Brain Research, 589 (1992) 353-357 © 1992 Elsevier Science Publishers B.V. All rights reserved 0006-8993/92/$05.00

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Enhancement of REM sleep with auditory stimulation in young and old rats G l o r i a A r a n k o w s k y - S a n d o v a l , W i l l i a m S. S t o n e a n d P a u l E. G o l d Department of Psychology, Giimer Hall, Universityof Virginia, Charlottesville, VA 22903 (USA) (Accepted 9 June 1992)

Key words: REM sleep; Sleep impairment; Aging; Rat; Fischer-344; Auditory stimulation

Auditory stimulation applied during rapid eye movement (REM) sleep enhances the duration of REM sleep in cats and humans. The present experiment investigated whether auditory stimulation would enhance REM sleep in young (3-6 months) rats, and also in old (22-24 months) rats which have impaired REM sleep. Baseline sleep records were obtained on two days. Sleep patterns were then assessed during auditory stimulation test sessions. In young rats, auditory stimulation was administered during each REM sleep bout. In old rats, auditory stimulation was administered on a fixed schedule (10 min of stimulation alternating with 15 min quiet). The day after the stimulation session, an additional sleep record (Day 2) was obtained for each rat. In young rats, auditory stimulation enhanced both REM sleep duration and total REM sleep time. In the old rats, which showed impaired sleep measures as compared to young animals, auditory stimulation enhanced both total REM sleep time and the number of REM sleep periods. Residual proactive effects of auditory stimulation (Day 2) were observed in both young and old rats. Thus, auditory stimulation is an effective manipulation with which to augment REM sleep in both young and old rats, and partially attenuates REM sleep impairments in old rats.

Aging is accompanied by deterioration of sleep patterns in rats, cats and humans 5's''J'~f'.The sleep impairments include reductions in total sleep time compounded by fragmentation of sleep, in which the average bout lengths of both slow wave sleep and rapid eye movement (REM) sleep are reduced. In aged rats, the most reliable measure of sleep deterioration appears to be decreases in REM sleep bout duration ~eaS'~7. Sensory stimulation administered during REM sleep augments REM sleep length and total time in young adult mammals. For example, auditory ~ and somatic 2 stimulation administered during REM sleep enhance the duration of these sleep episodes in normal cats. Auditory stimulation applied during REM sleep also increases REM sleep bout duration in humans ~LI3. Evidence that kainic acid lesions of the medial pontine reticular formation block the enhancement of REM sleep by sensory stimulation in cats suggests that systems in the medial ports may participate in the neural mechanisms responsible for mediating sensory stimulation enhancement of REM sleep 3. In addition, audi-

tory stimulation attenuates atropine-induced reductions in the duration of REM sleep in cats ~, and microinjections of cholinergic agonists into the pontine reticular formation result in sustained REM sleep 4, suggesting possible involvement of brainstem cholinergic systems in the effects of sensory stimulation on REM sleep. The purposes of the present experiment were to determine whether auditory stimulation would be effective in augmenting REM sleep measures in rats, as it is in cats and humans, and to determine whether auditory stimulation would also be effective in ameliorating deficits in REM sleep in aged rats. In past experiments, two treatments have been shown to attenuate REM sleep impairments in aged rats. These include exposure to enriched environments ~7 and systemic administration of glucose 14, a treatment which also attenuates learning and memory deficits in animals, including aged humans 1°. The findings reported here indicate that, as in cats, auditory stimulation enhances REM sleep duration in young rats. In addi-

Correspondence to: P.E. Gold, Department of Psychology, Gilmer Hall, University of Virginia, Charlottesville, VA 22903, USA. Fax: (1) (804) 982-4785.

