or mediate the effects of stress and are likely involved in
the effects of stress on sleep. This section will briefly review some of the major
neurochemical systems that link stress and sleep.
4.1 Hypocretin/Orexin
Hypocretin-1 and -2 are a set of neuropeptides that are derived from the same
precursor gene and produced by neurons located in the lateral hypothalamus. The
hypocretins are also called orexins as they were independently discovered by two
390 L. D. Sanford et al.
research groups in 1998 and separately named as hypocretins (de Lecea et al.
1998) or orexins (Sakurai et al. 1998). The hypocretin containing neurons have
widespread projections throughout the brain and play a role in a variety of func-
tions including autonomic control, neuroendocrine function, and feeding.
Numerous studies have also linked hypocretin to the regulation of the sleep–wake
cycle, particularly the induction and maintenance of wakefulness (Kilduff and
Peyron 2000; Sutcliffe and de Lecea 2002). Indeed, the hypocretin system acti-
vates various well-known wake-active and arousal promoting centers in the brain,
including the histaminergic tuberomammilary nucleus, the noradrenergic locus
coeruleus (LC), the serotonergic dorsal raphe, and the cholinergic cell clusters in
the brainstem and basal forebrain (Peyron et al. 1998b). Impaired hypocretin
transmission is a core pathophysiological factor of narcolepsy, a disease charac-
terized by uncontrollable onset of sleep (Nishino et al. 2000; Kornum et al. 2011).
Several lines of evidence indicate that hypocretins/orexins may also play a role
in the behavioral arousal and neuroendocrine activation associated with stress
(Winsky-Sommerer et al. 2005). A close and bidirectional relationship exists
between the hypocretin system and the HPA axis. Hypocretins stimulate the activity
of the HPA axis in a dose-dependent manner, an effect that seems to be mediated at
the hypothalamic level (Kuru et al. 2000; Samson et al. 2002) but not at the adrenal
level (Jaszberenyi et al. 2000). Under stressful conditions, a dual hypocretin-1/
hypocretin-2 receptor antagonist does not interfere with corticosterone secretion but
does reverse the immediate waking effect of novelty and social stressors (Steiner
et al. 2013). In turn, hypothalamic corticotropin releasing hormone (CRH) con-
taining neurons project directly to the lateral hypothalamus hypocretin containing
neurons, where CRH1 and 2 receptors are abundantly expressed (Winsky-Sommerer
et al. 2004). Indeed, studies in mice have shown that exposure to footshock and
restraint stress causes an activation of the lateral hypothalamic hypocretin neurons,
an effect that is mediated by CRH (Winsky-Sommerer et al. 2005).
4.2 Corticotropin Releasing Hormone
CRH is a major mediator of central nervous system responses to stressors (Koob
and Bloom 1985; Heinrichs et al. 1995; Koob 1999). Intracerebroventricular (ICV)
administration of CRH in rats produces many of the signs associated with anxiety in
humans, including increased wakefulness (Ehlers et al. 1986; Marrosu et al. 1990;
Chang and Opp 1998), altered locomotor activity, and an exaggerated startle
response (Swerdlow et al. 1986; Heilig et al. 1994). By comparison, CRH antag-
onists attenuate behavioral responses to stress (e.g. Aloisi et al. 1999; Basso et al.
1999; Deak et al. 1999).
CRH may not only play an important role in stress-induced wakefulness and
arousal, it may also be partly responsible for changes in sleep architecture during
the subsequent recovery phase (Gonzalez and Valatx 1997). However, the few
studies examining the role of CRH in stress-induced alterations in sleep have
Stress, Arousal, and Sleep 391
yielded conflicting data. This is exemplified with the work on restraint stress-
induced increases in REM sleep. The ICV administration of the broad CRH
antagonist a-helical CRH9–41 prior to restraint stress prevents the subsequent
increase in REM, but does not alter spontaneous REM, NREM, or wakefulness in
non-stressed rats (Gonzalez and Valatx 1997). In contrast, other investigators
found no effect of restraint stress applied at the beginning of the dark period on
subsequent sleep, and also found no effect of the CRH antagonist, astressin, on
sleep after restraint (Chang and Opp 2002). By comparison, restraint exposure at
the onset of the light period increases wakefulness and decreases both NREM and
REM, and ICV administration of astressin attenuates the increase in wakefulness
over a 5 h-period immediately after the end of restraint but does not alter arousal
during the period when restraint was applied (Chang and Opp 2002). There may
have been differences in the procedures used for restraint [e.g., whether or not it
was conducted in the home cage (Chang and Opp 2002)] that could have produced
different results in these studies.
A recent study (Kimura et al. 2010) examined baseline and recovery sleep
after sleep deprivation in conditional mouse mutants that overexpress CRH in the
entire central nervous system or only in the forebrain, including limbic structures.
