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Fragmentation of rapid eye movement sleep (REMS) is well described in individuals with posttraumatic stress disorder (PTSD) and likely has significant functional consequences. Fear-conditioned rodents may offer an attractive model of the changes in sleep that characterize PTSD. Following fear conditioning (FC), Wistar-Kyoto (WKY) rats, a strain known to be particularly stress-sensitive, have increased REMS fragmentation that can be quantified as a shift in the distribution of REMS episodes towards the more frequent occurrence of sequential REMS (inter-REMS episode interval ≤ 3 min) vs. single REMS (interval > 3 min). The α1 adrenoceptor antagonist prazosin has demonstrated efficacy in normalizing sleep in PTSD. To determine the utility of fear-conditioned WKY rats as a model of sleep disturbances typical of PTSD and as a platform for the development of new treatments, we tested the hypothesis that prazosin would reduce REMS fragmentation in fear-conditioned WKY rats. Sleep parameters and freezing (a standard measure of anxiety in rodents) were quantified at baseline and on days 1, 7, and 14 following FC, with either prazosin (0.01 mg/kg, i.p.) or vehicle injections administered prior to testing in a between-group design. Fear conditioning was achieved by pairing tones with a mild electric foot shock (1.0 mA, 0.5 s). One, 7, and 14 days following FC, prazosin or vehicle was injected, the tone was presented, freezing was measured, and then sleep was recorded from 11 AM to 3 PM. WKY rats given prazosin, compared to those given vehicle, had a lower amount of seq-REMS relative to total REMS time 14 days after FC. 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.

The recognition of rapid-eye-movement sleep (REM) and its association with dreaming in 1953 by Aserinsky and Kleitman opened a new world to explore in the brain. Discussions at two major symposia in the early 1960s reveal that a state with characteristics resembling both wakefulness and sleep was overturning accepted views of the regulation of the two states. Participants grappled with the idea that cortical activation could occur during sleep. They struggled with picking a name that would capture the essence of REM without focusing on just one aspect of the state. Questioning whether REM in cats could be homologous with that of humans suggested an anthropocentric focus on human dreaming as the essence of the state. The need for biochemical studies was evident given that deprivation of REM caused a rebound in the amount of subsequent REM, which indicated that simple synaptic activity could not support this phenomenon.

Negative emotionality affects sleep-wake behavior in humans and rodents, and the Wistar-Kyoto (WKY) rat strain is known for its stress-sensitive phenotype. Analyzing rapid eye movement sleep (REMS) microarchitecture by separating REMS into single (siREMS; inter-REM episode interval>3 min) and sequential (seqREMS; interval≤3 min) episodes, we previously reported that cued fear conditioning (CFC) increased REMS fragmentation in WKY compared to Wistar rats by increasing the number of seqREMS episodes. Since social support affects fear responsiveness in humans, we hypothesized that social interaction with a naive partner would affect the sleep-wake response to CFC in WKY rats. Thus, male WKY rats were assigned to either the social support or the social isolation group. Animals were fear-conditioned to 10 tones (800 Hz, 90 dB, 5 s), each co-terminating with a mild foot shock (1.0 mA, 0.5 s), at 30-s intervals. All subjects underwent a tone-only test both 24 h (Day 1) and again two weeks (Day 14) later. Social partnering was achieved by providing the fear-conditioned rat with 30 min of interaction with its naive partner immediately after CFC and during the tone presentations on Day 1 and Day 14. The results indicate that while CFC increased freezing behavior in socially isolated WKY rats, it increased grooming behavior in socially partnered rats. Socially partnered rats had increased sleep efficiency during the light phase and spent less time in NREMS during the dark phase. The number of siREMS episodes increased during both the light and dark phases in partnered rats, and the number of seqREMS episodes increased in socially isolated rats. Our findings suggest that social partnering may protect WKY rats from the REMS fragmentation that is observed following CFC in isolation.

Recent investigations of rapid eye movement sleep (REMS) continuity have emphasized the importance of transitions both into and out of REMS. We have previously reported that, compared to Wistar rats (WIS), Wistar–Kyoto rats (WKY) responded to fear conditioning (FC) with more fragmented REMS. Gamma oscillations in the electroencephalogram (EEG) are synchronized throughout the brain in periods of focused attention, and such synchronization of cell assemblies in the brain may represent a temporal binding mechanism. Therefore, we examined the effects of FC on EEG gamma range activity (30–50 Hz) at REMS transitions in WKY compared to WIS. Relative power in the gamma range (measured as a percent of total power) at Baseline and upon re-exposure to the fear-inducing conditioning stimulus was measured 35 s before REMS onset to 105 s after REMS onset (ARO) and 85 s before REMS termination (BRT) to 35 s after REMS termination. After baseline recording, rats received 10 tones, each co-terminating with an electric foot shock. On Days 1 and 14 post-conditioning, rats were re-exposed to three tones. Fast-Fourier transforms created power spectral data in the gamma frequency domain. Relative power was extracted from an average of 4–5 REMS transitions. Relative gamma power was always higher in WIS. On Day 14, at 15 s and 25 s ARO, WKY had significant increases in relative gamma power from Baseline. WIS had a significant increase on Day 1 at 25 s ARO. Despite the increases in relative gamma power, WKY never achieved levels attained by WIS. Moreover, at 5 s BRT, only WKY had a significant decrease in relative gamma power from Baseline to Day 14. 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.