354 tion, auditory stimulation also augments REM sleep measures in aged rats with otherwise low REM sleep values. Seven aged (22-24 months) and eight young (3-6 months) male rats of the Fischer-344 strain from the NIA colony (Harlan Industries, IN) were used for this study. Each animal was housed in an individual home cage with free access to water and food. The cages were kept in a colony room on a 12/12 light-dark cycle with lights on at 7.00 h. Before surgery, the animals received injections of atropine sulfate (0.1 rag/rat). Young rats were anesthetized with sodium pentobarbital (50 mg/kg) and old rats were anesthetized with the inhalant, methoxyflurane (to effect). At the completion of surgery all animals were treated with the antibiotic, Durapen (0.1 ml). Two contralateral stainless-steel screws were placed in the skull for cortical EEG recording (1 mm lateral at the level of bregma; 4 mm lateral at the level of lambda). The EMG was recorded from two stainless-steel wire electrodes implanted in the nuchai muscles. All electrodes were connected to an Amphenol microminiature connector strip and the assemblage was attached to the skull with dental cement. Experimental procedures were conducted between 10.(|0 h and 14.00 h each day. After a postsurgical perio(t of at least one week, the rats were habituated to the ret:ording chamber (30 × 30 × 30 cm, containing a speaker at the rear) for 4 h on each of 3 days. After habituation, two 4-h baseline sleep records were obt,'tincd for each rat prior to auditory stimulatio~ test sessions. The two baselines were averaged for statistical comparisons. The specific procedures employed for administration of auditory stimulation differed for young and old rats. In young rats, sleep stages were monitored during the auditory stimulation sessions. Auditory stimulation (2 kHz, 75-81) dB, 100 ms every 20 s, generated by a Hewlett-Packard Oscillator) was administered throughout each REM sleep bout. Because the duration of REM sleep periods is very short in aged rats, auditory stimulation could not be administered during these periods. Therefore, old rats received auditory stimulation on a fixed schedule: 1(1 min of auditory stimulation (parameters as abme) alternating with 15 min quiet; auditory stimulation was interrupted if a waking pe~'iod of more than 2 min occurred. Additional sleep records were obtained from both young and old rats on the day after the auditory stimulation session (referred to below as the Day 2 session). EEG and EMG records were evaluated in 30-s epochs which were scored as either awake, REM sleep or slow wave sleep (SWS) depending on which state

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Fig. I. Comparison of the baseli.e sleep values obtained from young and old rats. Note that old anin~,als had significant age-related changes in both SWS lind REM sleep measures. ** P 0.40). Total sleep time was slightly lower in aged rats, but this difference was not statistically sigr.ificant ( P > 0.1). The ANOVA revealed that auditory stimulation in young rats resulted in increased durations of REM sleep bouts as compared to baseline (F2a4 = 112.8, P < 0.001; means 183.8 + 7.8 vs. 107.2 + 5.7 s) (F,.'g. 2). During the Day 2 session, the duration of REM sleep was still significantly elevated above baseline values (128.8 + 8.2 vs. 107.2 + 5.7). Auditory stimulation also resulted in increased total REM sleep time (F2,~4 = 7.82, P < 0.005; means 30.05 + 2.5 vs. 23.8 + 1.9 min) and a decrease in the number of REM sleep bouts (F2.~4 = 4.87, P < 0.02; means 9.8 =l: 0.76 vs. 13.1 + 0.66). However, total REM sleep time and the number of REM sleep bouts returned to baseline levels during the Day 2 session. Auditory stimulation did not significantly alter SWS values in young rats (Fig. 2).

In old rats, auditory stimulation significantly enhanced both the number of REM sleep periods (F2.12 = 7, P < 0.009) and total REM sleep time (F:.~2 = 4.5, P < 0.05) during the auditory stimulation session. The values of both sleep parameters during the auditory stimulation condition were 17.1 + 1.7 vs. 13.5 + 1.5 and 26 + 3.8 vs. 17.7 + 2.4 rain, respectively. For the Day 2 sessions REM sleep bout number was increased to 19.2 + 1.6, and total REM sleep time showed a nonsignificant increase to 24.5 + 2 min. Neither SWS nor total sleep rime were significantly changed by auditory stimulation (Fig. 2). Consistent with previous findings ~2'~5'~7, the results obtained here indicate that several sleep measures are impaired in aged rats. Furthermore, auditory stimulation is an effective treatment with which to enhance REM sleep in both young and aged rats. Comparisons between the young and old rats revealed several significant age-related changes in sleep. Compared to young rats, aged rats exhibited significant decreases in both SWS and REM sleep bout durations. Moreover, although total SWS time did not differ by age, total REM sleep time was lower in old than in young rats. These changes were accompanied by an age-related increase in the number of SWS and waking periods. Together, the findings are consistent with the view that a decline in REM sleep, paired with gener-

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Fig. 2. Auditory stimulation induced significant changes in REM sleep patterns of young and old rats. The magnitude of these changes is depicted as the mean difference between the baselines of each group and the auditory stimulation and day 2 conditions. * P < 0.05, Dunnett's test.