In baseline recordings, homozygous mice with either global or forebrain over-
expression of CRH showed increased REM compared to controls and both
homozygous and heterozygous mice with global overexpression of CRH showed
enhanced recovery REM sleep after 6 h sleep deprivation. However, repeated
ICV administration of CRH during prolonged REM sleep deprivation in rats
inhibits the expected REM rebound (Machado et al. 2010). Enhanced REM sleep
recovery, but not NREM sleep recovery, was blocked by oral administration of
the CRH receptor type 1 (CRHR1) antagonist, DMP696, 1 h prior to the end of
sleep deprivation. Peripheral stress hormone levels were not elevated during
baseline and did not differ across genotypes after sleep deprivation. The authors
concluded that enhanced REM sleep in these mice was most likely induced
through the activation of CRHR1. Consistent with this conclusion is a report that
repeated administration of a-helical CRH9–41 in rats over 10 h of sleep depri-
vation also reduced the amount of REM sleep recovery (Gonzalez and Valatx
1998).
However, there is a separate line of research that demonstrates an inhibiting
effect of CRH on REM sleep. Fear conditioning with IS, an uncontrollable stressor,
and the presentation of fearful contexts and cues associated with IS are followed by
significant reductions in REM that occur in the first few hours after exposure
(Sanford et al. 2003a,c). In mice, ICV administration of CRH enhances the
reduction in REM sleep following fearful contexts, whereas ICV administration of
the non specific CRH antagonist, astressin, attenuates fear-induced reductions in
REM (Yang et al. 2009). Training with ES, and reminders of ES, can produce
significant enhancements in REM sleep (Sanford et al. 2010). Microinjections of
either saline or astressin prior to training produce similar, significant enhancements
in post-stress REM sleep relative to a non-shocked handling control condition,
whereas the increases in REM sleep are blocked by pretreatment with CRH (Yang
392 L. D. Sanford et al.
et al. 2011b). The effect of CRH seems to be relatively specific for REM sleep as
changes in NREM sleep and wakefulness were minimal. One potential explanation
for differences across studies is that administration of a CRH antagonist simply
blocked the initiation of neural processes that would have led to a subsequent
increase in REM sleep.
4.3 Prolactin
A variety of studies have indicated that prolactin can promote REM sleep. Both
systemic and ICV injection of prolactin enhances REM sleep in rats (Roky et al.
1995), whereas administration of a prolactin antiserum reduces the amount REM
sleep without affecting NREM sleep (Obal et al. 1992). Also, the amount of REM
sleep was found to be reduced in prolactin-deficient mice, which could be reversed
by prolactin replacement (Obal et al. 2005).
Several studies in laboratory rodents have shown that the plasma level of pro-
lactin increases in response to a wide variety of stressors, including restraint stress
and ether exposure (Lenox et al. 1980; Meerlo et al. 2001b) suggesting that it may
play a role in the effects of stress on sleep. A comparative study on different strains
of mice showed that C57BL/6 J mice and BALB/cJ mice had similar corticosterone
responses to restraint stress; however, the effects on prolactin and subsequent sleep
were quite different. Restraint stress caused a concomitant increase in prolactin and
REM sleep in the C57BL/6 J mice, but not in BALB/cJ mice, which supports the
idea that prolactin might be involved in the mechanism underlying restraint stress-
induced REM sleep (Meerlo et al. 2001b). Direct evidence for prolactin as a
mediator of stress-related increases in REM sleep comes from a study in rats
showing that an ether exposure-induced increase in REM sleep could be blocked by
hypophysectomy and by ICV administration of an antiserum to prolactin (Bodosi
et al. 2000). Other data implicating prolactin in stress-induced alterations in sleep
come from a study examining post-stress sleep in REM sleep-deprived rats sub-
sequently submitted to single or repeated sessions of footshock (Machado et al.
2008). REM sleep rebound was greater in the REM sleep-deprived rats that
received multiple sessions of footshock, and the increase was associated with higher
levels of prolactin (Machado et al. 2008).
Together these studies suggest that stressful stimuli and conditions that are
associated with strong increases in prolactin levels may be followed by sleep with
increased amounts of REM sleep. The precise mechanism of these effects of
prolactin remains to be clarified but may involve a direct stimulatory effect of
prolactin on cholinergic neurons in the mesopontine tegmental area involved in
REM-sleep induction (Takahashi et al. 2000).
