pii: sp-00034-14

http://dx.doi.org/10.5665/sleep.4184

ACUTE EXACERBATION OF SLEEP APNEA BY HYPEROXIA IMPAIRS COGNITIVE FLEXIBILITY

Acute Exacerbation of Sleep Apnea by Hyperoxia Impairs Cognitive Flexibility in Brown-Norway Rats Irina Topchiy, PhD1,6; Dionisio A. Amodeo, MA3; Michael E. Ragozzino, PhD3; Jonathan Waxman, MD, PhD1; Miodrag Radulovacki, MD, PhD1,5; David W. Carley, PhD1,2,4,6 1 5

Center for Narcolepsy, Sleep and Health Research, 2Department of Medicine, 3Department of Psychology, 4Department of Bioengineering, Department of Pharmacology, and 6Department of Biobehavioral and Health Sciences, University of Illinois at Chicago, Chicago, IL

Study Objectives: To determine whether learning deficits occur during acute exacerbation of spontaneous sleep related breathing disorder (SRBD) in rats with high (Brown Norway; BN) and low (Zucker Lean; ZL) apnea propensity. Design: Spatial acquisition (3 days) and reversal learning (3 days) in the Morris water maze (MWM) with polysomnography (12:00–08:00): (1) with acute SRBD exacerbation (by 20-h hyperoxia immediately preceding reversal learning) or (2) without SRBD exacerbation (room air throughout). Setting: Randomized, placebo-controlled, repeated-measures design. Participants: 14 BN rats; 16 ZL rats. Interventions: 20-h hyperoxia. Measurements and Results: Apneas were detected as cessation of respiration ≥ 2 sec. Swim latency in MWM, apnea indices (AI; apneas/hour of sleep) and percentages of recording time for nonrapid eye movement (NREM), rapid eye movement (REM), and total sleep were assessed. Baseline AI in BN rats was more than double that of ZL rats (22.46 ± 2.27 versus 10.7 ± 0.9, P = 0.005). Hyperoxia increased AI in both BN (34.3 ± 7.4 versus 22.46 ± 2.27) and ZL rats (15.4 ± 2.7 versus 10.7 ± 0.9) without changes in sleep stage percentages. Control (room air) BN and ZL rats exhibited equivalent acquisition and reversal learning. Acute exacerbation of AI by hyperoxia produced a reversal learning performance deficit in BN but not ZL rats. In addition, the percentage of REM sleep and REM apnea index in BN rats during hyperoxia negatively correlated with reversal learning performance. Conclusions: Acute exacerbation of sleep related breathing disorder by hyperoxia impairs reversal learning in a rat strain with high apnea propensity, but not a strain with a low apnea propensity. This suggests a non-linear threshold effect may contribute to the relationships between sleep apnea and cognitive dysfunctions, but strain-specific differences also may be important. Keywords: behavioral flexibility, cognitive deficit, hyperoxia, reversal learning Citation: Topchiy I, Amodeo DA, Ragozzino ME, Waxman J, Radulovacki M, Carley DW. Acute exacerbation of sleep apnea by hyperoxia impairs cognitive flexibility in brown-norway rats. SLEEP 2014;37(11):1851-1861.

INTRODUCTION Most individuals with sleep related breathing disorders (SRBD) develop cognitive deficits including, for example, impaired alertness and sustained attention, reduced working and long-term memory and executive dysfunctions, e.g., planning and mental flexibility.1–8 Among these cognitive domains, executive function is the most impaired in SRBD.6–8 Despite decades of research, clinical investigations have not clarified the mechanisms by which SRBD produces cognitive impairment. Efforts to elucidate the mechanisms underlying cognitive decline in SRBD have been hampered, in part by the likely multifactorial nature of these mechanisms, the considerable interindividual variability in the relationship between measures of apnea severity and cognitive function, and the noninvasive nature of clinical investigation. Additionally, the effect of standard SRBD treatments such as continuous positive airway pressure (CPAP) on cognitive deficits is inconsistent. Despite significant reduction of cognitive impairment by CPAP reported in a number of articles,9–11 there are studies showing

Submitted for publication January, 2014 Submitted in final revised form April, 2014 Accepted for publication April, 2014 Address correspondence to: Irina Topchiy, PhD, Center for Narcolepsy, Sleep and Health Research University of Illinois at Chicago, 845 South Damen Ave, (MC 802), Suite 215, Chicago, IL 60612; Tel: (312) 413-8461; Fax: (312) 996-5365; E-mail: [email protected] SLEEP, Vol. 37, No. 11, 2014

the absence of the improvement in some cognitive domains, including working memory and executive functions,12–14 even when a decrease in daytime sleepiness has been observed. Animal models could prove beneficial in understanding the mechanisms underlying cognitive impairments, as well as testing potential treatments to alleviate apnea-related cognitive deficits. Intermittent hypoxia and sleep fragmentation have been used to study significant aspects of sleep apnea in laboratory animals.15–20 However, to date no studies of cognitive deficits have been performed in animal models of spontaneous SRBD. Investigations of spontaneous sleep related apneas in rats by our laboratory and others revealed that apneas in rats are highly strain dependent.21–30 Specifically, we have demonstrated that Zucker Lean (ZL) rats express low levels of apnea,26 whereas Brown-Norway (BN) rats exhibit a high apnea propensity during sleep.24 Whether rats with high levels of spontaneous apneas exhibit cognitive deficits in comparison with rats that express low levels of apnea is currently unknown. Also unknown in patients or animals with SRBD is the effect of acute apnea exacerbation on cognitive function. This is important because individuals with chronic SRBD conditions commonly experience acute apnea exacerbations concurrently with alcohol, sedative, or hypnotic use, acute upper respiratory infection, or allergic rhinitis.31 Additionally, in patients using CPAP, interruptions of treatment (e.g., because of poor tolerance to the mask) can substantially increase an individual’s exposure to apneas, even during the course of a single night of sleep.32 Defining the effect of acute SRBD exacerbation on

