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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.

Social support, when provided following a traumatic experience, is associated with a lower incidence of stress-related psychiatric disorders. Our hypothesis was that providing a social interaction period with a naive conspecific would improve sleep architecture in response to cued fear conditioning in Wistar rats. Rats were randomly assigned to either the socially isolated or socially partnered groups. Rats assigned to the socially isolated group were individually housed following electrode implantation and fear conditioning. Rats assigned to the socially partnered group were initially paired-housed, and then one rat from each pair was randomly chosen for sleep electrode implantation and fear conditioning. Rats from both groups were habituated to a recording chamber, and baseline sleep was recorded over 22 hours. One day later (Training Day), they were fear-conditioned to 10 presentations of a tone (800 Hz, 90 dB, 5 sec) co-terminating with a mild electric foot shock (1.0 mA, 0.5 sec), at 30-sec intervals. While rats in the socially isolated group were left undisturbed in their home cage for 30-min, socially partnered rats interacted for 30 minutes with their non-stressed rat partner immediately after fear conditioning and while the auditory tones were presented on Days 1 and 14. The results indicated that social interaction increased sleep efficiency in partnered rats compared to isolated rats following the fear conditioning procedure. This was due to an increase in the amount of rapid eye movement sleep (REMS) during the light phase. Evaluation of REMS microarchitecture revealed that the increase in REMS was due to an increase in the number of single REMS episodes (siREMS), which represented a more consolidated REMS pattern. A surprising finding was that partnered rats had a greater number of sequential REMS episodes (seqREMS) at Baseline, on the Training Day and on Day 1 when compared to isolated rats. The greater number of seqREMS episodes in partnered rats may be due to the partnering procedure and not fear conditioning, as the effect was also seen at Baseline. Thus it appears that while the partnering procedure may have given rise to a fragmented REMS pattern, social partnering promoted a greater consolidation of REMS in response to the fear conditioning procedure.

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.

The amygdala (AMY) plays an important role in initiating appropriate neurobehavioral responses to emotionally arousing events. Its major efferents from the central nucleus (Ace) to the basal forebrain, hypothalamus and brainstem permit it to influence sleep mechanisms. To characterize further the neuronal activity of AMY during sleep and wakefulness, we recorded single neuronal activity in Ace across behavioral states in freely moving, normally behaving rats. Of the 49 neurons recorded from Ace, 24 neurons had firing patterns related to sleep-wakefulness (S-W). Of these, 50% (n = 12) had a high firing frequency during wakefulness (W) or both W and REM sleep (REM), 12% (n = 3) were non-REM (NREM)-related, 17% (n = 4) had a high firing rate in REM (REM-ON), and 20% (n = 5) fired at a low rate during REM. Because serotonin introduced into AMY during REM induces short-latency changes of state, we also studied the effects of low frequency (1 Hz) electrical stimulation of the dorsal raphe nucleus (DRN) on Ace neurons. All REM-ON neurons recorded from Ace were inhibited by DRN stimulation, and other cell types were unaffected. Thus, we found that the majority of cells in Ace related to S-W fired slowly during NREM and increased their discharge during W and/or REM, and that the DRN has the potential for modulating the spontaneous activity of REM-ON cells in rats.

Postural tone is reduced during slow-wave sleep (SWS) and absent during rapid eye movement sleep (REMS). In obstructive sleep apnea subjects, upper airway dilating muscles, including those of the tongue, show a similar pattern; this contributes to sleep-related airway obstructions. However, in healthy subjects, state-dependent changes in the activity of pharyngeal muscles are variable. In seven chronically instrumented Sprague-Dawley rats, an animal model used to study sleep and sleep-disordered breathing, we quantified lingual and postural muscle activity across the sleep-wake states by measuring the root mean square levels of the electromyograms (EMG) in successive 10s intervals collected during 2h of recording at a constant circadian time (1-3p.m.). The nuchal EMG was low and steady during SWS and further reduced with occasional twitches during REMS. In contrast, the mean lingual EMG during SWS was only 5.9+/-1.6% (S.E.) of its mean in wakefulness, and during REMS, it increased to 46+/-15% (S.E.) (p