Stress, Arousal, and Sleep 393
4.4 Monoamines
Serotonin (5-HT) containing neurons in the dorsal raphe nucleus (DRN), nor-
adrenaline (NA) containing neurons in the LC, and histamine containing neurons
in the tuberomammillary nucleus are wake-active and act directly on cortical and
subcortical regions to promote wakefulness (Jones 2005). The 5-HT and NA
systems are strongly stress-reactive (see discussion below) whereas there has been
less work on the role of the histaminergic system. However, it is involved with the
regulation of the stress response as central administration of histamine produces
increases in adrenocorticotropin and corticosterone (Rudolph et al. 1979; Knigge
and Warberg 1991) and blocking histamine synthesis or administration of antag-
onists block ACTH, beta-endorphin and prolactin responses to some stressors
(Rudolph et al. 1979; Seltzer et al. 1986; Knigge and Warberg 1991; Kjaer et al.
1993; Fleckenstein et al. 1994). There also appears to be heterogeneity in specific
histaminergic cells groups with respect to responding to different stressors (Miklos
and Kovacs 2003).
Interestingly, each of these systems has been implicated in the enhancement of
REM sleep that typically follows restraint stress. The increase is not found in
5-HT1A knockout mice (Boutrel et al. 2002; Popa et al. 2006) or in mice lacking
the 5-HT transporter (Rachalski et al. 2009). Administration of the serotonin
synthesis inhibitor para-chlorophenylalanine (Sinha 2006), neurotoxic destruction
of noradrenergic cells in LC (Gonzalez et al. 1995), and administration of the
histamine H1 receptor antagonist, chlorpheniramine, also prevent the increase in
REM sleep induced by restraint in rats (Rojas-Zamorano et al. 2009). However,
the actual cause of the attenuation of the REM sleep increase is not yet fully
understood. As indicated for CRH, alterations in these systems prior to stress
could simply alter the intensity of some elements of the stress response such that
the processes that result in the post-restraint increase in REM sleep are not
engaged.
5 Brain Regions Linking Stress, Arousal and Sleep
As discussed in the above section on stress mediators, there are several points of
overlap in the neural regions/systems involved in stress and those directly involved
in arousal. This section will focus on the amygdala and medial prefrontal cortex
(mPFC), two regions not typically considered as direct regulators of arousal and
sleep but which play significant roles in mediating the effects of stress on sleep and
arousal (see Fig. 2).
394 L. D. Sanford et al.
5.1 Amygdala and Stress-Induced Alterations in Arousal
and Sleep
Several lines of research have demonstrated that the amygdala is a significant
modulator of sleep. The majority of research on the role of the amygdala in reg-
ulating sleep has focused on its influence on REM sleep (e.g. Sanford et al. 1995,
Amygdala
BLA CNA
mPFC
PVN
Pituitary
Adrenal
glands
BNST
Fear-Induced
Sympathetic
Activation
Hippocampus
LH
Arousal/
Sleep
LC
Emotional
Stress
DRN
Fig. 2 This diagram illustrates the principal circuitry (shaded) that we are discussing in this section
along with some of their connections to other regions involved in stress and sleep. In this figure,
emotional stress would act on the amygdala which would be regulated by the hippocampus
(contextual information) and the mPFC (perceived stressor control). BLA would act on CNA and
the BNST to regulate the peripheral stress axis via PVN. Output from CNA would also impact LC
and DRN, which have roles in regulating REM sleep and arousal as well as in regulating PVN. Both
CNA and LC are involved in regulating fear-induced sympathetic activation via effects on LH. This
diagram is necessarily incomplete, but illustrates the central role of the amygdala in controlling the
stress axis, fear responses, and important components of the arousal system. Heavyweight arrows
indicate presumed critical connections for mediating the effects of stress on sleep. Lightweight
arrows indicate other connections that may play a role in regulating responses. Dashed arrows
indicate indirect pathways. BLA basolateral nucleus of the amygdala, BNST bed nucleus of the stria
terminalis, CNA central nucleus of the amygdala, DRN dorsal raphe nucleus, LC locus coeruleus,
LH lateral hypothalamus, mPFC medial prefrontal cortex, PVN paraventricular nucleus
Stress, Arousal, and Sleep 395
1998,2002; Calvo et al. 1996; Zhu et al. 1998; ); however, a number of studies
indicate that the amygdala can influence all sleep–wakefulness states (Sanford et al.
1995;1998,2006; Zhu et al. 1998). This influence most likely involves amygdalar
projections to thalamic, hypothalamic, and brainstem target regions (Amaral et al.
1992) that are involved in the control of sleep and arousal. These include direct
projections via the central nucleus of the amygdala [CNA; e.g. (Krettek and Price
1978; Inagaki et al. 1983; Price et al. 1987; Semba and Fibiger 1992; Peyron et al.
1998a)] and the lateral division of the bed nucleus of the stria terminalis [BNST;
reviewed in (Amaral et al. 1992; Davis and Whalen 2001)], the source of the major
descending outputs of the amygdala to brainstem regions linked to the regulation of
REM sleep.
