Dynamics of sleep-wake cyclicity across the fetal period in sheep (Ovis aries).

All adult mammals examined thus far exhibit sleep bout durations that follow an exponential distribution and wake bout durations that follow a power-law distribution. In altricial rodents such as rats and mice, exponential distributions of sleep bouts are found soon after birth, but the power-law distribution of wake bouts does not emerge until the third postnatal week. Also, both sleep and bouts consolidate across the early postnatal period. It is not known whether similar developmental processes occur in precocial species during the prenatal period. Here we characterize sleep-wake development in a precocial species, the domestic sheep (Ovis aries), from 114 to 148 days gestational age (DGA). Sleep and wake bout durations exhibited exponential distributions throughout the fetal period with some evidence of an emerging exponential-to-power-law transition for wake bouts toward the end of gestation. Both sleep and wake bouts consolidated in an orderly fashion across development and there was little evidence of circadian variation, even in the oldest subjects. These results indicate that similar patterns of sleep-wake organization are found prenatally in a precocial species as are found postnatally in altricial species. Data from more species are needed to fully realize the benefits of a developmental comparative approach for understanding the forces that have shaped the ontogeny and phylogeny of mammalian sleep.

Active medullary control of atonia in week-old rats.

Muscle atonia is a central feature of adult REM sleep which has recently been demonstrated to be a component of sleep in rats as young as 2 days of age (P2). The neural generation of atonia, which depends on mesopontine and medullary structures, is not fully understood in adults and has never been described in infants. In the present experiments we used electrical stimulation in decerebrated pups to identify an inhibitory area within the medial medulla of P7-10 rats. Muscle tone inhibition was consistently found on or near the midline within the ventromedial medulla, dorsal to the inferior olive, in an area that includes the nucleus gigantocellularis, nucleus paramedianus, and raphe obscurus. Chemical infusions in the same region revealed inhibitory responses to quisqualic acid but not to carbachol or corticotropin-releasing factor. Next, extracellular recordings within the medullary inhibitory area revealed neurons with atonia-on profiles; tone-on neurons were also found, typically at more lateral sites. Finally, in non-decerebrated pups, chemical lesions within the inhibitory area resulted in significant reductions in atonia durations, as well as decoupling of atonia from a second component of infant sleep, myoclonic twitching; specifically, twitches occasionally occurred during periods of high muscle tone, a condition reminiscent of "REM without atonia" as described in adults. In summary, we document the existence of an area within the ventromedial medulla of infant rats that (i) causes atonia when stimulated; (ii) contains units that exhibit atonia-related discharge profiles during sleep-wake cycling; and (iii) when lesioned, results in the partial loss of atonia and decoupling of the components of sleep. All together, these findings demonstrate that muscle atonia is actively regulated very early in ontogeny.

On the significance of similarities between ultrasonic vocalizations of infant and adult rats.

The communicatory significance of the 40 kHz vocalization of rat pups and the 22 kHz vocalization of adult rats have been topics of research for over three decades. The 40 kHz vocalization is emitted by pups during cold exposure, whereas the 22 kHz vocalization is emitted by adults following ejaculation, following defeat in aggressive encounters, as well as in other contexts. Recent research suggests that the 40 kHz vocalization is the acoustic by-product of a respiratory mechanism that enhances gas-exchange in the lungs during times of increased oxygen consumption. Furthermore, a reevaluation of research into the physiological basis of the 22 kHz vocalization suggests a similar conclusion. In the present paper, we discuss mechanistic and contextual aspects of ultrasound production. We conclude that these two vocalizations, produced by identical mechanisms and reflecting identical physiological states, are actually the same vocalization, albeit at different frequencies. This alternative view of ultrasound production has implications for our interpretation of the communicatory significance of these vocalizations.

Thermoregulatory and cardiac responses of infant spontaneously hypertensive and Wistar-Kyoto rats to cold exposure.