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cognitive flexibility, such as reversal learning, may be particularly important because cognitive flexibility is strongly correlated with success in daily living.10,33 Animal models will be valuable for probing the mechanisms of such deficits in cognitive flexibility. Numerous authors report that administration of supplemental oxygen to patients with sleep apnea can increase the frequency or duration of apneas,34–37 and we demonstrated that sustained hyperoxia induced a significant increase in the frequency of apneas in Sprague-Dawley rats without alteration in sleep architecture.38 However, unknown is what effect acute exacerbation of apneas by hyperoxia has on cognitive functioning in a rat model of spontaneous SRBD. In the current study, we test the hypothesis that acute exacerbation of SRBD by hyperoxia negatively affects spatial learning and cognitive flexibility in rat strains with high (BN) and low (ZL) baseline apnea propensity. METHODS Subjects Adult male BN (n = 15) and ZL (n = 16) rats weighing 300320 g served as subjects. Rats were individually caged in a temperature-controlled environment (22°C) on a 12/12 h light/ dark cycle (lights on at 08:00). All experimental procedures were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the University of Illinois at Chicago Institutional Laboratory Animal Care and Use Committee. Surgical Procedures Rats underwent stereotaxic surgery for implantation of electroencephalographic (EEG) and nuchal electromyographic (EMG) electrodes under ketamine:xylazine (80:5 mg/kg) anesthesia. All electrode leads were soldered to a miniature connector plug and the assembly was fixed to the skull with acrylic dental cement. Rats recovered after surgery for 7 days before commencing polysomnography (PSG) recordings and behavioral testing. After adaptation to the plethysmographic chamber, baseline PSG recordings were completed for all rats. Polysomnography Each rat underwent 20-h PSG recordings from 12:00 to 08:00 prior to day 1 of behavioral Morris water maze (MWM) testing (baseline) and again on day 3 of behavioral testing. EEG and nuchal EMG signals were passed via a cable through a sealed port in a bias-flow–ventilated whole-body plethysmograph (PLYUNIR/U, Buxco Electronics, Wilmington, DE), where changes in box pressure were measured relative to an integrated reference chamber to transduce calibrated tidal volume. All signals were amplified and filtered (100 Hz low-pass filter, CyberAmp 380, Axon Instruments, Molecular Devices, LLC, Sunnyvale, CA), digitized (250/s; Bio-Logic Sleepscan Premier, Natus, San Carlos, CA) and stored to disk. Sleep was scored visually in 30-sec epochs. Visual scoring was used to maintain the highest quality control, because algorithms to automatically score sleep have not been sufficiently validated across differing rat strains. Thirty-sec epochs were used because this is the most common duration for visual SLEEP, Vol. 37, No. 11, 2014

scoring in our own and other laboratories. Wakefulness was determined as a high-frequency, low-amplitude EEG with concomitant high EMG tone. Nonrapid eye movement (NREM) sleep was determined by increased spindles and delta activity in EEG together with decreased EMG, and rapid eye movement (REM) sleep was scored by presence of predominantly sawtooth theta activity and an absence of EMG tone. Both minutes and percentage of total recording time were calculated for wakefulness, NREM sleep, and REM sleep. In addition, the number and duration of waking, NREM and REM sleep bouts, the number of state transitions and, separately, the number of awakenings were tabulated for each recording. The stage transitions were defined when successive epochs were not assigned to the same stage. Arousals were not scored separately. We defined awakenings when transitions either from NREM or from REM sleep to wakefulness occurred. Apneas were detected as cessation of respiration for at least 2 sec. Because bony attachment of the hyoid bone lends mechanical stability to the upper airway, rats exhibit central apneas rather than obstructive apneas as observed in humans and some other species (English bulldogs, Yucatan miniature pigs). These central apneas occur spontaneously in rats and with the greatest frequency during REM sleep, as in humans. These events often are associated with brief EEG changes characteristic of arousal, as well as increases in blood pressure consistent with autonomic arousal. The apnea index (apneas per hour of sleep) and apnea density (apnea index × mean apnea duration) were separately computed for NREM, REM, and total sleep for each PSG. Behavioral Testing Testing in the MWM occurred from 09:00 to 11:00. Between testing and PSG recording (11:00 to 12:00), rats were allowed to rest in their home cages. The MWM apparatus consisted of a circular pool 1.71 m in diameter and 59 cm in height with the interior surface painted white. The escape platform (diameter: 9.5 cm; height: 14.5 cm) was located 22 cm from the pool rim. The water was made opaque by adding powdered milk. The water temperature was kept constant at 20 ± 2°C to motivate animals, but to not be so stressful as to inhibit learning.39 In each experiment, rats were tested in cohort groups of four (two BN and two ZL rats). Animals were required to swim to a hidden platform submerged 2 cm below the water surface. Each rat was tested across six consecutive daily sessions. For each daily session, rats were taken from the vivarium and placed in the testing room 3 min before testing. For each trial, a rat was placed in the water at one of four randomly chosen locations near the rim, facing the outside of the pool. When a rat reached the platform, it was allowed to remain on it for 20 sec to promote orientation to the visual cues in the room. Between trials, a rat was placed into an empty cage with a heating pad for 60 sec. If a rat did not reach the platform within 90 sec during the trial session, it was guided to it and placed there for 20 sec before being returned to the holding chamber. In these cases, a rat was given a swim latency score of 90 sec. This maximum limit was imposed to prevent fatigue, which could affect subsequent trials. During acquisition training, rats received four trials per daily session for 3 consecutive days. In acquisition, the goal platform

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remained in the same location. On the fourth day, the platform was relocated to the opposite quadrant, e.g., southeast to northwest or northwest to southeast. In reversal learning, rats were tested on learning and remembering the new location of the escape platform for 3 consecutive days. All swim tests were recorded by a video camera connected to an image analyzer (Water Maze Version 4.20, Columbus, OH). Swim latency (the time to locate the platform) was measured for each trial. The average scores for each rat on each day were used for subsequent statistical analyses. To assess spatial acquisition and reversal learning in both groups of rats, the following indices were calculated: (1) acquisition index (swim latency on day 3 of acquisition subtracted from the day 1 latency); (2) switch index (swim latency on day 4 subtracted from the day 3 latency); (3) reversal learning index (swim latency on day 6 subtracted from the day 4 latency). Hyperoxia Exposure To explore the effect of acute apnea exacerbation on reversal learning, eight randomly chosen BN and eight ZL rats were assigned to undergo 20-h exposure to hyperoxia on day 3 between acquisition and reversal learning. The remaining eight ZL and six BN rats underwent sham hyperoxia, breathing room air throughout. Each individual animal that underwent 3 days of the spatial acquisition (BN: n = 14; ZL: n = 16) and was then randomly assigned to receive either room air (BN: n = 6; ZL: n = 8) or hyperoxia (BN: n = 8; ZL: n = 8) following testing on day 3. All aspects of behavioral testing and PSG recordings were conducted as previously described. To achieve acute hyperoxia, the plethysmographic chamber was flushed with 100% oxygen at a rate of 2.5 L/min for 20h from 12:00 to 08:00 the next morning. This flow rate is more than one order of magnitude greater than the minute ventilation of the rat and is sufficient to prevent rebreathing and associated changes in respiratory control. All other recording sessions were conducted by flushing the chamber with room air. Data Analysis A three-way repeated-measures analysis of variance (ANOVA) was used to assess the differences in apnea indices and sleep stage durations using strain (BN or ZL) and treatment (room air or hyperoxia) as between subjects effects and recording (baseline and day 3) as a within-subjects (repeatedmeasure) factor. Separate ANOVAs were performed for NREM, REM, and total sleep. These ANOVA models were useful for examining interaction terms. Additional one-factor ANOVAs controlled by Fisher protected least significant difference (PLSD) were conducted to examine individual contrasts. Three-way ANOVA models using strain and gas as betweensubjects factors and test day as a repeated measure were calculated to test swim latency separately for acquisition (days 1-3) and reversal learning (days 4-6). Pearson correlations between behavioral indices (acquisition index, switch index, and reversal learning index) and PSG (sleep/apnea) data were calculated. Acquisition index was correlated with PSG data for the baseline and day 3 recordings. Switch index and reversal learning index were correlated with PSG data on day 3 (either room air or hyperoxia conditions). SLEEP, Vol. 37, No. 11, 2014

Apneas per hour (mean ± SEM)

40

BN

ZL

35

*

30 25 20 15

*

10 5 0

NREM

REM

Figure 1—Frequency of apneas in total sleep in BN and ZL rats (BN: n = 14; ZL: n = 16) at baseline conditions estimated over 20 h recording; * P < 0.005. BN, Brown Norway; NREM, nonrapid eye movement; REM, rapid eye movement; SEM, standard error of the mean; ZL, Zucker Lean.