The amygdala is important in the regulation of behavioral, physiological, and
neuroendocrine responses to stress (Roozendaal et al. 1991a,b; Bohus et al. 1996)
and it appears to be a vital interface between stressful events and their impact on
sleep and arousal. The BNST is an important relay for the influence of the amygdala
on the hypothalamic paraventricular nucleus (PVN) (Forray and Gysling 2004), the
final common pathway for information influencing the HPA axis (Pacak and
Palkovits 2001; Herman et al. 2004) and a key site for integrating neuroendocrine,
autonomic, and behavioral responses to stress (Chrousos 1998). GABA-ergic
neurons in BNST can directly inhibit PVN and reduce ACTH secretion (Herman
et al. 2004). By comparison, CNA has minimal direct projections to PVN (Prewitt
and Herman 1998) and lesions of CNA do not directly influence PVN activation
(Prewitt and Herman 1997) though CNA can influence PVN via trans-synaptic
pathways through the dorsomedial hypothalamic nucleus and BNST (Prewitt and
Herman 1998).
CNA does play a role in regulating the effects of stress on sleep, whereas a
possible role for BNST has not been established. Inhibition of the CNA suppresses
REM sleep whereas its activation [e.g., with electrical stimulation (Smith and
Miskiman 1975)] can promote REM sleep in some situations. For example, func-
tional inactivation of CNA with microinjections of the GABA
A
agonist, muscimol,
produces a relatively selective decrease in REM sleep whereas blocking GABAergic
inhibition with the GABA
A
antagonist, bicuculline, enhances REM sleep (Sanford
et al. 2002). Functional lesions of the CNA by TTX, which inactivates both cell
bodies and fibers of passage also decrease REM sleep and reduce arousal (Tang et al.
2005c). The decrease in REM sleep can occur without recovery (Tang et al. 2005c), a
finding also reported for training with IS and fearful cues and contexts.
That stress-induced inactivation of CNA is involved in stress-induced reduc-
tions in REM sleep is also suggested by the lack of Fos activation in CNA after
conditioned fear (Liu et al. 2003). Functionally, this hypothesis is supported by
findings that bicuculline microinjected into CNA attenuates footshock-induced
reductions in REM sleep whereas inactivation of CNA with muscimol did not (Liu
et al. 2009). However, it should be noted that findings that activation of CNA
promotes and inactivation of CNA reduces REM sleep appear at odds with the
prevailing conventional view that CNA activation is responsible for regulating fear
396 L. D. Sanford et al.
responses via projections to the periaqueductal gray and other brainstem areas
[Reviewed in (Duvarci et al. 2011)]. In fact, CNA neurons do fire in response to
footshock stress (Rosenkranz et al. 2006) and in response to conditioned stimuli
(Duvarci et al. 2011). However, CNA is inhibited by stimulation of the basal and
lateral nuclei of the amygdala (Rosenkranz et al. 2006) both of which show high
Fos expression after footshock (Liu et al. 2003). Thus, it is possible that CNA
activation during fearful/stressful events does regulate fear behavior in wakeful-
ness, but subsequently, with certain stressors, can be inhibited to decrease REM
sleep in the post-stress period.
The involvement of the basolateral nucleus of the amygdala (BLA) in the
control of sleep is indicated by reports that bilateral electrolytic and chemical
lesions of BLA increase NREM sleep and total sleep time in rats (Zhu et al. 1998)
and that bilateral chemical lesions of the amygdala produce more consolidated
sleep in chair restrained Rhesus monkeys (Benca et al. 2000). Electrical and
chemical stimulation of BLA also increase low voltage, high frequency activity in
the cortical EEG and decrease NREM sleep and total sleep time, respectively
(Dringenberg and Vanderwolf 1996; Zhu et al. 1998).
In general, the evidence suggests that CNA is more involved in the regulation of
REM sleep than that of NREM sleep and that by comparison, BLA has a greater
role in the regulation of NREM sleep and arousal. However, it is important to note
that BLA regulates CNA output and therefore likely controls its influences on
REM. Fibers from BLA also course through CNA on to the BNST which has
brainstem targets similar to those of CNA (Davis and Whalen 2001), thereby
providing an additional pathway by which BLA can influence brainstem regions.
Indeed, it was recently found that microinjections into BLA of the Group II
metabotropic glutamate (mGlu) receptor agonist, LY379268, selectively reduced
REM sleep without significantly altering wakefulness or NREM sleep (Dong et al.
2012). By comparison, microinjection of LY379268 into CNA did not significantly
alter sleep. Thus, group II mGlu receptors may influence specific cells in BLA that
control descending outputs (possibly via CNA or BNST) that in turn regulate REM
sleep generator regions in the brainstem.