Pavlovian conditioning is commonly used to investigate the mechanisms of fear learning. Because the Wistar–Kyoto (WKY) rat strain is particularly stress-sensitive, we investigated the effects of a psychological stressor on sleep in WKY compared to Wistar (WIS) rats. Male WKY and WIS rats were either fear-conditioned to tone cues or received electric foot shocks alone. In the fear-conditioning procedure, animals were exposed to 10 tones (800 Hz, 90 dB, 5 s), each co-terminating with a foot shock (1.0 mA, 0.5 s), at 30-s intervals. In the shock stress procedure, animals received 10 foot shocks at 30-s intervals, without tones. All subjects underwent a tone-only test both 24 h (Day 1) and again two weeks (Day 14) later. Rapid eye movement sleep (REMS) continuity was investigated by partitioning REMS episodes into single (inter-REMS episode interval > 3 min) and sequential (interval ≤ 3 min) episodes. In the fear-conditioned group, freezing increased from baseline in both strains, but the increase was maintained on Day 14 in WKY rats only. In fear-conditioned WKY rats, total REMS amount increased on Day 1, sequential REMS amount increased on Day 1 and Day 14, and single REMS amount decreased on Day 14. Alterations were due to changes in the number of sequential and single REMS episodes. Shock stress had no significant effect on REMS microarchitecture in either strain. 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.

LEARNING TO ASSOCIATE AVERSIVE EVENTS WITH ENVIRONMENTAL STIMULI THAT RELIABLY PREDICT THESE EVENTS IS INDISPENSABLE TO THE SURVIVAL of organisms. Pavlovian fear conditioning is an example of such learning in which an emotionally neutral conditioned stimulus (CS), such as a tone, is paired with an aversive, unconditioned stimulus (US), usually electrical footshock.1 The CS, by virtue of its relationship with the US, acquires aversive properties and elicits responses normally induced by threatening stimuli, such as freezing and ultrasonic vocalizations.2 This paradigm has been used in numerous studies to explore mechanisms that may underlie the psychophysiological alterations associated with posttraumatic stress disorder (PTSD). Experiencing traumatic and aversive events in humans can induce several long-term behavioral and physiological disturbances, including changes in sleep.3,4 Sleep alterations also result from exposure to fear conditioning in both rats5–7 and mice.8,9 One observes changes in vigilance states characterized predominantly by decreased REM sleep (REMS), while NREM sleep (NREMS) remains unaffected.5,6,8 Although the effects of fear conditioning on REMS can be assessed by looking at REMS in toto, various stressors can also alter its microarchitectural pattern (i.e., parcellation of REMS into sequential and single episodes) in rats.10 REMS can be characterized as sequential-REMS (seq-REMS) (comprised of REMS episodes separated by ≤ 3 min intervals, which appear in clusters), and single-REMS (sin-REMS) (with episodes preceded and followed by >3 min intervals).10 This distinction is important because stressors such as low ambient temperature and immobilization have differential effects on sin-REMS and seq-REMS.10,11 For example, rats placed in a cold environment show a reduction in REMS amount. During the recovery period at a normal room temperature, REMS is increased via an increase in the number of seq-REMS bouts. Because temperature is not tightly regulated during REMS due to an absence of hypothalamic control, Amici et al10 suggest that the brief intervals of wakefulness or NREMS punctuating a REMS cluster allow sufficient REMS to be made up by ensuring short periods of homeostatic regulation of the body during a cluster, and that this could not occur, were the REMS deficit to be made up by extended periods of sin-REMS. Similarly, after immobilization stress, the increase in REMS is associated with only a modest increase in sin-REMS, but a considerable increase in seq-REMS, which may result from recovery from sleep deprivation during the immobilization procedure.11 A bimodal distribution of REMS intervals also exists in other species, including humans.10 Altered sleep quality and/or quantity can itself be stressful to an organism and contribute to the emotional and behavioral disturbances symptomatic of psychiatric disorders. We have reported that exposure to fear-inducing tones (the CS), previously paired with brief, mild electrical footshock, alters both REMS and its microarchitecture,5 but the persistence of these effects over time has received less research attention.8 Interestingly, there is often a progressive increase in memory strength over time following an aversive stimulus (measured as a change in the magnitude of the freezing response), without further exposure to the stimulus itself: this has been referred to as an incubation process.12 Therefore, in this study, we evaluated the impact of reexposure to fearful cues on the sleep architecture and REMS microarchitecture of rats, both 24 hr (short-term effect, Day 1) and two weeks (long-term effect, Day 14) after conditioning. In addition, we examined the effects of reexposure to the CS on a more common behavioral index of anxiety, freezing. We and others have reported earlier that military veterans with PTSD have increased phasic muscle activity during REMS13–15; hence, we also evaluated the frequency of myoclonic twitches as a measure of phasic REMS events. Several studies suggest that fear conditioning alters the amount and microarchitecture of REMS, but does not alter the sleep efficiency or NREMS amount.5,6,8,16 Hence, in this study we hypothesized that reexposure to cues associated with footshock should alter REMS microarchitecture, primarily by changing the sin-REMS, seq-REMS, and cluster amount. We also expected that fear conditioning would increase the number of myoclonic twitches during REMS. Finally, we hypothesized that changes in REMS microarchitecture and myoclonic twitches are also due to conditioned anxiety, and as such should correlate with freezing, a well-established indicator of conditioned anxiety.

Objective: The nasal cycle, which is present in a significant number of people, is an ultradian side-to-side rhythm of nasal engorgement associated with cyclic autonomic activity. We studied the nasal cycle during REM/non-REM sleep stages and examined the potentially confounding influence of body position on lateralized nasal airflow. Methods: Left- and right-side nasal airflow was measured in six subjects during an eight-hour sleep period using nasal thermistors. Polysomnography was performed. Simultaneously, body positions were monitored using a video camera in conjunction with infrared lighting. Results: Significantly greater airflow occurred through the right nasal chamber (relative to the left) during periods of REM sleep than during periods of non-REM sleep (p