Nonparametric generalized additive model (GAM) analysis and locally weighted regression (LOESS) nonlinear fitting methods were used to delineate the dependence between sleep/ apnea and behavioral indices in the continuum of the combined data of BN and ZL rats. RESULTS Sleep and Apnea Characteristics of BN and ZL rats At baseline, BN rats expressed both greater apnea frequency and apnea density in comparison with ZL rats for total sleep, NREM sleep, and REM sleep (Figure 1, Tables 1 and 2). The total apnea index in BN rats was more than double that observed in ZL rats (P = 0.0005) and NREM sleep (P = 0.0003) and almost double in REM sleep (P = 0.008). There were no significant differences in the amount of total sleep, NREM sleep, and REM sleep between strains at baseline (Tables 1 and 2). ZL rats did, however, exhibit more fragmented sleep, characterized by a greater number of REM sleep bouts (P < 0.004), state transitions (P < 0.006) and awakenings (P < 0.045) (Tables 1 and 2). Exposure to 20 h of sustained hyperoxia increased apnea index in total sleep both in BN (34.3 ± 7.4 versus 22.46 ± 2.27 at baseline) and ZL rats (15.4 ± 2.7 versus 10.7 ± 0.9 at baseline). This effect was most evident during REM sleep in both BN (81.32 ± 11.9 versus 36.28 ± 5.6) and ZL (44.5 ± 12.7 versus 19.2 ± 2.2) rats (Table 1 and Figure 2). A three-way ANOVA revealed a significant effect of strain on both apnea index and apnea density during total sleep (P < 0.001), NREM sleep (P < 0.001), and REM sleep (P < 0.001) (Table 2). Hyperoxia (versus room air) significantly increased both apnea index and apnea density in REM sleep (P = 0.025 and P = 0.014, respectively) and decreased total number of awakenings (P = 0.03). Effect of day was revealed in REM sleep apnea index (P = 0.002) and apnea densities in total sleep (P = 0.045), NREM sleep (P = 0.005), and REM sleep (P < 0.001) (Table 2).

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Table 1—Sleep and apnea data at baseline and day 3 in Brown Norway and Zucker Lean rats exposed to room air and hyperoxia Baseline BN rats (n = 14)

Room air

ZL rats (n = 16)

Hyperoxia

BN rats (n = 6)

ZL rats (n = 8)

BN rats (n = 8)

ZL rats (n = 8)

Sleep architecture Wake NREM sleep REM sleep No. wake bouts No. NREM bouts No. REM bouts Wake bouts length NREM bouts length REM bouts length Num. stage transitions No. awakenings total

43.98 ± 2.29 48.7 ± 1.81 7.22 ± 0.72 167.8 ± 8.9 181.7 ± 8.0 43.64 ± 3.72 3.2 ± 0.3 3.2 ± 0.1 2 ± 0.1 395.1 ± 21.5 167.2 ± 8.9

45.76 ± 1.99 46.65 ± 1.66 7.52 ± 0.6 191.4 ± 12.7 191.3 ± 8.6 49.19 ± 3.78 a 3.1 ± 0.2 2.9 ± 0.2 1.7 ± 0.01 a 425.3 ± 15.2 178.9 ± 9.4

45.5 ± 2.27 46.6 ± 1.89 7.8 ± 0.7 151.2 ± 8.4 164.3 ± 8.5 42.5 ± 5.9 3.7 ± 0.2 3.4 ± 0.2 2.3 ± 0.1 357.3 ± 18.8 150.3 ± 8.4

46.3 ± 1.61 46.1 ± 1.74 7.6 ± 0.58 208.0 ± 8.6 219.3 ± 7.9 48.8 ± 3.8 2.7 ± 0.2 a 2.5 ± 0.1 a 1.9 ± 0.1 a 476.25 ± 15.6 a 207.4 ± 8.7 a

46.1 ± 3.1 45.9 ± 2.3 7.9 ± 0.9 144.4 ± 19.3 157.8 ± 18.8 46.6 ± 4.0 6.9 ± 3.3 3.4 ± 0.3 1.9 ± 0.1 368.6 ± 22.3 144.0 ± 1 9.2

49.4 ± 2.3 42.6 ± 2.0 7.9 ± 0.4 166.1 ± 15.6 175.4 ± 16.2 53.1 ± 3.9 3.9 ± 0.6 3 ± 0.2 1.8 ± 0.1 400.2 ± 32.6 161.4 ± 15.3

Sleep apnea indices Apnea index total Apnea density total NREM apnea index NREM apnea density REM apnea index REM apnea density

22.46 ± 2.27 66.4 ± 7.8 20.7 ± 2.14 61.0 ± 7.1 36.28 ± 5.6 107.8 ± 18.0

10.7 ± 0.9 a 32.3 ± 2.7 a 9.3 ± 0.8 a 29.2 ± 10.8 a 19.2 ± 2.2 a 56.4 ± 7.3 a

18.25 ± 1.4 59.03 ± 6.89 16.01 ± 1.7 51.08 ± 7.95 33.2 ± 4.59 106.84 ± 17.63

11.9 ± 1.75 a 35.83 ± 5.45 a 9.46 ± 1.49 a 28.94 ± 4.75 a 27.26 ± 4.34 77.92 ± 13.89

34.3 ± 7.4 112.7 ± 20.6 26.7 ± 7.0 86.8 ± 18.5 81.32 ± 11.9 272.1 ± 41.1

15.4 ± 2.7 a 53.8 ± 8.4 a 9.9 ± 1.1 a 36.1 ± 4.0 a 44.5 ± 12.7 a 148.1 ± 39.5 a

a P < 0.05, comparison between BN and ZL rats. Sleep variables are presented as percentages of total recording time. BN, Brown Norway; NREM, nonrapid eye movement; REM, rapid eye movement; ZL, Zucker Lean.

Table 2—Three-way analysis of variance (P values) over sleep and apnea indices in Brown Norway and Zucker Lean rats at baseline and day 3 in room air and hyperoxia groups Strain Sleep architecture Wake NREM sleep REM sleep No. REM bouts No. stage transitions No. awakenings total

0.23 0.12 0.63 0.004 * 0.006 * 0.045 *

Sleep apnea indices Apnea index total Apnea density total NREM apnea index NREM apnea density REM apnea index REM apnea density

< 0.001 * < 0.001 * < 0.001 * 0.001 * 0.001 * < 0.001 *

Day

Gas

Strain × Day

Strain × Gas

Day × Gas

Strain × Day × Gas

0.22 0.11 0.69 0.42 0.48 0.37

0.26 0.17 0.96 0.75 0.07 0.03 *

0.96 0.78 0.51 0.34 0.15 0.31

0.48 0.67 0.24 0.44 0.99 0.71

0.92 0.99 0.71 0.31 0.99 0.54

0.16 0.18 0.37 0.46 0.015 * 0.03 *

0.21 0.045 * 0.9 0.005 * 0.002 * < 0.001 *

0.25 0.18 0.68 0.1 0.025 * 0.014 *

0.96 0.75 0.95 0.59 0.78 0.57

0.71 0.9 0.73 0.8 0.57 0.68

0.007 * < 0.001 * 0.04 * 0.004 * 0.001 * < 0.001 *

0.032 * 0.023 * 0.055 0.63 0.037 * 0.036 *

Room Air group: BN: n = 6; ZL: n = 8. Hyperoxia group: BN: n = 8; ZL: n = 8. BN, Brown Norway; NREM, nonrapid eye movement; REM, rapid eye movement; ZL, Zucker Lean; the asterisk denotes significant differences.