The amygdala (including extended amygdala) is a critical region for the central
effects of CRH, and it appears to mediate a number of the anxiogenic effects of
CRH as evidenced by intra-amygdala microinjections of CRH agonists and
antagonists [Reviewed in (Davis and Whalen 2001)]. For example, local appli-
cation of CRH or urocortin (Sajdyk et al. 1999) into the BLA in rats produces
dose-dependent increases in anxiety behaviors. CRH in the amygdala also plays a
significant role in regulating stress-induced alterations in sleep.
It was reported that microinjections of the CRHR1 antagonist, antalarmin, into
CNA in rats block fear-induced reductions in REM sleep and attenuate Fos
expression in regions important in stress and REM sleep regulation including the
PVN, LC, and DRN (Liu et al. 2011). Similarly, bilateral microinjections of anta-
larmin into BLA in rats do not alter spontaneous sleep, but do block the reduction in
REM sleep produced by inescapable footshock (Wellman et al. 2013). Further,
microinjecting antalarmin into BLA prior to shock training also blocked the
Stress, Arousal, and Sleep 397
subsequent effects of contextual fear on REM sleep, but did not block fear memory or
behavior as indicated by freezing. These data indicate that CRH receptors within
the CNA and BLA are important in the regulation of stress- and fear-induced
alterations in REM sleep, and also suggest that BLA plays a role in modulating how
stressful memories influence sleep. The hippocampus is also likely to be involved.
Information regarding fear conditioned contexts is first processed in the hippo-
campus and followed by BLA with output through CNA [reviewed in (LeDoux
2000)] and possibly BNST (Davis and Whalen 2001).
5.2 REM Regulatory Regions, Medial Prefrontal Cortex
and Stressor Control
Stress often has a prominent effect on REM sleep (Sanford et al. 2003a,b,c; Jha
et al. 2005). Thus, it is not surprising that brain regions directly implicated in the
regulation REM sleep have significant roles in mediating the stress response.
These include the LC and DRN. LC noradrenergic neurons and DRN serotonergic
neurons are virtually silent during REM sleep and their activation may inhibit its
generation (Steriade and McCarley 1990). LC and DRN also have connections to
the PVN. PVN receives a large noradrenergic projection from brainstem A1 and
A2 groups and a smaller projection from LC (Dunn et al. 2004). However, lesions
of LC do reduce ACTH and corticosterone responses to acute stress (Ziegler et al.
1999), and there are suggestions that LC may impact PVN indirectly via limbic
structures [reviewed in (Herman and Cullinan 1997)]. DRN has collateral sero-
tonergic projections to CNA and PVN (Petrov et al. 1992,1994), and 5-HT
agonists enhance PVN activity as indicated by increased corticosterone levels and
Fos expression (Mikkelsen et al. 2004). Indirect pathways may also play a role in
serotonergic regulation of PVN (Herman and Cullinan 1997).
As discussed above, stressor controllability appears to be an important parameter
in the effects of stress on sleep. Brainstem noradrenergic and serotonergic regions
play important roles in stressor controllability. For example, IS in rats produced
sustained increases in NA turnover in various brain regions regardless of stress
duration, whereas with ES, NA utilization was reduced after rats had learned the
coping response (Tsuda et al. 1987). IS also activates DRN serotonergic neurons to a
greater degree than ES thereby increasing 5-HT in DRN and in target areas (Amat
et al. 1998a,b; Hammack et al. 2002; Bland et al. 2003a,b). Administration of CRH
into DRN produced behavioral changes like those seen with IS, whereas microin-
jection of a nonselective CRH antagonist blocked the behavioral changes normally
seen with IS (Hammack et al. 2002,2003a,b). The application of CRH to LC also
increases NA release (Van Bockstaele et al. 1998).
The alterations in 5-HT and NA after inescapable and ES are consistent with
their putative roles as inhibitory modulators of REM sleep and with the respective
increases and decreases in REM sleep after controllable and uncontrollable stress.
However, the evaluation of controllability requires assessment and evaluation of
398 L. D. Sanford et al.
information at the cortical level (Maier et al. 2006). The mPFC has been found to
be a critical region in the perception of control and in mediating the consequences
of stress (Maier et al. 2006; Smith and Vale 2006; Akirav and Maroun 2007). For
example, blocking activation of the ventral mPFC with muscimol did not alter
escape behavior in rats presented with IS, but blocking ventral mPFC in rats
presented with ES produced failure in escape learning and greater fear condi-
tioning (Maier et al. 2006). By comparison, activation of ventral mPFC with
picrotoxin prior to IS promoted later escape learning in rats provided an oppor-
tunity to escape shock in a shuttlebox (Maier et al. 2006).
Unfortunately, the role of the mPFC in mediating the effects of stressor con-
trollability on sleep has not been examined. However, part of the influence of
mPFC is enacted through its effects on the DRN and possibly LC (Maier et al.