Hypoglycemia resulting from excess of exogenous or endogenous insulin elicits central nervous system activation that contributes to counterregulatory hormone secretion. In adult humans without diabetes, hypoglycemia occurring during sleep usually produces cortical activation with awakening. However, in adult humans with type 1 diabetes, hypoglycemic arousal appears blunted or absent. We hypothesized that insulin injection sufficient to produce hypoglycemia would induce awakening in adult male rats. Polysomnographic studies were carried out to characterize the effect of insulin injection on measures of sleep and waking during a circadian time of increased sleep. Compared to a baseline day, insulin treatment more than doubled the time spent awake, from 18.4 ± 2.6% after saline injection to 48.0 ± 5.5% after insulin. Insulin injection also reduced rapid eye movement sleep (REMS) from 27.3 ± 1.8% to 5.6 ± 1.3%. The percent of time in non-REM sleep (NREMS) sleep was not different between saline and insulin days, however, NREMS after insulin was fragmented, with increased number and decreased duration of episodes. These electrophysiological data indicate that insulin-induced hypoglycemia is an arousing stimulus in rats, as in nondiabetic adult humans. We also studied the effect of insulin on activation of selected arousal-related neurons using immunohistochemical detection of Fos. Fos-immunoreactivity increased in orexin (OX) neurons after insulin, from 8.7 ± 4.9% after saline injection to 37 ± 9% after insulin. Basal forebrain cholinergic nuclei also showed increased Fos-immunoreactivity after insulin. These correlated behavioral and histological data provide targets for future studies of the neural pathways underlying hypoglycemic arousal.

To examine the influence of conditioned fear stimuli on sleep-wake states, we recorded sleep in Sprague-Dawley rats after exposure to tones previously paired with footshock. After habituation to a recording chamber and the recording procedure, a baseline sleep recording was obtained the next day. One day later, experimental animals were exposed to shock training designed to induce conditioned fear (FC), consisting of five tone-footshock pairings. The 5-s tones (conditioned stimuli; CS) co-terminated with 1-s footshocks (unconditioned stimuli; US). The next day sleep was recorded for 4 h in the recording chamber after presentation of five CSs alone. Sleep efficiency (total sleep time/recording period) and REM sleep (REM) and non-REM (NREM) measures were determined. While sleep efficiency was not significantly changed after CS presentation, the percentage of total sleep time spent in REM (REM percentage) was reduced in the FC animals. The reduction in REM percentage in the FC animals was due to a decrease in the number of REM bouts. In a separate experiment, we repeated the procedures, except the tones and shocks were presented in an explicitly unpaired (UP) fashion. The next day, presentation of the tones increased REM percentage in the UP group. Results are discussed in terms of the decreases in REM as a response to conditioned fear, and the relevance of these findings to the sleep changes seen in post-traumatic stress disorder (PTSD).

Background A prominent sleep disturbance, likely including a disruption of rapid eye movement sleep (REMS) continuity, characterizes posttraumatic stress disorder (PTSD). We set out to develop a fear conditioning paradigm in rats that displays alterations in sleep architecture analogous to those in PTSD. Methods Baseline polysomnographic recordings of rats were performed in a neutral context to which the rats had been habituated for several days. Rats were then shock- or mock-trained in a distinctly different context, and their sleep was studied the following day in that context. A separate group of rats was shock-trained and studied in the neutral context on the following 2 days. Results Rats that slept in the neutral context exhibited a REMS-selective increase in sleep 24 hours after training and increases in REMS and non-REMS 48 hours after training. In contrast, rats that slept in the presence of situational reminders of the training context exhibited a REMS-selective decrease in sleep 24 hours later. Animals that were mock-trained showed no changes in sleep. Conclusions Shock training induced days-long changes in sleep architecture that were disrupted when the animal was exposed to situational reminders of the training context.

Serotonin [5-hydroxytryptamine (5-HT)] plays an inhibitory role in rapid-eye-movement (REM) sleep although the exact mechanism(s) and site(s) of action are not known. It is commonly assumed that 5-HT exerts its influence on REM sleep via input from the dorsal raphe nucleus (DRN) directly onto cholinergic neurons involved in the generation of REM sleep. 5-HT 2 receptor sites have been found on cholinergic neurons in the laterodorsal tegmental nucleus (LDT) and pedunculopontine tegmental nucleus (PPT). We locally microinjected the 5-HT 2 agonist DOI ((±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl) and the 5-HT 2 antagonist, ketanserin, in LDT in rats to determine whether these receptor sites are involved in the regulation of behavioral states. DOI and ketanserin primarily affected REM sleep, by significantly decreasing or increasing, respectively, the number, but not the duration, of REM sleep episodes. DOI specifically decreased the occurrence of clusters of REM sleep episodes appearing at intervals less than or equal to 3 min (sequential episodes) without affecting single episodes separated by more than 3 min. An opposite effect of ketanserin on REM sleep clusters, although not statistically significant, was observed.

Fear conditioning is thought to model anticipatory anxiety. Inbred mouse strains exhibit different levels of reactivity to aversive environmental stimuli, which may reflect anxiety. We examined the effects of fear conditioning on sleep in mouse strains that differ on behavioral measures of anxiety. Mice (BALB/cJ [C], C57BL/6J [B6], CB6F1/J [CB6], n = 7-10 per strain) were implanted with transmitters for recording sleep by telemetry. Baseline sleep was recorded, and the mice were trained to associate a cue (tone) with footshock (15 cue-shock pairings on 4 consecutive days). Sleep was recorded after shock training and again 4 to 5 days later after presentation of the cue alone. Shock training produced a relatively selective suppression of rapid eye movement sleep (REM) that was greater in the C strain compared to the B6 and CB6 mice. Post-training exposure to the cue alone suppressed REM in all strains. The C strain exhibited a relatively greater immediate suppression of REM, and the CB6 hybrid mice showed the greatest overall suppression of REM. These data demonstrate that stimuli associated with an aversive event can alter sleep and suppress REM in much the same way as exposure to the event itself. Fear conditioning may provide a model for examining genetic and neural mechanisms underlying the influence of anxiety on sleep.