As expected, day by gas interaction was found in all apnea measures (apnea indices and apnea densities in total, NREM, and REM sleep; Table 2). Interaction between strain, day and gas was revealed in total (P = 0.032) and REM (P = 0.037) sleep apnea indices and total (P = 0.023) and REM (P = 0.036) sleep apnea densities, with more severe SRBD during hyperoxia and in BN rats. Additionally, interactions between strain, day, and gas were revealed in the number of state transitions (P = 0.015) and number of awakenings (P = 0.03; Table 2). SLEEP, Vol. 37, No. 11, 2014

There were no significant effects of strain, gas, or day on the percentages of total, NREM, or REM sleep. Spatial Acquisition and Reversal Learning in BN and ZL rats Results of spatial discrimination learning and reversal learning are illustrated in Figures 3 and 4. In the spatial acquisition test, both BN and ZL rats showed a significant decrease in swim latency from day 1 to day 3 (Figure 3). A two-way ANOVA with repeated measures on swim latency for spatial

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SLEEP, Vol. 37, No. 11, 2014

1855

Apneas per hour (mean ± SEM)

A

50

BN

B

40 35

*

30 25

*

20 15 10 5

Baseline

50 45 40 35 30

Day 3_Room air

#

100

Apneas per hour

Apneas per hour (mean ± SEM)

ZL

45

0

80

*

*

60

*

40 20 0

Baseline

25

Hyperoxia

*

20 15 10 5 0

Baseline

Day 3_Hyperoxia

Figure 2—Frequency of apneas in total sleep on day 3 in subsets of BN and ZL rats. (A) Exposed to room air (BN: n = 6; ZL: n = 8). (B) Exposed to 20 h hyperoxia (BN: n = 8; ZL: n = 8) as compared to the baseline values in these groups; Insert shows comparison between rapid eye movement apnea indices at baseline and hyperoxia conditions (day 3) in the subset of BN and ZL rats; * P < 0.05—comparison between BN and ZL rats; # P < 0.05—comparison between baseline and hyperoxia. BN, Brown Norway; SEM, standard error of the mean; ZL, Zucker Lean.

Latency to platform, seconds

acquisition revealed a significant effect of day (P < 0.001), but no significant effect of strain (P = 0.52), reflecting that both strains exhibited equivalent learning across test sessions. There was a trend toward a day by strain interaction (P = 0.07), with ZL rats exhibiting a shorter mean swim latency (16.81 ± 2.54 sec versus 30.38 ± 5.5 sec) on day 3. For spatial reversal learning in the room air condition, both rat strains exhibited similar latencies across days 4 to 6 (Figure 4A). A two-way ANOVA with repeated measures showed a significant effect for day (P = 0.006), but no significant effect for strain (P = 0.4) or day by strain interaction (P = 0.78), again indicating that both groups significantly reduced latencies across reversal learning session in an equivalent fashion. In reversal learning, rats may exhibit perseverative behavior by navigating in the quadrant that contained the submerged platform during the preceding acquisition phase. To determine the degree in which rats exhibited such perseverativebehavior, an analysis was conducted on the percent path length spent in the correct acquisition quadrant during reversal learning (Figure 4B). A two-way ANOVA with repeated measures was conducted on the percent path length in the previously correct acquisition quadrant. There was no significant strain effect (P = 0.93), but there was a significant day effect (P < 0.05) because both strains exhibited a decreased path length in the correct acquisition quadrant. In the hyperoxia condition, BN rats displayed higher swim latencies than ZL rats across all reversal learning days although their reversal learning index was equivalent to ZL rats (Figure 4A). A two-way ANOVA with repeated measures showed a significant effect for day (P = 0.001) and a significant effect for strain (P = 0.037). The strain by day interaction was not significant (P = 0.83). Observation of the hyperoxia condition rats in reversal learning suggested that the BN rats were navigating longer in the quadrant that previously contained the submerged platform. A two-way ANOVA with repeated measures was conducted on the percent path length in the previously correct acquisition quadrant. There was a significant strain effect (P < 0.01) reflecting that BN rats exhibited a significantly greater path length in the previously correct acquisition quadrant (Figure 4B). There was also a significant day effect (P < 0.001), indicating that both strains decreased their path length in the correct acquisition quadrant across days. All groups exhibited a similar swim speed ranging from 23 cm/sec to 27 cm/sec. Importantly, even rats in the hyperoxia condition exhibited comparable swim speeds across days. To determine whether swim speed changed between acquisition and reversal learning, a three-way ANOVA with repeated measures was conducted on swim speed for day 3 (last acquisition session) and day 4 (first reversal learning session) of water maze testing. The analysis indicated that there was not a significant effect of day (P = 0.92), strain (P = 0.11), or gas (P = 0.87). There also was not a significant strain by gas interaction (P = 0.71). Thus, hyperoxia exposure did not alter swim speed. A three-way ANOVA with repeated measures on swim latency for reversal learning (days 4-6) demonstrated a significant effect of day (P < 0.001), strain (P = 0.003), and gas

Spatial Acquisition

60 50 40 30 20 10 0

BN

1

ZL

2

3

Days Figure 3—Latency to platform on the acquisition phase of a spatial discrimination task in the Morris water maze in BN (n = 14) and ZL (n = 16) rats. BN, Brown Norway; ZL, Zucker Lean. Cognitive Flexibility in Sleep Apnea—Topchiy et al.

BN_RA

Latency to platform (mean ± SEM)

A

60

% of Path Length in Acquisition Quadrant (mean ± SEM)

ZL_RA

Table 3—Correlation of sleep and apnea indices with indices of behavior at room air conditions in the combined groups of Brown Norway and Zucker Lean rats.

ZL_Hyperox

Spatial Reversal Learning

Acquisition index

50 40 30

*

20 10 0

B

BN_Hyperox

*

Reversal Index

4

35

5

Days

6

Spatial Reversal Learning

30 25

*

20

*

Reversal learning index

Correlation Sleep architecture Wake NREM sleep REM sleep No. wake bouts No. NREM bouts No. REM bouts Wake bouts length NREM bouts length REM bouts length No. stage transitions No. awakenings total

r

P

r

P

0.09 -0.24 0.39 0.27 0.15 0.42 -0.15 -0.08 -0.31 0.10 0.13

0.65 0.19 0.03 * 0.18 0.44 0.01 * 0.44 0.69 0.11 0.60 0.50

0.37 -0.33 -0.16 -0.10 -0.09 -0.01 0.25 -0.06 -0.35 -0.14 -0.10

0.18 0.24 0.57 0.73 0.76 0.96 0.41 0.80 0.25 0.61 0.75

Sleep apnea indices Apnea index total Apnea density total NREM apnea index NREM apnea density REM apnea index REM apnea density

-0.27 -0.30 -0.26 -0.29 -0.26 -0.31

0.07 0.04 * 0.05 * 0.03 * 0.21 0.09

-0.48 -0.50 -0.49 -0.50 -0.20 -0.17

0.07 0.08 0.07 0.05 * 0.47 0.54

The asterisk denotes significant correlation.