356 ally fragmented sleep patterns, are prominent characteristics of age-related changes in sleep in rats t2'mS-m7. Some specific discrepancies between our results and some prior findings are that, for example, Rosenberg et al. j2 did not observe an age-related increase in the number of SWS bouts as seen here. Also, Van Gool and Mirmiran 17 found a decrease in total SWS time, and Stone et al? 5 reported a decrease in the number of REM sleep periods; neither of these measures exhibited significant age-related changes in the present experiment. Still, the overall pattern of reduced REM sleep values and disrupted continuity of sleep are consistent across these experiments. Auditory stimulation administered during REM sleep increased the duration of REM sleep bouts in young rats. This finding is consistent with previous work showing that auditory stimulation increased REM sleep in both cats L6 and humans ~LI3. Thus, auditory stimulation, and probably other sensory stimulation as well, augment REM sleep in several species. Of additional interest, the increases in the REM sleep duration and total REM sleep time were accompanied by a reduction in the number of REM sleep bouts, perhaps reflecting a tendency of total REM sleep to be maintained at a constant amount through the recording session. The length of REM sleep bout durations remained elevated on the Day 2 sessions, i.e. 24 h after auditory stimulation. Thus, the effects of auditory stimulation on REM sleep outlast the treatment for at least a day. Recently, a similar result was seen in humans after 4 nights of auditory stimulation administered during REM sleep in normal volunteers t'~. Because REM sleep bout duration baselines were short in aged rats, it was not possible to administer the auditory stimulation during REM sleep and the stimulation was therefore administered on a fixed schedule. The efficacy of this alternate treatment was not unexpected since the latency for appearance of REM sleep can be shortened in the cat by applying auditory stimu. lation during the stage of SWS that precedes REM sleep episodes ~'. Using the fixed schedule of administration of auditory stimulation, the treatment increased the number of REM sleep bouts in 2-year-old rats, resulting in restoration of total REM sleep time in aged rats to levels near the baseline values of young rats. As in young rats, residual effects of auditory stimulation were still evident on the Day 2 test sessions. However, the proactive effect in old rats was an increase in the number of REM sleep bouts, while the proactive effect in young rats was on the duration of REM sleep bouts. It is unclear whether the difference in the measures affected in young and old rats is a consequence of age or of the differences in schedule of