Studies using various methodologies have implicated n. reticularis pontis oralis (RPO) and n. subcoeruleus (SubC) in the generation of rapid eye movement sleep (REM). In rats, electrolytic lesions in these regions may give rise to the phenomenon of REM without atonia (REM-A), in which the electrophysiological features of REM are normal except that atonia is absent and elaborate behaviors may be exhibited. However, electrolytic lesions damage both cell bodies and fibers of passage, and the neural reorganization and adaptation that can occur post-lesion can complicate interpretation. Tetrodotoxin (TTX) is a sodium channel blocker that temporarily inactivates both neurons and fibers of passage and thus may be functionally equivalent to an electrolytic lesion, but without allowing time for neural adaptation. In this study, we examined the influence of microinjections of TTX into RPO and SubC on sleep in freely behaving rats. Rats (90 day old male Sprague-Dawley) were implanted with electrodes for recording EEG and EMG. Guide cannulae were implanted aimed into RPO or SubC. Each animal received one unilateral microinjection (TTXUH: 5.0 ng/0.2 microl) and two bilateral microinjections (TTXBL: 2.5 ng/0.1 microl; TTXBH: 5.0 ng/0.2 microl) of TTX, and control microinjections of saline alone (SAL). The injections were made 2 h following lights on, and sleep was recorded for the subsequent 22 h. Sleep was scored from computerized records in 10 s epochs. Recordings from the 10-h light period and the 12-h dark period were examined separately. TTX inactivation of RPO could decrease REM and non-REM (NREM), whereas inactivation of SubC produced relatively more specific decreases in REM with smaller effects on NREM. The results complement studies that have implicated RPO and SubC in REM generation. REM-A was not observed, suggesting that REM-A is a complex phenomenon that requires time for reorganization of the nervous system after insult.

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.

Scientists frequently disagree on the interpretation of data. Such disagreements follow an informal set of rules, where one assumes that the contestants are honestly engaged even though biases may cloud their minds. A new group of individuals with medical training operates under a different set of rules, however: any statement or argument may be used to support the animal rightists' contention that using animals to advance human medicine is wrong. These "medical scientists" pervert the scientific discourse in which most of us engage. Their fabrications are egregious. They take legitimate scientists' statements out of context, construct statements out of larger passages to twist arguments in their favor, and cite works that actually are contrary to their arguments for effect. This essay reveals the distortions by a number of such medically trained individuals that I and several colleagues have uncovered.

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.

The amygdala projects massively via its central nucleus (CNA) into brain stem regions involved in alerting and ponto-geniculo-occipital (PGO) wave generation. Electrical stimulation of CNA is known to enhance the acoustic startle response (ASR) and influence spontaneous PGO waves. The role of the amygdala in the modulation of ASR and elicited PGO waves (PGOE) was investigated in albino rats. Electrically stimulating CNA within 25 ms prior to an auditory stimulus enhanced ASR and PGOE amplitude in a similar way, with the largest response occurring when the electrical and auditory stimuli were given simultaneously. The data suggest that CNA modulates alerting mechanisms.