15 10 5 0

4

5

Days

6

Figure 4—(A) Latency to platform on the phase of reversal learning in BN and ZL rats under conditions of room air and following 20 h exposure to hyperoxia. (B) Percent path length in the correct acquisition quadrant during reversal learning in the Morris water maze under conditions of room air and following 20 h exposure to hyperoxia. * P < 0.05. BN, Brown Norway; hyperox, hyperoxia; SEM, standard error of the mean; RA, room air; ZL, Zucker Lean.

(P = 0.013) with a trend toward a significant strain by gas interaction (P = 0.06). Correlation of Sleep and Apnea Measures With MWM performance The similarity of spatial acquisition and sleep measures, as well as the overlap in apnea measures, in BN and ZL rats provided a possibility to determine whether there was a relationship between the acquisition performance and either sleep or apnea measures in the combined BN and ZL group (Table 3 and Figure 6). Acquisition performance was characterized by the acquisition index, which represented the difference in swim latencies between day 1 and day 3 of acquisition. For the sleep measures, there was a significant positive correlation between acquisition performance SLEEP, Vol. 37, No. 11, 2014

and REM sleep as a percentage of the total time of the baseline PSG recording session (r = 0.39; P = 0.03). Other analyses did not reveal a significant correlation of acquisition performance with wake, NREM sleep, or the number of state transitions and awakenings (P > 0.05 for each; Table 3). In general, there was an overall negative correlation with acquisition performance and all apnea measures (Figure 5). However, the only significant negative correlations were between acquisition performance and total apnea density (r = -0.3; P < 0.05), NREM apnea index (r = -0.26; P < 0.05) and NREM apnea density (r = -0.29; P < 0.05). In some cases a relationship between sleep or apnea measures and acquisition performance demonstrated a nonlinear threshold effect. Figure 6A shows that in the combined group of BN and ZL rats a relationship between the amount of REM sleep and acquisition performance has a nonlinear character (GAM test: P = 0.012) with a positive effect of REM sleep on acquisition performance, beginning when REM sleep exceeds 8% of the total recording time. Figure 6B shows the nonlinear relationships between NREM apnea index and acquisition performance (GAM test: P = 0.016) and demonstrates that acquisition performance degrades only for NREM apnea index above approximately 10 apneas per hour. During room air breathing, reversal learning index did not correlate significantly with any sleep measures (Table 3). As for acquisition index, overall there were negative correlations between apnea measures and reversal learning performance. However, the only significant negative linear correlation was between NREM apnea density and reversal learning index (r = -0.52; P < 0.05).

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A

80

40 20 0 4

6

8

10

-20 -40

-80

REM sleep as a % of the total time of the experiment

0

5

10

15

REM sleep (% of exp.time)

80

B

60

Reversal learning index

Acquisition index

0

-60 2

B

40 20

60

Switch index

Acquisition index

A

40 20 0 0

5

10

15

Apnea index in NREM

20

25

BN

50

ZL

40 30 20 10 0

Figure 5—Dependences between acquisition index and (A) rapid eye movement (REM) sleep (r = 0.5; P = 0.03). (B) Apnea index in nonrapid eye movement (NREM) sleep (r = -0.3; P = 0.05) in the combined group of Brown Norway and Zucker Lean rats. The straight lines show linear correlation. The smooth curves were fitted to the data using the nonlinear locally weighted regression (LOESS) method.

0

50

100

150

Apnea index in REM sleep Figure 6—(A) Correlation between rapid eye movement (REM) sleep as a percent from the time of the experiment during exposure to hyperoxia and switch index in the combined group of Brown Norway (BN) and Zucker Lean (ZL) rats (r = -0.6; P = 0.01). (B) Correlation between apnea index in REM sleep and reversal learning index in BN (r = -0.8; P = 0.03) and ZL rats (r = -0.3; P = 0.49). BN: n = 8; ZL: n = 8.

To analyze the relationships between sleep or apnea measures with a behavioral switch from acquisition to reversal learning following exposure to hyperoxia, we correlated measures of sleep and apnea on day 3 (during hyperoxia) with the switch index and the reversal learning index. Both BN and ZL rats exposed to hyperoxia revealed a negative correlation between switch index and REM sleep as a percentage of the total recording time on day 3. However, only in BN rats was this correlation statistically significant (r = -0.72; P = 0.04; Table 4). A similar negative correlation between the switch index and the percentage of REM sleep was observed in the pooled group of BN and ZL rats (Table 4; Figure 6A). Additionally, apnea index and apnea density in REM sleep had negative correlations with reversal learning index in both BN and ZL rats exposed to hyperoxia. However, only in BN rats was this correlation statistically significant (P < 0.05; Table 4; Figure 6B). DISCUSSION The current study confirms that acute hyperoxia induces acute exacerbation of SRBD in both BN and ZL rats with the greatest effect on REM-related apnea expression, extending SLEEP, Vol. 37, No. 11, 2014

60

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previous observations in Sprague-Dawley rats.38 Further, we show that despite a baseline apnea index more than double that of ZL rats breathing room air, BN rats are unimpaired in both the spatial acquisition and reversal learning tasks. However, during acute apnea exacerbation by hyperoxia, BN rats exhibit impaired reversal learning whereas ZL rats do not. These findings suggest that acute exacerbation of SRBD by hyperoxia in a rat strain that exhibits high levels of spontaneous sleep apneas can lead to deficits in cognitive flexibility, but not in a rat strain that has low levels of spontaneous sleep apneas. Moreover, in both strains, cognitive performance shows a negative relationship to numerous measures of SRBD severity. Baseline Conditions The current findings confirm previous reports that BN rats exhibit a higher number of sleep apneas compared to that of ZL rats24,26 and further showed that BN rats have significantly higher apnea indices and apnea densities in both REM and NREM sleep. In contrast, BN and ZL rats exhibited similar overall expression of wake, NREM sleep, and REM sleep, although sleep was somewhat more fragmented in ZL rats than Cognitive Flexibility in Sleep Apnea—Topchiy et al.

Table 4—Correlation of sleep and apnea indices during exposure to hyperoxia on day 3 with switch index (A) and reversal learning index (B) in Brown Norway and Zucker Lean rats.