Modafinil, a novel non-amphetamine stimulant recently approved for the treatment of narcolepsy, has been shown to increase waking in both animals and humans. However, its mechanism of action is currently unknown. Earlier research into the brain structures responsible for the wake-producing actions of modafinil implicated the central nucleus of the amygdala (ACe) as a possible site of action [Neuroscience 87 (1998) 905-911; Neurosci. Lett. 241 (1998) 95-98]. The present experiments were designed to test the hypothesis that the ACe is, at least in part, involved in the wake-producing actions of modafinil. In the first experiment, rats with lesions of the ACe were injected systemically with varying doses of modafinil and sleep was recorded. At the highest dose, modafinil significantly increased waking and decreased sleep. However, there was no interaction between the lesion and the effect of the drug. In the second experiment, varying doses of modafinil were injected directly into the ACe and sleep was recorded. Injection of modafinil into the ACe did not affect sleep architecture. Thus, ACe does not play a simple role in modafinil's wake-promoting action. We suggest that more complex testing will be required to elucidate its role.

Background: Hyperarousal in posttraumatic stress disorder (PTSD) is manifested during sleep as well as waking. Elevated rapid eye movement sleep (REMS) phasic activity, likely signifying central nervous system alerting, has been identified in PTSD. The authors reasoned that PTSD compared to control subjects would show particularly increased REMS phasic activity on the first night of polysomnography, with adaptation to a novel environment. Methods: First-night polysomnograms of 17 veterans with PTSD were compared with those of 11 control subjects. Sleep was also studied in subsets of both groups over two nights. Results: On the first night, the PTSD subjects had a higher density of rapid eye movements in the first REMS period. This measure was increased on the first compared to the second night, but there was no interaction effect between night and group. Conclusions: REMS changes are again demonstrated in veterans with PTSD. Introduction to a novel environment activated a REMS phasic process, but not differentially in PTSD compared to control subjects.

In 1976, Bob Bowker and I reported that waves seemingly identical to spontaneous PGO waves (usually called spikes then) could be elicited by sounds in REM sleep as well as NREM sleep. We proposed that ponto-geniculo-occipital (PGO) waves were probably evidence of the spontaneous excitation of the startle network. This conclusion stemmed from Dement’s report that cats under the influence of the anti-serotonergic drug, p-chlorophenylalanine (PCPA), startled every time a PGO wave occurred when they were “awake.” We later changed from “startle” to “alerting” because we considered that the waves reflected the activation of a system responsible for detection of a stimulus, fundamental to the organization of the critical behavioral response of orienting, with startle being a less organized expression of a response to an unexpected stimulus. The focus on eye activity and dreams may have led other workers away from what is in our opinion their real significance: a sign of internal alerting in the brain (as distinct from behavioral arousal), a fundamental and “peculiar” aspect of REM sleep.

In contrast to the many neural studies into the mechanisms of sleep onset and maintenance, few studies have focused specifically on awakening from sleep. However, the abrupt electrographic changes and large brief cardio-respiratory activation at awakening suggest that a distinct, transiently aroused, awake state may exist compared to later wakefulness. To test this hypothesis we utilized the acoustic startle reflex, a standard un-conditioned reflex elicited by a sudden loud noise. This reflex is modulated under specific conditions, one being a diminution of startle when a quieter pre-stimulus is presented immediately before the loud stimulus. This pre-pulse inhibition (PPI) is used as a measure of sensorimotor gating, with smaller PPI indicating less filtering of sensory inputs and increased responsiveness to external stimuli. Eight rats with electrodes for recording sleep-wake state were studied. An accelerometer measured startle responses. The startle reflex was elicited by 115 dB, 40 ms tones. PPI was produced by 74 dB, 20 ms tones preceding the 115 dB tone by 100 ms. Responses within 100 ms were measured. Stimuli were applied either 3-10 s after spontaneous awakenings, or in established wakefulness (30 s). Responses to the startle stimuli alone were similar in the different awake states (P = 0.821). However, PPI was smaller at awakening from non-REM sleep compared to established wakefulness (45.4 +/- 7.5% vs. 74.3 +/- 6.1%, P = 0.0002). PPI after awakening from REM sleep (52.8 +/- 17.9%) was not significantly different than established wakefulness (P = 0.297). Reduced PPI of the startle reflex at awakening from non-REM sleep supports the hypothesis that wakefulness immediately after spontaneous sleep episodes is neurophysiologically distinct from later wakefulness and associated with reduced gating of motor responses to sensory inputs. Spontaneous activation of this distinct, transiently aroused, state upon awakening may serve a protective function, preparing an animal to respond immediately to potentially threatening stimuli.

The acute administration of drugs that block norepinephrine (NE) reuptake suppresses rapid eye movement (REM) sleep in cats and other mammals. The mechanism is presumed to involve NE acting on cells in a pontine REM sleep-generator region. Postsynaptic noradrenergic receptor mechanisms have not been identified. In the present experiments, we tested the ability of the alpha-1 antagonist prazosin and the beta antagonist propranolol to reverse the REM sleep suppression produced by the NE reuptake blocker desipramine (DMI) in the cat. DMI reduced the number of REM sleep episodes, the REM percentage (REM sleep time/total sleep time), and the average REM sleep episode duration. The co-administration of prazosin, but not propranolol, increased the REM percentage and the average REM sleep episode duration toward the placebo level. The co-administration of the peripherally-acting, anti-hypertensive agent hydralazine did not reverse the DMI-induced REM sleep suppression. While the identity of the brain region(s) involved in mediating the alpha-1 noradrenergic suppression of REM sleep by DMI remains unclear, there is reason to consider forebrain structures including the amygdala as well as the pontine areas that generally have been implicated in REM sleep control.