Fractionations are 20- to 100-ms pauses in diaphragm activity that occur spontaneously during rapid-eye-movement (REM) sleep, sometimes in association with pontogeniculooccipital (PGO) waves. Auditory stimuli can elicit fractionations or PGO waves during REM sleep, non-REM (NREM) sleep, and waking; however, their interrelationship has not been investigated. To determine whether the two phenomena are produced by a common phasic-event generator in REM sleep, we examined PGO waves and fractionations that were elicited by auditory stimuli (tones) presented to freely behaving cats across states. Tones elicited PGO waves and two types of fractionations: short-latency fractionation responses (SFRs; 10- to 60-ms latencies) and long-latency fractionation responses (LFRs; 60- to 120-ms latencies). Both a PGO wave and a SFR were elicited in 60–70% of trials across states, but each could be elicited alone. The latencies and durations of elicited SFRs were similar across states, but the latencies of elicited PGO waves in REM sleep (mean 62.5 ms) were significantly longer than in waking or NREM sleep. Elicited SFRs consistently occur with shorter latencies than do PGO waves, in contrast to spontaneous fractionations, which have a variable relationship to PGO waves and usually occur 10–40 ms after the onset of the PGO wave. The LFR then, elicited most frequently during REM sleep, resembles a spontaneous fractionation in its temporal relationship to the PGO wave and may reflect the bias toward motoneuronal inhibition characterizing REM sleep but not NREM sleep or waking. We conclude that, although PGO waves and SFRs share some features, like LFRs they probably are generated by different neuronal populations. In three cats there was no correlation between PGO waves and fractionations, whereas in one cat they were associated in REM sleep (LFRs and SFRs) and waking (SFRs only). Thus the majority of evidence argues against the existence of a common phasic-event generator in REM sleep.

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.

Ponto-geniculo-occipital (PGO) waves and an elicited analogue (PGOE) may be recorded in the pons of rats. Cholinergic cells in the pedunculopontine tegmental (PPT) and laterodorsal tegmental (LDT) nuclei are implicated in the generation of PGO waves. Serotonin (5-HT) may inhibit the generation of PGO waves, and possibly PGOE. We examined the role of 5-HT1A receptor mechanisms in the generation of auditory-elicited PGOE in rats. Administration of 8-OH-DPAT [8-hydroxy-2-(n-dipropylamino)tetralin] into PPT did not significantly affect PGOE amplitude or response frequency. Binding of [3H]CN-IMI ([3H]cyanoimipramine) to 5-HT uptake sites located presynaptically was used as a measure of 5-HT innervation. Quantitative autoradiographic analysis of [3H]CN-IMI binding indicated a moderate to low degree of 5-HT innervation of PPT and a moderately high innervation of LDT compared to the dorsal raphe nucleus (DRN). Binding of [3H]8-OH-DPAT to 5-HT1A receptors revealed few receptor sites in PPT, and a low to moderate number of receptors in LDT compared to binding in DRN. The results suggest that inhibitory serotonergic modulation of PGOE is probably not mediated through a 5-HT1A receptor mechanism in PPT.

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.

Cholinergic neurons in the pedunculopontine tegmental (PPT) and the laterodorsal tegmental (LDT) nuclei are implicated in the generation of rapid eye movement sleep (REM) and ponto-geniculo-occipital (PGO) waves. Serotonin (5-HT) has a role in sleep-wake regulation and appears to inhibit PGO wave generation. We studied the effects of the central infusion of the relatively specific 5-HT1A receptor agonist 8-hydroxy-2-(n-dipropylamino)tetralin (DPAT) and the less specific 5-HT1 receptor agonist 1(3-chlorophenyl)piperazine (mCPP) on the regulation of REM and on PGO wave generation. DPAT (0.0, 0.002, 0.01, 0.08, and 0.8 microgram/0.5 microliter normal saline) and mCPP (0.0, 0.02, 0.2, 2.0, and 20.0 micrograms/0.5 microliter normal saline) were infused unilaterally into the peribrachial region of PPT (PB) in cats. Additionally, DPAT (0.01 microgram/0.5 microliter) was infused bilaterally into PB in a separate experiment. Low dosages of DPAT (unilateral or bilateral) decreased successful entrances into REM (0.01 microgram) and time spent asleep (0.002 microgram and 0.01 microgram) without affecting outward behavior. No dosage of mCPP significantly decreased the number of REM episodes, and neither drug decreased REM episode duration once REM had been entered. Neither drug affected the rate of PGO waves independently of modulating behavioral state. We propose that 5-HT1A receptor mechanisms have an inhibitory role in actual REM initiation, possibly by facilitating endogenously generated excitation of brainstem startle mechanisms at the onset of REM.