A

BN rats (n = 8) Correlation Sleep architecture Wake NREM sleep REM sleep No. Wake bouts No. NREM bouts No. REM bouts Wake bouts length NREM bouts length REM bouts length No. stage transitions No. awakenings total

0.42 -0.27 -0.72 0.9 0.9 -0.38 -0.79 -0.71 -0.6 0.40 0.90

Sleep apnea indices Apnea index total Apnea density total NREM apnea index NREM apnea density REM apnea index REM apnea density

0.24 0.20 0.18 0.13 0.59 0.52

B

r

ZL rats (n = 8)

P

BN & ZL rats (n = 16)

r

P

r

0.30 0.52 0.04 * 0.003 * 0.006 * 0.35 0.02 * 0.05 * 0.09 0.33 0.003 *

0.21 -0.17 -0.36 0.47 0.39 -0.48 -0.58 -0.34 0.09 0.01 0.40

0.62 0.68 0.38 0.23 0.35 0.22 0.12 0.39 0.83 0.97 0.31

0.35 -0.24 -0.61 0.72 0.68 -0.38 -0.69 -0.6 -0.4 0.20 0.70

0.18 0.37 0.01 0.001 * 0.003 * 0.15 0.003 * 0.01 * 0.13 0.46 0.02 *

0.57 0.64 0.66 0.75 0.12 0.18

-0.14 -0.17 -0.38 -0.50 0.01 0.06

0.74 0.68 0.35 0.16 0.98 0.87

-0.13 0.10 0.06 -0.01 0.34 0.34

0.73 0.80 0.23 0.98 -0.76 -0.80

BN rats (n = 8)

ZL rats (n = 8)

P

BN & ZL rats (n = 16)

Correlation Sleep architecture Wake NREM sleep REM sleep No. wake bouts No. NREM bouts No. REM bouts Wake bouts length NREM bouts length REM bouts length No. stage transitions No. awakenings total

r

P

r

P

r

P

-0.27 0.13 0.55 -0.56 -0.61 0.09 0.67 0.47 0.96 -0.07 -0.59

0.52 0.76 0.15 0.14 0.10 0.83 0.07 0.24 < 0.01 * 0.86 0.14

-0.28 0.25 0.34 -0.57 -0.49 0.47 0.58 0.54 -0.37 -0.07 -0.44

0.50 0.55 0.41 0.10 0.21 0.23 0.13 0.16 0.36 0.87 0.26

-0.27 -0.39 0.39 -0.55 -0.54 0.26 0.49 0.45 0.30 -0.08 -0.50

0.30 0.45 0.09 0.03 * 0.02 * 0.33 0.05 * 0.07 0.24 0.76 0.04

Sleep apnea indices Apnea index total Apnea density total NREM apnea index NREM apnea density REM apnea index REM apnea density

-0.55 -0.60 -0.51 -0.50 -0.76 -0.80

0.15 0.12 0.20 0.17 0.03 * 0.02 *

-0.19 -0.14 0.02 0.22 -0.29 -0.30

0.64 0.74 0.97 0.58 0.49 0.42

-0.28 -0.30 -0.22 -0.20 -0.39 -0.40

0.30 0.30 0.40 0.47 0.13 0.13

BN rats: n = 8; ZL rats: n = 8. The asterisk denotes significant correlation. BN, Brown Norway; NREM, nonrapid eye movement; REM, rapid eye movement; ZL, Zucker Lean.

BN rats. There were no significant differences in percent time awake versus total time asleep in both strains. However, because of the water maze testing during the first 4 h of the light phase, we missed the initial 4 h of recording, which could reduce the amount of sleep recorded at the daytime. Additionally, the aversive situation of the water maze testing might have reduced the subsequent sleep time during the light phase. Despite the robust difference in spontaneous sleep apneas at baseline between BN and ZL rats, the two strains performed equivalently in both spatial acquisition and reversal learning SLEEP, Vol. 37, No. 11, 2014

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tasks. This finding differs from previous studies reporting impaired spatial acquisition in rodents exposed to intermittent hypoxia (IH),17–20 a finding that may in part result from hypoxiainduced dysfunction of the hippocampus.19 However, previous studies have used relatively severe levels of inspired hypoxia (e.g., 6–10%), and frequency of hypoxia (30–60 events per hour), which may have contributed to a greater effect on spatial acquisition. Indeed, even then, the effect can require several days of IH to be manifested.18 In contrast, even BN rats exhibit only 15–30 spontaneous apneas per hour of sleep under Cognitive Flexibility in Sleep Apnea—Topchiy et al.

baseline conditions, and these most probably are associated with only mild to moderate hypoxemia. Further, the chronic nature of the SRBD in BN and ZL rats may have resulted in adaptations that preserved baseline cognitive function, at least to some extent. Despite the fact that acquisition of the spatial task in the MWM did not differ significantly between BN and ZL rats, NREM apnea index at baseline demonstrated a negative nonlinear relationship with the acquisition index (Figure 6B). Beyond a threshold (approximately 10 events per hour) rats with higher NREM apnea index at baseline tended to acquire the task more poorly. Additionally, although the reversal learning index was similar in BN and ZL rats under baseline (room air) conditions, apnea density in NREM sleep on day 3 negatively correlated with reversal learning. Thus, broadly speaking, both spatial acquisition and reversal learning were negatively related to NREM SRBD under baseline conditions. Beyond breathing measures, acquisition index and REM sleep percentage at baseline were positively correlated (Figure 6A). This observation is consistent with the view that REM sleep plays a positive role in the dynamics of learning.40 Again, this relationship demonstrated a nonlinear threshold effect, with improving cognitive performance beyond a REM sleep percentage of approximately 8% of recording time. A beneficial role of REM sleep in learning is suggested by numerous animal and human studies.40–43 Acute Apnea Exacerbation by Hyperoxia Hyperoxia increased apnea frequency in both BN and in ZL rats, which is consistent with our previous finding in SpragueDawley rats.38 Further, hyperoxia evoked an increase in apnea density in both BN and ZL rats. These effects were particularly evident during REM sleep. Despite significant increases in apnea index and apnea density for both strains, only BN rats exhibited impaired reversal learning in comparison to rats exposed to room air. This suggests a possible threshold effect of SRBD on cognitive processing. In accordance with this view, although hyperoxia significantly increased SRBD in ZL rats, apnea index under hyperoxia merely reached the baseline level of apneas in BN rats. In this light, it is perhaps unsurprising that reversal learning following hyperoxia in ZL rats was not worse than under control conditions for BN rats. Furthermore, no differences were observed in the switch index or overall reversal learning of hyperoxia-exposed ZL rats as compared to control ZL rats maintained on room air. Although our observations are consistent with a threshold effect for the effect of acute apnea exacerbation on cognitive flexibility (revealed by the switch cost), we cannot rule out that this simply reflects a constitutive difference between the BN and ZL strains. It is striking that although rats were exposed to acute apnea exacerbation by hyperoxia only on day 3, swim latencies for BN rats remained elevated throughout days 4–6, in comparison with ZL rats. Despite this fact, swim latencies decreased equivalently from day 4 to day 6 in both strains. This suggests that the deficit in BN rats exposed to acute SRBD exacerbation by hyperoxia does not represent an impairment in memory or retention of a newly learned discrimination, but rather in cognitive flexibility needed for task switching. The increased reversal learning latencies observed in BN rats exposed to acute SLEEP, Vol. 37, No. 11, 2014