Publisher Summary This chapter illustrates that control during sleep is complex, lacking the need to modulate movement of an individual through the external world that is frequently, but not always, generated by the conscious desires of the waking brain. When disease damages the multiple checks placed on organized movement during non-rapid eye movements (NREM) or rapid eye movements (REM) sleep, life-threatening events are possible. Cessation of movement, reduction of muscle tone, and periodically striated muscle atonia interrupted by irregularly occurring twitches are cardinal signs of sleep in all land mammals, including human beings. This progression parallels the changes in the electroencephalogram (EEG) as an individual becomes drowsy and then progresses through the various stages of NREM sleep and, finally, the “paralytic” state of REM sleep with its periodic myoclonic twitches. Thus, a thorough understanding of the neural mechanisms responsible for motor control during sleep is a prerequisite to the development of more refined treatments.

Ponto-geniculo-occipital (PGO) waves spontaneously occur in the pons, lateral geniculate body (LGB), and occipital cortex during rapid eye movement sleep (REM), and PGO-like waves (PGOE) may be elicited in LGB during sleep and waking. Because REM has been hypothesized to be a state of continual "orienting" or "hyper-alertness," we tested whether the amplitudes of PGOE in "alerting" situations (the abrupt onset of a loud sound or presentation of a novel stimulus within a series of stimuli) that evoke orienting responses (OR) would be greater than those following stimuli without OR. We also compared PGOE accompanying OR to PGOE during REM and NREM when OR are absent. The amplitudes of PGOE in W were greatest when OR were observed, and the amplitudes of PGOE accompanying OR were not significantly different from PGOE amplitudes in REM. Likewise, the amplitudes of PGOE during REM were not significantly different from those of the highest amplitude spontaneous PGO waves. We propose that the presence of PGOE signals registration of stimuli and that stimuli of sufficient significance to induce behavioral OR in waking also elicit PGOE of significantly greater amplitudes in all behavioral states. These findings support the hypothesis that the presence of high-amplitude PGO waves in REM indicates that the brain is in a state of more-or-less continual orienting.

Serotonin (5-HT) is implicated in the regulation of both behavioral arousal and a brainstem alerting system that operates in wakefulness and in rapid eye movement sleep (REM). Activation of the brainstem alerting system is marked by the presence of ponto-geniculooccipital (PGO) waves that occur in association with orienting in wakefulness and spontaneously in REM. Local application of serotonergic agents into REM and PGO wave regulatory regions can alter REM, but there is conflicting evidence as to whether 5-HT in the brainstem can independently influence PGO wave generation. A potential site of action of 5-HT outside the brainstem is the amygdala, which can influence arousal as well as neurobiological responses to novel and significant stimuli. The amygdala also modulates the occurrence and amplitude of PGO waves. We discuss the linkages between arousal and alerting systems and the role 5-HT may play in their regulation at brainstem and amygdalar sites.

Drugs that block monoamine reuptake initially suppress rapid eye movement (REM) sleep in the cat and other species. Less is known about the effects of repeated drug administration. Desipramine (DMI) and sertraline [1S, 4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1 -naphthylamine] (SER), which are relatively specific in blocking norepinephrine and serotonin reuptake, respectively, were each given to cats fro approximately two and a half weeks. Six-hour sleep polygraphic records were obtained under the placebo condition, after acute drug administration, and again during chronic drug administration. DMI and SER both reduced REM sleep percentage acutely and in each case. Significant tolerance then developed. These actions of DMI and SER reflected changes in mean REM sleep episode duration as well as REM sleep episode number. Such differential effects of acute and chronic monoamine reuptake blockade on REM sleep behavior in the cat may ultimately be correlated with pharmacological changes at the receptor level.

Psychological stressors have a prominent effect on sleep in general, and rapid eye movement (REM) sleep in particular. Disruptions in sleep are a prominent feature, and potentially even the hallmark, of posttraumatic stress disorder (PTSD) (Ross, R.J., Ball, W.A., Sullivan, K., Caroff, S., 1989. Sleep disturbance as the hallmark of posttraumatic stress disorder. American Journal of Psychiatry 146, 697-707). Animal models are critical in understanding both the causes and potential treatments of psychiatric disorders. The current review describes a number of studies that have focused on the impact of stress on sleep in rodent models. The studies are also in Table 1, summarizing the effects of stress in 4-h blocks in both the light and dark phases. Although mild stress procedures have sometimes produced increases in REM sleep, more intense stressors appear to model the human condition by leading to disruptions in sleep, particularly REM sleep. We also discuss work conducted by our group and others looking at conditioning as a factor in the temporal extension of stress-related sleep disruptions. Finally, we attempt to describe the probable neural mechanisms of the sleep disruptions. A complete understanding of the neural correlates of stress-induced sleep alterations may lead to novel treatments for a variety of debilitating sleep disorders.

A subjective disturbance of sleep, including the occurrence of repetitive, stereotypical anxiety dreams, is characteristic of posttraumatic stress disorder (PTSD). The phenomenology of the PTSD anxiety dream has seemed most consistent with an underlying rapid eye movement (REM) sleep dysfunction. However, motor behavior reportedly can accompany PTSD dreams, and normal REM sleep typically involves a nearly total paralysis of the body musculature. As a means of understanding this discrepancy, anterior tibialis muscle activity during sleep was studied in a group of Vietnam combat veterans with current PTSD and in an age-matched normal control group. The PTSD subjects had a higher percentage of REM sleep epochs with at least one prolonged twitch burst; they also were more likely to have periodic limb movements in sleep, during nonrapid eye movement sleep. Both these forms of muscle activation also have been observed in REM behavior disorder (RBD), a parasomnia characterized by the actual enactment of dream sequences during REM sleep. The identification of RBD-like signs in PTSD adds to the evidence for a fundamental disturbance of REM sleep phasic mechanisms in PTSD.