Cardiovascular function during cold exposure is dependent on effective thermoregulation. This dependence is particularly apparent in infants. For example, we have previously demonstrated that in infant rats during cold exposure, cardiac rate is directly related to their ability to produce heat endogenously. The primary source of endogenous heat production for infant rats is brown adipose tissue (BAT). Because of the dependence of cardiac rate on effective thermoregulation in the cold and because hypertension in spontaneously hypertensive rats (SHR) is influenced by the preweanling environment, in this study we examined the thermoregulatory and cardiac rate responses of infant SHR and Wistar-Kyoto rats (WKY) to varying levels of cold exposure. In experiment 1, 7- to 8-day-old SHR and WKY were acclimated at a thermoneutral air temperature (35 degrees C) and then exposed to successive decreases in ambient temperature (30.5 degrees C, 26.5 degrees C, 23 degrees C, and 17 degrees C) while thermal and metabolic measures were recorded. Although both strains increased BAT thermogenesis and oxygen consumption in response to cold exposure, SHR cooled more than WKY and exhibited lower levels of oxygen consumption at the lowest air temperatures. Experiment 2 was identical to experiment 1 except that cardiac rate was also measured. Again, SHR exhibited substantial thermoregulatory deficits compared with WKY; in addition, they were less able than WKY to maintain cardiac rate at the 2 lowest air temperatures tested. Finally, in experiment 3, infant SHR exhibited diminished BAT thermogenesis in response to a range of doses of a selective beta3-adrenoceptor agonist. We hypothesize that long-term thermoregulatory deficits during the early postnatal period influence cardiovascular function and contribute to the development of hypertension in SHR.

Do infant rats cry?

In the current revival of interest in the emotional and mental lives of animals, many investigators have focused attention on mammalian infants that emit distress vocalizations when separated from the home environment. Perhaps the most intensively studied distress vocalization is the ultrasonic vocalization of infant rats. Since its discovery, this vocalization has been interpreted both as a communicatory signal for the elicitation of maternal retrieval and as the manifestation of emotional distress. In contrast, the authors examined the cardiovascular causes and consequences of the vocalization, and on the basis of this work, they hypothesized that the vocalization is the acoustic by-product of the abdominal compression reaction (ACR), a maneuver that results in increased venous return to the heart. Therefore, the vocalization may be analogous to a sneeze, serving a physiological function while incidentally producing sound.

Hypothalamic contribution to sleep-wake cycle development.

Infant mammals cycle rapidly between sleep and wakefulness and only gradually does a more consolidated sleep pattern develop. The neural substrates responsible for this consolidation are unknown. To establish a reliable measure of sleep-wake cyclicity in infant rats, nuchal muscle tone was measured in 2-, 5-, and 8-day-old rats, as were motor behaviors associated with sleep (i.e. myoclonic twitching) and wakefulness (e.g. kicking, stretching). Sleep-wake cycles of 2-day-old rats were characterized by short periods of muscle atonia followed by equally short periods of high tone. In 8-day-olds, sleep periods lengthened significantly and disproportionately in relation to awake periods. Next, locus coeruleus (LC) lesions in 8-day-olds resulted in rapid sleep-wake cycling similar to that exhibited by 2-day-olds; in addition, LC lesions had no effect on the duration of awake periods. Finally, transections caudal, but not rostral, to the anterior hypothalamus also reinstated rapid cycling in 8-day-olds, again without affecting the duration of awake periods. This last finding implicates neural structures within the anterior hypothalamus (e.g. ventrolateral preoptic area) in the modulation of sleep-wake cyclicity. The temporal coherence of atonia and myoclonic twitching was not disrupted by any of the manipulations. These results suggest the presence of a bistable mesopontine circuit governing rapid sleep-wake cycling that does not include the LC and that comes increasingly under hypothalamic control during the first postnatal week. This circuit may represent a basic building block with which other sleep components become integrated during ontogeny.

Both hypoxia and milk deprivation diminish metabolic heat production and ultrasound emission by rat pups during cold exposure.