SRBD exacerbation by hyperoxia also cannot be explained by a change in swim speed because this was consistent in all groups between acquisition and reversal learning. Instead, the increased reversal learning latencies in BN rats exposed to acute SRBD exacerbation by hyperoxia likely reflects these rats “perseverating” in the quadrant that contained the submerged platform in acquisition. This finding has potential relevance for human SRBD because acute exacerbations occurring along with upper respiratory infections, allergic rhinitis, alcohol or sedative use, and poor adherence to positive airway pressure treatment are common in individuals with sleep apnea syndrome. Our findings further suggest that a single night of SRBD exacerbation by hyperoxia may impair cognitive function for several days. Future studies will be needed to define the full period of cognitive deficit following acute SRBD exacerbation; to identify whether increasing the degree or duration of such exacerbations may produce other cognitive deficits; and to explore whether specific treatments may counteract the negative consequences of an acute SRBD exacerbation. The strongest predictor of increased swim latency on day 4 (when the escape platform was moved) in BN rats was the REM apnea index during hyperoxia. This supports the view that elevated SRBD, even without significant intermittent hypoxia, exerts a deleterious effect on cognitive performance. However, it is interesting to note that although hyperoxia did not alter the percentage of REM sleep per se, REM sleep percentage on day 3 revealed strong negative correlation with the switch cost index in BN rats (Figure 6A). In other words, animals with more REM sleep during hyperoxia exhibited longer swim latencies on day 4, when the platform was moved. This is in contrast to our observation that higher REM sleep percentage in baseline recordings was associated with improved cognitive performance in the acquisition task. Because hyperoxia produced a maximal increase in apnea index during REM sleep, we may speculate that higher volumes of REM sleep on day 3 during hyperoxia produced a negative effect on cognitive flexibility simply because of the additional exposure to apneas. Alternatively, increased REM sleep may have more directly reinforced the initial acquisition learning from the previous 3 days, rendering cognitive flexibility lower on day 4 for those animals. Various evidence suggests that there are different types of cognitive flexibility. In order to successfully switch choice patterns, a patient must initially inhibit the previously correct choice pattern and switch to an alternative choice pattern, but must also maintain that switch by actively inhibiting selection of the previously correct choice pattern. Either one or both of these functions could be impaired during elevated SRBD or acute SRBD exacerbation. These functions may dissociate among different brain circuitry or neurotransmitter systems.44,45 Specifically, Ragozzino and colleagues have demonstrated that distinct reversal learning error patterns arise from altered function of specific brain regions.44-47 For example, the prefrontal cortex is critical for the initial shift away from a previously relevant choice pattern, whereas the striatum and thalamus are critical for maintaining the new relevant choice pattern after being initially selected.44–47 Neuroimaging studies in patients with SRBD showed that frontal and prefrontal cortex, middle and posterior cingulate area, temporoparieto–occipital cortices, the thalamus, some of the basal ganglia, and the cerebellar regions

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exhibit decreased activity and metabolism.14,48 These structures also were shown to be impaired in REM sleep fragmentation and deprivation studies.49 On this basis, it is not surprising that patients with SRBD experience cognitive deficits, but specific relationships between discrete brain areas and particular forms of cognitive deficit in SRBD remain to be established. The animal model presented here may provide an important approach for defining such structure-function relationships in a natural animal model of SRBD. In summary, the current study demonstrated that acute exposure to 20-h hyperoxia increased SRBD in both BN and ZL rats, with the greatest effect on REM sleep apneas. This acute SRBD exacerbation by hyperoxia significantly impaired reversal learning performance in BN but not ZL rats, suggesting a threshold effect for the effect of SRBD on cognitive flexibility. This view is further supported by the nonlinear negative correlation between REM apnea index and set-switching performance in BN rats exposed to hyperoxia. More generally, both strains demonstrated a significant negative threshold-related dependence between apnea indices and cognitive performance in both acquisition and reversal learning tasks. These results suggest that acute apnea exacerbation in individuals with SRBD may make them vulnerable to acute deficits in executive function. Future studies will be necessary to determine the effect of acute apnea exacerbation on other cognitive domains, and to establish the period of vulnerability following acute apnea exacerbation and to define the specific mechanisms by which these deficits are mediated. The approach described here may allow specific structure-function relationships to be defined in a natural animal model of spontaneous SRBD and its acute exacerbation. ACKNOWLEDGMENTS The authors acknowledge Drs. Alana Steffen and Chang Park for assistance with non-linear statistical analysis and Milka Dokic for technical support of the experiments. DISCLOSURE STATEMENT This was not an industry supported study. David W. Carley (from before November 2011 and until August 2012 served as a director and consultant for Pier Pharmaceutical (now acquired by Cortex Pharmaceutical); from August 2012 until September 2012 served as a director of Cortex Pharmaceutical. Neither Pier nor Cortex has any relationship with content or execution of the study described in the submitted manuscript. The research was supported by University of Illinois at Chicago Chancellor’s Discovery Fund for multidisciplinary research and NIH grant AG016303. The other authors have indicated no financial conflicts of interest. REFERENCES

1. Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP. Pathophysiology of sleep apnea. Physiol Rev 2010;90:47–112. 2. Veasey S. Insight from animal models into the cognitive consequences of adult sleep-disordered breathing. ILAR J 2009;50:307–11. 3. Felver-Gant JC, Bruce AS, Zimmerman M, Sweet LH, Millman RP, Aloia MS. Working memory in obstructive sleep apnea: construct validity and treatment effects. J Clin Sleep Med 2007;3:589–94. 4. Beebe DW, Groesz L, Wells C, Nichols A, McGee K. The neuropsychological effects of obstructive sleep apnea: a meta-analysis of norm-referenced and case-controlled data. Sleep 2003;26:298–307.