administration of auditory stimulation to the two age groups. With regard to the mechanism by which auditory stimulation modulates REM sleep, there is evidence that the medial reticular formation of the pens may contribute to this phenomenon. Auditory or somatic stimulation does not enhance REM sleep if administered to cats following neurotoxic lesions of the medial pontine reticular formation a. Moreover, auditory stimulation during REM sleep augments the spontaneous firing rate of a population of reticular neurons, suggesting that an increase in the excitability of such neurons may participate in enhancement of REM sleep by sensory stimulation7. Thus, the present findings demonstrate that the facilitating influence of auditory stimulation on REM sleep processes is not restricted to young animals, but is also present in aged rats which have impaired REM sleep parameters. The mechanisms underlying REM sleep may thus retain the capacity to respond to treatments during senescence, resulting in enhanced REM sleep and, more generally, attenuation of age-related sleep deficits. Supported by research grants from ONR (NO001489-J-1216), NIA (AG 07648), and NSF (BNS-9012239). G.A. was sunported by a Postdoctoral Fellowship from the Fogarty Foundation. I Arankowsky.Sandoval, G., Prdspero-Garch, O,, Aguilar-Roblero, R., and Drucker-Colfn, R., Cholinergic reduction . f REM sleep duration is reverted by auditory stimulation, Br~ia Res,, ?,75 (1986) 377-380. 2 Arankowsky.Sandoval, G., Aguilar, Roblero, R., Pr6spero-Garcfa, O., and Drucker-Col[n, R., Rapid eye movement (REM) sleep and PGO spike density are increased by somatic stimulation, Brai,~ Res., 400 (1987) 155-158. 3 Arankowsky-Sandoval, G., Garcia-Hermlndez, F., AguilarRoblero, R., and Drucker-Colin, R., REM sleep enhancement induced by sensory stimulation is prevented by kainic acid lesion of the pontine reticular formation, Brain Res., 494 (1989) 396-400. 4 Baghdoyan, H.A., Rodrigo-Angulo, M.L., McCarley, R.W,, and Hobson, J.A., Site-specific enhancement and suppression of desynchronized sleep signs following cholinergic stimulation of three brainstem regions, Brain Res., 306 (1984) 39-52. 5 Bowersox, S.S., Baker, T.L, and Dement, W.C., Sleep-wakefulness patterns in the aged cat, Electroeneephalog. Clin. Neurophysiol,, 58 (1984) 240-252. 6 Drucker-Colfn, R,, Bernal-Pedraza, J., Fern~ndez-Cancino, F., and Morrison, A., Increasing PGO spike density by auditory stimulation increases the duration and decreases the latency of rapid eye movement (REM) sleep, Brain Res., 278 (1983) 308-312. 7 Drucker-Colfn, R., Arankowsky-Sandoval, G., Pr6spero-Garc[a, O., Jimenez-Anguiano, A.. and Merchant-Nancy, H., The regulation of REM sleep: some considerations on the role of vasoactive intestinal peptide, acetylcholine and sensory modafities, In: M. Mancia and G. Marini (Eds.), Tile Diencephalon and Sleep, Raven Press (1990) 313-330. 8 Eleftheriou, B.E., Zolovich, AJ. and Elias, M.F., Electroencephalographic changes with age in male mice, Gerontologia, 21 (1975) 21-30. 9 Hayashi, Y. and Endo, S., All night sleep polygraphic recordings of healthy aged persons: REM and slow wave sleep, Sleep, 5 (1982) 277-283.

357 10 Manning, C.A., Hall, J.L. and Gold, P.E. Glucose effects on memory and other neuropsychological tests in elderly humans, Psychol. ScL, 5 (1990)307-311. 11 Mouze-Amady, M., Sockeel, P. and Leconte, P., Modification of REM sleep behavior by REMs contingent auditory stimulation in man, Physiol. Behat,., 37 (1986) 543-548. 12 Rosenberg, R.S., Zepelin, H. and Rechtschaffen, A., Sleep in young and old rats, J. Gerontol., 34 (1979) 525-532. 13 Sal[n-Pascual, R., Granados-Fuentes, D., De la Fuente, J.R. and Drucker-Col[n, R., Effects of auditory stimulation during rapid eye movement (REM) sleep in healthy volunteers and depressed patients, Psychiatry Res., 38 (1991) 237-246.

14 Stone, W.S. and Gold, P.E., Sleep and memory, relationships in intact old and amnestic young rats, Neurobiol. Aging, 99 (1988) 719- .'7. 15 Stone, W.S., AItman, H.J., Berman, R.F, CaldweU, D.F. and Kilbey, M.M., Association of sleep parameters and memory in intact old and nucleus basalis-lesioned young rats, Bdzat,. Neurosci., 103 (1989) 755-764. 16 van Gool, W.A. and Mirmiran, M., Age-related changes in the sleep pattern of male adult rats, Brain Res., 279 (1983) 394-398. 17 van Gool, W.A., and Mirmiran, M., Effects of aging and housing in an enriched environment on sleep-wake patterns in rats, Sleep, 9 (1986) 335-347.

Enhancement of REM sleep with auditory stimulation in young and old rats.

Auditory stimulation applied during rapid eye movement (REM) sleep enhances the duration of REM sleep in cats and humans. The present experiment inves...
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