2006), providing a potential substrate for regulating alterations in REM sleep. For
example, consistent with the discussion above, activation of mPFC inhibits DRN
(Maier et al. 2006; Smith and Vale 2006). The prelimbic mPFC also has robust but
restricted projections to the BLA and CNA, whereas the infralimbic mPFC pro-
jects to the medial, basomedial, cortical nuclei as well as to the CNA (Vertes
2004). There are projections from the mPFC to GABAergic neurons in the
intercalated nuclei which have inhibitory control over CNA output, but there are
conflicting reports regarding their specific origin within mPFC (see Vertes 2004).
However, these projections from the mPFC to brainstem regulatory regions and the
amygdala provide a substrate by which stressor controllability could influence
REM sleep.
6 Stress, Sleep and Neuronal Plasticity: Implications
for Stress-Related Disorders
Both NREM and REM sleep have putative roles in regulating neuronal plasticity
and synaptic strength (Benington and Frank 2003; Tononi and Cirelli 2006;
Meerlo et al. 2009; Havekes et al. 2012). Stress-induced changes in sleep and sleep
architecture might lead to alterations in these plasticity processes and ultimately
brain function. In fact, some of the changes in plasticity and brain function tra-
ditionally linked to stress may in part be related to alterations in sleep.
Work on stress and plasticity has distinguished the effects of acute and chronic
stress. Acute stress can impact functional plasticity whereas chronic stress can dif-
ferentially alter structural plasticity across brain regions. For example, chronic stress
results in dendritic atrophy and reductions in spine density in the hippocampus
(Magarinos and McEwen 1995a,b; Magarinos et al. 1997; Sandi et al. 2003; Stewart
et al. 2005) and prefrontal cortex (Wellman 2001; Cook and Wellman 2004; Radley
and Morrison 2005; Liston et al. 2006; Radley et al. 2006). Similar types of chronic
stress produce increased dendritic arborization and increased spine density in BLA
spiny neurons (Mitra et al. 2005; Vyas et al. 2006) and spine down-regulation in the
medial amygdala (Bennur et al. 2007). Some stress-induced changes in the
Stress, Arousal, and Sleep 399
hippocampus (Sandi et al. 2003; Stewart et al. 2005) and prefrontal cortex appear to
be reversible whereas those in the amygdala are not [Reviewed in (Christoffel et al.
2011)]. Acute restraint, tail shock, and environmental stress impair long-term
potentiation (LTP) in the hippocampus (Foy et al. 1987) and acute environmental
stress can enhance long-term depression (Xu et al. 1997). However, stress-induced
impairment in hippocampal LTP was significantly less in rats allowed to escape
footshock than in yoked controls receiving identical shock, but not allowed to escape
(Shors et al. 1989). This control mediated attenuation occurred even after a week of
daily training sessions with relatively intense shock (30 trials, 1 mA, 1.5 s mean
duration).
Although both sleep and stress can impact neuronal plasticity, their potential
interactions in mediating alterations in plasticity have been minimally explored. The
presence of interactions is indicated by the strong effects that stress can have on sleep
as well as the demonstrated and hypothesized roles each has in mediating various
aspects of plasticity. Importantly, post-stress sleep may have an adaptive function in
coping with stress. This is suggested by the directionally different post-stress
changes in REM sleep that occur following uncontrollable and controllable stress
(Sanford et al. 2010) and the normalization in REM sleep that occurs following fear
extinction versus the continued suppression of REM sleep in animals that still show
fear (Wellman et al. 2008). These differences suggest that sleep and specific stress
parameters may interact in mediating synaptic plasticity associated with stress-
related learning and memory and/or the emotional valence of the memory. Indeed, a
variety of authors have made suggestions consistent with this hypothesis, e.g., REM
sleep functions to weaken unwanted memory traces in the cortex (Crick and
Mitchison 1983); intact REM sleep aids in the processing of memory for trauma
(Mellman et al. 2002,2007); and REM sleep may play an important role in con-
solidating memories for aversive events and for ‘‘decoupling’’ those memories from
their emotional charge (Nishida et al. 2009; Walker 2009).
Best et al. proposed that pyramidal neurons in the hippocampus change from a
firing pattern that supports LTP in wakefulness to one that supports depotentiation
during REM sleep; thereby putatively ‘‘resetting’’ the hippocampus after memories
have been transferred to the frontal cortex and clearing the way for the formation of
future memories (Best et al. 2007). If true, reductions in REM sleep induced by IS,
particularly those that occur without recovery REM sleep (Sanford et al. 2003a,c),
could impair this process. Impairment could also involve stress-induced enhance-
ment of NA and 5-HT which facilitate LTP and may impede depotentiation
[Reviewed in (Best et al. 2007)]. By comparison, enhancements of REM sleep and
corresponding decreased activity in noradrenergic and serotonergic regions could
facilitate the adaptive processing of strong memories. Post-stress NREM sleep may
also be important. This is suggested by reports that rats trained with IS in an intense
learned helplessness paradigm show increased light NREM sleep as well as
decreased REM sleep (Adrien et al. 1991).