SLEEP, Vol. 37, No. 11, 2014

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5. Wallace A, Bucks RS. Memory and obstructive sleep apnea: a metaanalysis. Sleep 2013;36:203–20. 6. Olaithe M, Bucks RS. Executive dysfunction in OSA before and after treatment: a meta-analysis. Sleep 2013;36:1297–305. 7. Saunamaki T, Jehkonen M. A review of executive functions in obstructive sleep apnea syndrome. Acta Neurol Scand 2007;115:1–11. 8. Lis S, Krieger S, Hennig D, et al. Executive functions and cognitive subprocesses in patients with obstructive sleep apnoea. J Sleep Res 2008;17:271–80. 9. Barnes M, Houston D, Worsnop CJ, et al. A randomized controlled trial of continuous positive airway pressure in mild obstructive sleep apnea. Am J Respir Crit Care Med 2002;165:773–80. 10. Engleman HM, Martin SE, Deary IJ, Douglas NJ. Effect of CPAP therapy on daytime function in patients with mild sleep apnoea/hypopnoea syndrome. Thorax 1997;52:114–9. 11. Henke KG, Grady JJ, Kuna ST. Effect of nasal continuous positive airway pressure on neuropsychological function in sleep apnea-hypopnea syndrome. A randomized, placebo- controlled trial. Am J Respir Crit Care Med 2001;163:911–7. 12. Barbe F, Mayoralas LR, Duran J, et al. Treatment with continuous positive airway pressure is not effective in patients with sleep apnea but no daytime sleepiness: a randomized, controlled trial. Ann Intern Med 2001;134:1015–23. 13. Bédard MA, Montplaisir J, Malo J, Richer F, Rouleau I. Persistent neuropsychological deficits and vigilance impairment in sleep apnea syndrome after treatment with continuous positive airways pressure (CPAP). J Clin Exp Neuropsychol 1993;15:330–41. 14. Ferini-Strambi L, Baietto C, Di Gioia MR, et al. Cognitive dysfunction in patients with obstructive sleep apnea (OSA): partial reversibility after continuous positive airway pressure (CPAP). Brain Res Bull 2003;61:87–92. 15. Gozal D, Daniel JM, Dohanich GP. Behavioral and anatomical correlates of chronic episodic hypoxia during sleep in the rat. J Neurosci 2001;21:2442–50. 16. McCoy JG, McKenna JT, Connolly NP, et al. One week of exposure to intermittent hypoxia impairs attentional set-shifting in rats. Behav Brain Res 2010;210:123–6. 17. Perry JC, D’Almeida V, Lima MM, et al. Intermittent hypoxia and sleep restriction: motor, cognitive and neurochemical alterations in rats. Behav Brain Res 2008;189:373–80. 18. Ward CP, McCoy JG, McKenna JT, Connolly NP, McCarley RW, Strecker RE. Spatial learning and memory deficits following exposure to 24 h of sleep fragmentation or intermittent hypoxia in a rat model of obstructive sleep apnea. Brain Res 2009;1294:128–37. 19. Goldbart A, Row BW, Kheirandish L, et al. Intermittent hypoxic exposure during light +phase induces changes in cAMP response element binding protein activity in the rat CA1 hippocampal region: water maze performance correlates. Neuroscience 2003;122:585–90. 20. Nair D, Zhang SX, Ramesh V, et al. Sleep fragmentation induces cognitive deficits via nicotinamide adenine dinucleotide phosphate oxidase-dependent pathways in mouse. Am J Respir Crit Care Med 2011;184:1305–12. 21. Carley DW, Berecek K, Videnovic A, Radulovacki M. Sleep-disordered respiration in phenotypically normotensive, genetically hypertensive rats. Am J Respir Crit Care Med 2000;162:1474–9. 22. Carley DW, Radulovacki M. REM sleep and apnea. In: Mallik BN, Inoue S, eds. Rapid eye movement sleep. New Dehli-Madras-Bombay-CalcuttaLondon: Narosa Publishing House, 1999:286–300. 23. Carley DW, Radulovacki M. The laboratory rat as a model of sleep-related breathing disorders. In: Carley DW, Radulovacki M, eds. Sleep-related breathing disorders: experimental models and therapeutic potential. New York: Marcel Dekker, 2003:265–95. 24. Carley DW, Trbovic SM, Radulovacki M. Hydralazine reduces elevated sleep apnea index in spontaneously hypertensive (SHR) rats to equivalence with normotensive Wistar-Kyoto rats. Sleep 1996;19:363–6. 25. Carley DW, Trbovic S, Radulovacki M. Sleep apnea in normal and REM sleep-deprived normotensive Wistar-Kyoto and spontaneously hypertensive (SHR) rats. Physiol Behav 1996;59:827–31. 26. Radulovacki M, Trbovic S, Carley DW. Hypotension reduces sleep apneas in Zucker lean and Zucker obese rats. Sleep 1996;19:767–73. 27. Mendelson WB, Martin JV, Perlis M, Giesen H, Wagner R, Rapoport SI. Periodic cessation of respiratory effort during sleep in adult rats. Physiol Behav 1988;43:229–34.

Cognitive Flexibility in Sleep Apnea—Topchiy et al.

28. Sato T, Saito H, Seto K, Takatsuji H. Sleep apneas and cardiac arrhythmias in freely moving rats. Amer J Physiol 1990;259:R282–7. 29. Thomas AJ, Austin W, Friedman L, Strohl KP. A model of ventilatory instability induced in the unrestrained rat. J Appl Physiol 1992;73:1530–6. 30. Strohl KP, Thomas AJ, St Jean P, Schlenker EH, Koletsky RJ, Schork NJ. Ventilation and metabolism among rat strains. J Appl Physiol 1997;82:317–23. 31. Berg S. Obstructive sleep apnoea syndrome: current status. Clin Resp J 2008;2:197–201. 32. Kohler M, Stoewhas AC, Ayers L, et al. Effects of continuous positive airway pressure therapy withdrawal in patients with obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med 2011;184:1192–9. 33. Razani J, Casas R, Wong JT, Lu P, Alessi C, Josephson K. Relationship between executive functioning and activities of daily living in patients with relatively mild dementia. Appl Neuropsychol 2007;14:208–14. 34. Fletcher EC, Munafo DA. Role of nocturnal oxygen therapy in obstructive sleep apnea. When should it be used? Chest 1990;98:1497–504. 35. Gold AR, Schwartz AR, Bleecker ER, Smith PL. The effect of chronic nocturnal oxygen administration upon sleep apnea. Am Rev Respir Dis. 1986;134:925–9. 36. Martin RJ, Sanders MH, Gray BA, Pennock BE. Acute and long-term ventilatory effects of hyperoxia in the adult sleep apnea syndrome. Am Rev Respir Dis 1982;125:175–80. 37. Alford NJ, Fletcher EC, Nickeson D. Acute oxygen in patients with sleep apnea and COPD. Chest 1986;89:30–8. 38. Christon J, Carley DW, Monti D, Radulovacki M. Effects of inspired gas on sleep-related apnea in the rat. J Appl Physiol 1996;80:2102–7. 39. Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 2006;1:848–58.

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40. Walker MP, Liston C, Hobson JA, Stickgold R. Cognitive flexibility across the sleep- wake cycle: REM-sleep enhancement of anagram problem solving. Brain Res Cogn Brain Res 2002;14:317–24. 41. Poe GR, Walsh CM, Bjorness TE. Cognitive neuroscience of sleep. Prog Brain Res 2010;185:1–19. 42. Walter T. REM illumination: Memory consolidation. Grove City, Ohio: Lotus Magnus, LLC, 2007. 43. Datta S. Avoidance task training potentiates phasic pontine-wave density in the rat: a mechanism for sleep-dependent plasticity. J Neurosci 2000;20:8607–13. 44. Ragozzino ME. The contribution of the medial prefrontal cortex, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility. Ann N Y Acad Sci 2007;1121:355–75. 45. Palencia CA, Ragozzino ME. The influence of NMDA receptors in the dorsomedial striatum on response reversal learning. Neurobiol Learn Mem 2004;82:81–9. 46. Ragozzino ME, Rozman S. The effect of rat anterior cingulate inactivation on cognitive flexibility. Behav Neurosci 2007;121:698–706. 47. Brown HD, Baker PM, Ragozzino ME. The parafascicular thalamic nucleus concomitantly influences behavioral flexibility and dorsomedial striatal acetylcholine output in rats. J Neurosci 2010;30:14390–8. 48. Yaouhi K, Bertran F, Clochon P, et al. A combined neuropsychological and brain imaging study of obstructive sleep apnea. J Sleep Res 2009;18:36–48. 49. Thomas M, Sing H, Belenky G, et al. Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity. J Sleep Res 2000;9:335–52.

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Acute exacerbation of sleep apnea by hyperoxia impairs cognitive flexibility in Brown-Norway rats.

To determine whether learning deficits occur during acute exacerbation of spontaneous sleep related breathing disorder (SRBD) in rats with high (Brown...
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