Lesions of the dorsal pontine tegmentum release muscle tone and motor behaviour, much of it similar to orienting during wakefulness, into rapid eye movement sleep (REM), a state normally characterized by paralysis. Sleep after pontine lesions may be altered, with more REM-A episodes of shorter duration compared to normal REM. We examined behaviour, ponto-geniculo-occipital (PGO) waves (which may be central markers of orienting) and sleep in lesioned cats: (i) to characterize the relationship of PGO waves to behaviour in REM-A; (ii) to determine whether post-lesion changes in the timing and duration of REM-A episodes were due to activity-related awakenings: and (iii) to determine whether alterations in sleep changed the circadian sleep/wake cycle in cats. Behavioural release in REM-A was generally related to episode length, but episode length was not necessarily shorter than normal REM in cats capable of full locomotion in REM-A. PGO wave frequency was reduced overall during REM-A, but was higher during REM-A with behaviour than during quiet REM-A without overt behaviour. Pontine lesions did not significantly alter the circadian sleep/wake cycle: REM-A had approximately the same Light/Dark distribution as normal REM. Differences in the patterning of normal REM and REM-A within sleep involve more than mere movement-induced awakenings. Brainstem lesions that eliminate the atonia of REM may damage neural circuitry involved in REM initiation and maintenance; this circuitry is separate from circadian control mechanisms.

The subjective sleep disturbance in posttraumatic stress disorder (PTSD), including the repetitive, stereotypical anxiety dream, suggests dysfunctional rapid eye movement (REM) sleep mechanisms. The polysomnograms of a group of physically healthy combat veterans with current PTSD were compared with those of an age-appropriate normal control group. Tonic and phasic REM sleep measures in the PTSD subjects were elevated on the second night of recorded sleep. Increased phasic REM sleep activity persisted in the PTSD group on the subsequent night. During the study, an anxiety dream occurred in a PTSD subject in REM sleep. The results are consistent with the view that a dysregulation of the REM sleep control system, particularly phasic event generation, may be involved in the pathogenesis of PTSD. The finding of a specific disturbance of sleep unique to PTSD may have significant implications for the design of effective treatments for PTSD.

SUMMARY Ponto-geniculo-occipital (PGO) waves are spontaneously-occurring macropotential waveforms recorded in the pons, lateral geniculate body (LGB) and occipital cortex. PGO waves mark the onset and course of rapid eye movement sleep (REM). PGO-like waves can be recorded in several brain areas including the thalamic central lateral nucleus (CL). Alerting stimuli elicit PGO waves (PGOE) from LGB and waves from CL (CLE) in all behavioural states. We compared spontaneous activity in LGB and CL across behavioral states to examine the relationship of CL waves to PGO waves. Spontaneous waves in LGB and CL may occur concurrently or separately in all states. Although REM is marked by a high level of LGB PGO activity, CL waves are rare. Frequencies of CL and LGB waves are similar in non-REM (NREM) although the waves do not necessarily occur at the same time. These findings suggest that the widespread phasic activity recorded throughout the brain in sleep cannot be assumed to be a non-specific unitary phenomenon propagated from a single brainstem generator.

Dreaming in sleep must depend on the activity of the brain as does cognition and memory in wakefulness. Yet our understanding of the physiological subtleties of state differences may still be too primitive to guide theories adequately in these areas. One can state nonetheless unequivocally that the brain in REM is poorly equipped to practice for eventualities of wakefulness through dreaming, or for consolidating into memory the complex experiences of that state.[Hobson et al., Nielsen, Solms, Vertes & Eastman, Revonsuo]

Waves similar to ponto-geniculo-occipital (PGO) waves occurring spontaneously in the lateral geniculate body (LGB), pons, and occipital cortex during rapid eye movement (REM) sleep can be elicited in the LGB and the cortex by tones in waking (W), non-rapid eye movement sleep (NREM), and REM. In W, the elicited waves (PGOE) sometimes accompany orienting responses (OR). We have hypothesized that REM is a state resembling exaggerated "orienting" in part because spontaneous PGO waves similar to PGOE accompanying OR are constantly observed in REM. The present experiment tested whether: (1) PGOE and OR were strongly correlated in W across a large number of tone presentations as might be predicted if PGOE were central wave form markers for a state of orienting; and (2) recovery of responsiveness of PGOE to tones would then be greater in REM than NREM, as might be expected if REM but not NREM were a state in which central mechanisms of orienting were highly active. Tones were presented in W and then in REM and NREM to six cats in order to measure the degree of habituation of OR and PGOE simultaneously. PGOE and OR exhibited a degree of independence: the former were readily produced in W despite the rapid decline in OR across trials. Recovery in the amplitude of PGOE occurred in both NREM and REM. The recovery tended to be greater in REM than NREM, although this was not statistically significant. Refinements of the theory that REM represents a state of exaggerated internal orienting are discussed.

Waves similar to spontaneous ponto-geniculo-occipital (PGO) waves of paradoxical sleep (PS) in cats are elicited by tones and can be considered a form of evoked potential termed PGOE. The aims of the present experiment were to determine: (1) the effects of tone intensity on the probability of producing PGOE; (2) the effects of intensity on the amplitude and latency of PGOE across slow-wave sleep (SWS) and PS; (3) whether the effects of intensity on PGOE are similar to those on a particular form of auditory evoked potential known as the mid-latency response (MLR). Increasing the intensity of the stimulus from 60 to 100 in 10 dB increments resulted in increased probability, increased amplitude, and decreased latency of PGOE in both SWS and PS. This pattern was similar to published findings with MLR, and latencies of PGOE (roughly 60-100 msec) fell within the range of 'C wave' type of MLR recorded in intralaminar nuclei of the thalamus of cats. The possibility that PGOE and MLR share underlying mechanisms and represent the same phenomenon is discussed with particular attention to the function of the mechanisms during alerting and orienting.