Sleep disturbances both before (Bryant et al. 2010) and after (Lavie 2001)
traumatic events have been linked to the development of stress-related pathology.
However, it is important to note that stress and the temporary alterations in sleep
400 L. D. Sanford et al.
associated with it typically do not give rise to persisting or detrimental effects. This
suggests that being able to distinguish normal stress responses from those that can
lead to pathology is likely key to fully understanding the processes leading to stress-
related disorders. As stress-induced dysregulation of neuronal plasticity and
remodeling of neural circuits are implicated in a variety of psychiatric disorders
(McEwen 2007; Christoffel et al. 2011) understanding the role sleep plays in
mediating the effects of stress on neuronal plasticity also may be critical for
understanding how stress comes to produce persisting and pathological changes in
the brain.
Acknowledgments The contribution of L.D.S. was supported by NIH research grants MH64827
and EVMS institutional funds. D.S. was supported by research grants from FAPESP (98/14303-3)
and Associação Fundo de Incentivo à Pesquisa and she is the recipient of a research fellowship
from CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico).
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... The architecture and intensity of sleep depends not only on the conditions of an animal's sleeping environment (see Section 3), but also on the quality of its wakefulness. For instance, sleep can be altered in response to stressors endured during wakefulness (reviewed in Lo Martire et al., 2020; Sanford et al., 2015). A stressor is defined as an actual or perceived threat to homeostasis (Reeder and Kramer, 2005). ...
... However, no studies of this sort have incorporated stress-induced sleep alterations as a potential link between social status and fitness. Research on rodents shows that exposure to a stressor can drive changes to subsequent sleep homeostasis, both in the short-and long-term (Lo Martire et al., 2020;Pawlyk et al., 2008;Sanford et al., 2015). This is unsurprising given that many components of the stress-response (i.e., neurochemical systems) are known to overlap with those involved in sleep (Sanford et al., 2015). ...
... Research on rodents shows that exposure to a stressor can drive changes to subsequent sleep homeostasis, both in the short-and long-term (Lo Martire et al., 2020;Pawlyk et al., 2008;Sanford et al., 2015). This is unsurprising given that many components of the stress-response (i.e., neurochemical systems) are known to overlap with those involved in sleep (Sanford et al., 2015). Therefore, mammals living in social hierarchies may experience statusspecific sleep alterations associated with stress. ...
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Social status among group-living mammals can impact access to resources, such as water, food, social support, and mating opportunities, and this differential access to resources can have fitness consequences. Here, we propose that an animal's social status impacts their access to sleep opportunities, as social status may predict when an animal sleeps, where they sleep, who they sleep with, and how well they sleep. Our review of terrestrial mammals examines how sleep architecture and intensity may be impacted by (1) sleeping conditions and (2) the social experience during wakefulness. Sleeping positions vary in thermoregulatory properties, protection from predators, and exposure to parasites. Thus, if dominant individuals have priority of access to sleeping positions, they may benefit from higher quality sleeping conditions and, in turn, better sleep. With respect to waking experiences, we discuss the impacts of stress on sleep, as it has been established that specific social statuses can be characterized by stress-related physiological profiles. While much research has focused on how dominance hierarchies impact access to resources like food and mating opportunities, differential access to sleep opportunities among mammals has been largely ignored despite its potential fitness consequences.
... In animals, the psychological aspect of stress becomes an important factor relative to its effect on sleep. For example, in rats and mice, the occurrence of sleep after stress appears to be highly influenced by situational variables including whether the stressor was controllable and/or predictable, whether the individual had the possibility to learn and adapt, and by the relative resilience and vulnerability of the individual experiencing stress (132). In this respect, deeper or longer NREM sleep reportedly follows acute social stress (133,134), whilst stress experienced in response to restraint is followed by a selective increase in REM sleep (86,135). ...
... The increase in sleep states reported in animals post-stress contrasts with sleep reductions often observed in humans, where stress-based memories of past events as well as worries and expectations can disrupt and reduce human sleep. In that respect, compared to some animals, the human brain has the capacity to turn a single acute stressor or previous life event, or even one situated in the future, into a persistent and chronic stress state (132). Other psychological stressors in humans have also been reported to reduce the quality of sleep through increased levels of sleep fragmentation (137). ...
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... concentrating, and sleep problems [20,[31][32][33][34][35][36][37][38]. Though the infection with SARS-CoV-2 is a recent fact and the fundamental processes of the body functioning in this illness require more exploration, patterns of alterations to the circadian rhythms have been investigated in many disorders. ...