Rat pups (7-9 days of age) were made cold and hypoxic simultaneously while interscapular temperature, rectal temperature, and ultrasound emission were monitored. These hypoxic pups cooled faster than control pups, which indicates decreased thermogenesis and decreased oxygen consumption, and produced less ultrasound. In a separate experiment, pups deprived of milk for 24 hr cooled faster and also produced less ultrasound than did nondeprived littermates. Further analyses revealed that those pups that cooled the slowest (and thus used the most oxygen) vocalized the most, both among control animals as well as across the two manipulated groups. This finding suggests that ultrasound emission covaries with thermogenesis. The observed pattern is opposite to that predicted by traditional communication hypotheses of rat pup vocalizations and favors understanding the sounds as symptoms of laryngeal braking.

Ultrasonic vocalizations by rat pups in the cold: an acoustic by-product of laryngeal braking?

Isolated rat pups respond to cold exposure physiologically by increasing metabolic heat production and behaviorally by emitting ultrasound. The relationship between these 2 responses was investigated by monitoring oxygen consumption, heat production by brown adipose tissue, respiratory rate, and ultrasound production during cold exposure in pups 10-12 days of age. All 3 physiological measures increased contemporaneously with the initiation of ultrasound. Pups also exhibited a respiratory pattern characterized by the prolongation of expiratory duration in relation to inspiratory duration. Ultrasound was often detected during these prolonged expirations, suggesting that pups were using laryngeal braking. Laryngeal braking is thought to enhance oxygen uptake in the lungs. Thus, ultrasound may be an acoustic by-product of a respiratory maneuver that increases oxygen delivery to metabolically active tissues during cold exposure.

Dual mechanisms of twitching during sleep in neonatal rats.

Twitches of the limbs during REM sleep in adult mammals result from descending motor activation from the brainstem. In contrast, many spontaneous movements in embryos appear similar to REM-related twitches and result from the local firing of spinal motor neurons. To determine which mechanism produces twitches in neonates, we analyzed twitching in 5- and 8-day-old rat pups that had spinal cords transected in the lower thoracic region. This transection separated motor units controlling forelimb movements from motor units controlling hindlimb movements. Spinal transection did not significantly affect the amount of forelimb twitching. In contrast, the amount of hindlimb twitching in transected pups was reduced by only 35%-50%. Given that hindlimb twitching was not eliminated by spinal transection, it is concluded that there are 2 independent mechanisms producing twitches at these ages.

Thermogenesis, myoclonic twitching, and ultrasonic vocalization in neonatal rats during moderate and extreme cold exposure.

Physiological and behavioral responses of 2- and 7-8-day-old rats were monitored during moderate and extreme cold exposure. During moderate cold exposure (30 degrees C < or = air temperature < or = 32.5 degrees C), pups at both ages increased heat production, maintained an elevated interscapular temperature, and maintained baseline levels of myoclonic twitching, a behavior commonly associated with active sleep. During extreme cold exposure (21 degrees C < or = air temperature < or = 25 degrees C), pups at both ages continued producing metabolic heat, but now exhibited pronounced decreases in interscapular temperature and decreased rates of myoclonic twitching. Furthermore, the 7-8-day-old pups exhibited significant increases in ultrasound production, and males vocalized more than females. These results suggest the presence of a narrow subthermoneutral zone in neonates in which nonshivering thermogenesis is regulated and sleep-related behaviors are protected.

Active sleep in cold-exposed infant Norway rats and Syrian golden hamsters: the role of brown adipose tissue thermogenesis.

It was previously hypothesized that brown adipose tissue (BAT) thermogenesis helps to maintain high rates of myoclonic twitching during cold exposure in infant rats (M. S. Blumberg & M. A. Stolba, 1996). To test this hypothesis, the sensitivity of twitching to various levels of cold exposure was assessed in week-old rats that were untreated or whose BAT thermogenesis was inhibited using a ganglionic blocker. Because week-old golden hamsters do not exhibit BAT thermogenesis, their sleep behaviors during cold exposure also were examined. Additional investigations in infant rats were conducted in which supplemental heat was provided to the interscapular region using a thermode and in which BAT was activated pharmacologically in ganglionically blocked pups. The results support the hypothesis that myoclonic twitching is sensitive to the prevailing air temperature and the activation of BAT thermogenesis.