Norepinephrine (NE) and serotonin (5HT) likely inhibit the generation of ponto-geniculo-occipital (PGO) waves. Either desipramine (DMI) or sertraline (SER:1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthyl amine) was administered in the cat for 2.5 weeks to probe noradrenergic and serotonergic mechanisms, respectively. Placebo days were compared with the first day of drug and with days that followed 2.5 weeks of drug (chronic). PGO rates during REM sleep and the preceding transition period were significantly decreased by either chronic DMI or SER. Cat PGO waves resemble waves that accompany alerting to intense or novel stimuli in wakefulness. Depressive disorders in humans have features of hyperarousal; PGO wave suppression by antidepressant drugs may relate to clinical antidepressant actions.

Bilateral pontine tegmental lesions produce in cats the phenomenon known as rapid eye movement (REM) sleep without atonia. During episodes of REM sleep without atonia cats are capable of exhibiting such complex behaviors as head-raising, body-righting, standing, and in some cases, walking and attacking. Since release of such behaviors implies disinhibition of specific motor systems, the purpose of this study was to determine whether the administration of chloramphenicol (CAP), which is known to attenuate the firing frequencies of cells that become activated during REM and motor activity, could reverse this phenomenon. Cats with dorsolateral tegmental pontine (DLTP) lesions producing REM without atonia were thoroughly studied in terms of the muscular and behavioral activity they displayed during REM before and after systemic CAP administration. Thiamphenicol (TAP), a CAP analogue that does not reduce neuronal firing frequency during REM sleep, was used as a control drug. The results of these experiments showed that CAP but not TAP induced a return of the atonia during REM sleep. It is suggested that the return of atonia induced by CAP in DLPT lesioned cats is caused by attenuation in the activity of medial reticular neurons which have somatotopical representation. Such cells, which have high levels of activity during REM sleep and motor activation in wakefulness, are normally overwhelmed by the inhibitory mechanism of the atonia of REM. The return of atonia and consequent reduction in complex behavior following CAP administration may be due to withdrawal of the excitatory influence of these neurons.

Summary High-amplitude waves, similar in distribution and configuration to pontogeniculo-occipital (PGO) spikes recorded in cats, were recorded from the area of the locus coeruleus of chronically implanted, unanesthetized albino rats. The mean frequency of spiking during paradoxical sleep (PS) was 19 per min and the amplitudes of the spikes ranged from 0.07 to 0.28 mV. Based on these findings and those of a previous report, it was concluded that these spikes are homologous with PGO spikes recorded in cats. It was also found that spikes identical to the spontaneously occurring spikes of PS could be produced during wakefulness and in all states of sleep with external auditory stimulation. These elicited spikes were not accompanied by eye movements. Initial stimulus presentations resulted in EEG desynchronization, orienting movements and PGO spikes. With continued stimulus presentations, EEG and other signs of alerting would habituate followed by a gradual habituation of the spikes. The latency to the appearance of an evoked spike ranged from 20 to 24 msec. These findings are in agreement with recent studies in cats showing that PGO spikes occur in response to external, auditory stimuli in wakefulness and all stages of sleep in addition to their spontaneous occurrence just prior to and during PS.

Ponto-geniculo-occipital (PGO) waves are macropotential waveforms occurring spontaneously during paradoxical sleep (PS) in the pons, the lateral geniculate body (LGB), and the occipital cortex of the cat. In our earlier work (6, 20) tones elicited waves in the LGB and the occipital cortex during both slow wave sleep (SWS) and PS that resembled PGO waves in form and amplitude. Using a limited and variable number of trials, we observed that these elicited waveforms, which we term elicited PGO waves (PGOE), seemed to decline rapidly in amplitude and probability during SWS but not during PS. The present two experiments served as a more rigorous test of the hypothesis that the rate of habituation of PGOE would be more rapid in SWS. In a first experiment seven cats were studied in up to four sessions in PS and four in SWS; each session consisted of 32 1000-Hz, 90-dB SPL tones lasting 90 ms. We found that (i) the number of PGOE was significantly greater in PS; (ii) the mean amplitude of the waves was greater in PS; (iii) the probability of eliciting a wave tended to decline faster in SWS, but some decline also occurred in PS; and (iv) on the first trial, PGOE were more easily produced in SWS. Results of a second experiment with five cats suggested that the decline in the probability of PGOE in PS was not accounted for by differences in the ease of eliciting them at different times into a PS episode. The role of the dorsal raphe nucleus (DRN) in modulating state-dependent differences in PGOE is discussed.

This study sought to determine whether caudal spinal neurons with axons ascending the spinal cord contribute to inhibitory phenomena during sleep. Spinal cords were transected at the eighth thoracic segment, usually under Halothane anesthesia, in seven cats with implanted recording electrodes. After transection, release of forelimb extensor tone (Schiff-Sherrington phenomenon) appeared during wakefulness and was evident when killed several weeks later. A mildly opisthotonic posture with increased tone in forelimb extensors was assumed and maintained as the cats passed from drowsiness into synchronized sleep. They never lay in a normal curled-up posture but with arousal could overcome the extensor posture. This effect largely vanished after 48 hr. Thus ascending fibers play a role in inhibiting antigravity tone in synchronized sleep. Release of epaxial and limb extensor motor neurons during paradoxical sleep could be detected for as long as 1 week after transection. Proximal limb and neck movements occurred more frequently than normally, and the head could even be held off the floor. However, collapses of neck and forelimb extensor tone accompanied rapid eye movements. These results suggest that ascending fibers influence tonic inhibitory mechanisms operating on motor neurons during paradoxical sleep, but not the phasic inhibition associated with rapid eye movements.