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Background All elements of everyday life have been seriously and significantly impacted by the global COVID-19 outbreak. Previous research has demonstrated a connection between infectious disease epidemics and sleep disturbances as well as psychological discomfort, such as traumatic stress, melancholy, and anxiety. Objectives The study aimed to summarize current evidences about sleep quality and sleep disorders for patients that had Covid-19 infection Methods For article selection, the PubMed database and EBSCO Information Services were used. All articles relevant with our topic and other articles were used in our review. Other articles that were not related to this field were excluded. The data was extracted in a specific format that was reviewed by the group members. Conclusion Our study included 8 studies in total. Patients with recovered COVID-19 showed a statistically significant prevalence of insomnia than control groups. Patients must be advised to follow-up if they have trouble sleeping as a result. Early detection and treatment of people who are experiencing insomnia are crucial to prevent long-term harmful effects as increase in the intensity of depression, anxiety, and post-traumatic stress that were shown to be substantially correlated with poor sleep quality.
... Alterations in non-REM sleep phases may therefore predispose health-related problems. In addition, altered sleep architecture was shown to increase stress levels by increasing stress hormones [39][40][41][42]. These findings especially after recovering from the infection support the fact that COVID-19 may present with long-standing symptoms such as autonomic and neurologic disturbances. ...
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Background: Coronavirus 2019 (COVID-19) patients have increased sleep disturbances and decreased sleep quality during and after the infection. Current published literature focuses mainly on qualitative analyses based on surveys and subjective measurements rather than quantitative data. Objective: We assess the long-term effects of COVID-19 through sleep patterns from continuous signals collected via wearable wristbands. Methods: Patients with a history of COVID-19 were compared to a control arm of individuals who never had COVID-19. Baseline demographics were collected for each subject. Linear correlations amongst the mean duration of each sleep phase and the mean daily biometrics were performed. The average duration for each subject's total sleep time and sleep phases per night were calculated and compared between the two groups. Results: The study includes 122 COVID-19 patients and 588 controls. Total sleep time was positively correlated with respiratory rate (RR) and oxygen saturation (SpO2). Increased awake sleep phase was correlated with increased heart rate (HR), decreased RR, heart rate variability (HRV), and SpO2. Increased light sleep time was correlated with increased RR and SpO2 in COVID-19 group. Deep sleep duration was correlated with decreased HR, and increased RR and SpO2. When comparing different sleep phases, long COVID-19 patients had decreased light sleep time (244±67 vs 258±67, P=.003), and decreased deep sleep (123±66 vs 128±58, P =.02). Conclusions: Regardless of the demographic background and symptom levels, patients with a history of COVID-19 infection demonstrated altered sleep architecture when compared to matched controls. Sleep of COVID-19 patients was characterized by decreased total sleep, and deep sleep.
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Sleep is suggested to be crucial for the processing and storage of new informations. The enhancement of both, spindle activity within NREM (non-rapid eye movement sleep) and theta activity within REM is suggested to serve as background activity for the synchronization of those neuronal pathways, that were involved in the registration and, later on, participate in the long term storage of new informations in defined brain regions. In the present study, the presentation of a novel object to rats enhanced the amount of preREMS, an intermediate sleep stage with high spindle activity, within the first 2 hours of the subsequent sleeping phase. Four hours later, the amount of REMS was increased, as well. There were no changes in the EEG power spectra of nonREMS, preREMS and REMS. The increase of preREMS and REMS amounts and the related spindle and theta activity are suggested to stand for the processing and storage of new informations about the presented novel objects.
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Rapidly evolving brain neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) Eire proving fruitful in exploring the pathogenesis and pathophysiology of posttraumatic stress disorder (PTSD). Structural abnormalities in PTSD found with MRI include nonspecific white matter lesions and decreased hippocampal volume. These abnormalities may reflect pretrauma vulnerability to develop PTSD, or they may be a consequence of traumatic exposure, PTSD, and/or PTSD sequelae. Functional neuroimaging symptom provocation and cognitive activation paradigms using PET measurement of regional cerebral blood flow have revealed greater activation of the amygdala and anterior paralimbic structures (which are known to be involved in processing negative emotions such as fear), greater deactivation of Broca's region (motor speech) and other nonlimbic cortical regions, and failure of activation of the cingulate cortex (which possibly plays an inhibitory role) in response to trauma- related stimuli in individuals with PTSD. Functional MRI research has shown the amygdala to be hyperresponsive to fear-related stimuli in this disorder. Research with PET suggests that cortical, notably hippocampal, metabolism is suppressed to a greater extent by pharmacologic stimulation of the noradrenergic system in persons with PTSD. The growth of knowledge concerning the anatomical and neurochemical basis of this important mental disorder will hopefully eventually lead to rational psychological and pharmacologic treatments.