Previous studies have shown that the activity of serotonin-containing raphe neurons in cats is almost completely suppressed during rapid eye movement (REM) sleep. However, since raphe unit activity is known to be grossly correlated with the level of behavioral arousal or tonic motor activity, this decrease in activity during REM sleep may be simply due to the fact that tonic EMG activity or motoric output is at a minimum. On the other hand, raphe unit activity may be related to the state (i.e. REM sleep) of the organism. To test these competing hypotheses, in the present study we compared raphe unit activity in normal cats with that in cats that display REM sleep without atonia (produced by bilateral lesions of the pontine tegmentum). These lesioned cats manifest episodes which, by all criteria, appear to be REM sleep except that they display overt behavior, presumably because the mechanism normally responsible for producing atonia has been disrupted. Although the activity of raphe neurons in lesioned cats during REM sleep without atonia was significantly below that seen in these cats during waking, the level of activity was often impressive. This is especially true when those animals that displayed the greatest degree of tonic motor activity during REM sleep (group IV animals) are considered separately. In these cats, the depression was only 40.5% below their quiet waking level, whereas in lesioned cats displaying less tonic motor activity (Group II animals), raphe discharge rate was 65.6% below their quiet waking level. The discharge rate of raphe neurons during REM sleep in lesioned cats was more than 6-fold greater than that seen in normal animals. These data, in conjunction with other recent results from our laboratory, suggest that the decrease in raphe unit activity during REM sleep is largely a concomitant of the atonia which characterizes that state. These data are discussed within the general context of the relationship between raphe unit discharge and the activity of central motor systems.

REM sleep is the most antiepileptic state in the sleep-wake cycle for human generalized epilepsy, yet the neural mechanism is unknown. This study verified the antiepileptic properties of REM sleep in feline generalized epilepsy and also isolated the responsible factors. Conclusions are based on 20 cats evaluated for generalized EEG and motor seizure susceptibility before and after dissociation of specific REM sleep components. Bilateral electrolytic lesions of the medial-lateral pontine tegmentum created a syndrome of REM sleep without atonia. Systemic atropine created a syndrome of REM sleep without thalamocortical EEG desynchronization. Identical results were obtained in two seizure models, systemic penicillin epilepsy and electroconvulsive shock. (1) Normal REM sleep retarded the spread of EEG seizure discharges and had even more potent anticonvulsant effects. (2) Selective loss of 'sleep paralysis' (skeletal muscle atonia) during REM abolished REM sleep protection against myoclonus and convulsions without affecting generalized EEG paroxysms. (3) Conversely, selective loss of thalamocortical EEG desynchronization abolished REM sleep protection against generalized EEG seizures without affecting clinical motor accompaniment. These results suggest that the descending brainstem pathways which mediate lower motor neuron inhibition also protect against generalized motor seizures during REM sleep. Protection against spread of EEG paroxysms is governed by a separate mechanism, presumably the ascending brainstem pathways mediating intense thalamocortical EEG desynchronization during REM sleep. Clues as to the nature of this differentia] mechanism are provided by the physiological characteristics of REM sleep.

Bilateral pontine tegmental lesions in cats release a state of paradoxical sleep (PS) without atonia that possess all other electrographic criteria of PS. PS without atonia has been previously considered as a unitary phenomenon, but the present work demonstrates that different behavioral syndromes result from different lesion placements. Five of 25 cats exhibited the minimal syndrome of increased proximal limb and head movements. The head was not raised; and coordinated behavior was not seen. The nuchal electromyogram (EMG) showed tone for 25-100% of such an episode. Selective destruction of the origin (n = 2) or caudally projecting fibers (n = 1), of the tegmentoreticular pathway released this minimal syndrome of unorganized limb and head movements. This pathway had previously been proposed to mediate atonia, but the present work demonstrates that additional damage is necessary to release tone completely as well as the elaborate behaviors discussed below. Eight cats raised their heads, righted their forequarters, and moved head, neck and forelimbs in movements resembling orienting, staring, reaching and attempting to stand. The lesions releasing such behavior were centered at P = 3.0, H = 2.0, V = -4.0, and damaged a region projecting to the superior colliculus. Two cats with slightly more ventral lesions did not exhibit the orienting behavior. Six cats demonstrated violent phasic behavior resembling attack punctuating tonic periods of quiet staring or searching movements. Attack resulted from damage extending rostroventrally into the midbrain at P = 2.0, H = 2.5, V = -4.5 (4/6) or from unilateral damage to a lateral pathway arising in the central amygdalar nucleus (2/6). In 4 cats, coordinated fore- and hindlimb activation resulted in locomotion during PS. Walking resulted from larger, more ventral lesions centered at P = 3.0, H = 2.0, V = -5.5. Considering the anatomy of the lesions in relationship to brain stem systems known to play a role in orienting, attack and locomotion, we conclude that inhibitory systems were damaged by these lesions and that PS without atonia is not simply a state during which neural activity of normal PS can be expressed behaviorally.

Publisher Summary This chapter discusses the raphe unit activity in cats displaying rapid eye movement (REM) sleep without atonia. In one of the experiments described in this chapter, bilateral electolytic lesions were placed in the dorsal pontine tegmentum of adult cats. Animals displaying clear episodes of REM sleep without atonia were selected during a six-week post-operative observation and recovery period. The rate of firing of dorsal raphe nucleus (DRN) units during waking in lesioned cats was approximately 25% slower than that displayed by normal cats. The discharge pattern of these units in lesioned cats was somewhat less regular than that seen in normal cats. In normal cats, there was a progressive decrease in the activity of serotonin-containing neurons from waking down through drowsy, slow-wave sleep, and finally becoming virtually quiescent in REM sleep. The overall pattern was very similar in lesioned cats, except when they entered REM sleep. During REM sleep, these cats raised their heads and fore-portions of their bodies and the unit activity at this time showed either no change or a small decrease as compared to slow-wave sleep.

In this section we shall focus our attention on the broad range of integrated neural activity that extends from attentive arousal through the various sleep states to a state of prolonged dormancy, hibernation. Central issues herein are (1) the relationships among the different activity states-how they differ and how they are similar-and (2) the means by which the normal central nervous system is able to switch back and forth among central activity states. Although we will not resolve the second problem here, there are interrelationships among the states which have rarely, if ever, been discussed in open forum before, so we can reasonably expect an increment in our understanding.