A comparative analysis of huddling in infant Norway rats and Syrian golden hamsters: does endothermy modulate behavior?

In infant rats, huddling improves surface-to-volume ratios and provides metabolic savings during cold exposure. It is unclear, however, whether endothermy is also a necessary component of huddling. In the present experiment, huddles composed of infant Norway rats (2- or 8-day-olds), which produce heat endogenously, or Syrian golden hamsters (8-day-olds), which do not produce heat endogenously, were exposed to decreases in air temperature. Behavioral and physiological responses were monitored throughout the test. Rats, especially at 8 days of age, were better able to thermoregulate using huddling than hamsters, due in part to endogenous heat production. Furthermore, 8-day-old rats exhibited behavioral responses that promote heat retention, suggesting that both physiological and behavioral mechanisms contribute to effective thermoregulation during huddling in the cold.

Cardiovascular concomitants of ultrasound production during cold exposure in infant rats.

Two experiments explored the cardiovascular consequences of extreme cold exposure and their relationship with ultrasound production in infant rats. Experiment 1 addressed the thermoregulatory and cardiovascular concomitants of ultrasound production during cold exposure in rats pretreated with saline or the ganglionic blocker chlorisondamine (5 mg/kg). For both groups, emission of ultrasound was associated with hypothermia and bradycardia. Experiment 2 explored whether the hypothermia experienced by pups in Experiment 1 is associated with increased blood viscosity, which is an important factor affecting venous return to the heart. Blood viscosity increased significantly as temperature decreased from 38 degrees C to 22 degrees C. These experiments suggest that, during extreme cold exposure, decreased cardiac output and increased blood viscosity combine to diminish venous return. The authors have hypothesized that pups respond to decreased return by recruiting the abdominal compression reaction, a physiological maneuver that propels blood back to the heart, resulting in emission of ultrasound as an acoustic by-product.

Cardiovascular mediation of clonidine-induced ultrasound production in infant rats.

In infant rats, administration of the alpha2 adrenoceptor agonist clonidine simultaneously evokes ultrasound production and bradycardia. In this study the authors examined in 8-day-old rats whether these 2 responses to clonidine are causally related. In Experiment 1 pups were pretreated with saline or prenalterol (0.1 or 1.0 mg/kg), a beta1 adrenoceptor agonist that increases cardiac rate, followed by administration of clonidine (1.0 mg/kg). Prenalterol pretreatment suppressed clonidine-induced ultrasound production at both doses. Prenalterol also increased skin temperature, however, suggesting that suppression of ultrasound was modulated in part by increased body temperature. Consistent with this suggestion, in Experiment 2 mild hyperthermia significantly inhibited clonidine-induced ultrasound production. Finally, in Experiment 3 the authors found that the pretreatments used in Experiments 1 and 2 prevent or dampen the effects of clonidine on cardiac rate. These results suggest that clonidine's effect on ultrasound production is mediated by its effects on the cardiovascular system.

Spontaneous motor activity in fetal and infant rats is organized into discrete multilimb bouts.

Spontaneous motor activity (SMA) is a ubiquitous feature of fetal and infant behavior. Although SMA appears random, successive limb movements often occur in bouts. Bout organization was evident at all ages in fetal (embryonic day [E] 17-21) and infant (postnatal day [P] 1-9) rats, with nearly all bouts comprising 1-4 movements of different limbs. A computational model of SMA, including spontaneous activity of spinal motor neurons, intrasegmental and intersegmental interactions, recurrent inhibition, and descending influences, produced bouts with the same structure as that observed in perinatal rats. Consistent with the model, bouts were not eliminated on E20 after cervical spinal transection, suggesting that the brain is not necessary to produce bout organization. These investigations provide a foundation for understanding the contributions of SMA to neuromuscular and motor development.

Impact of extending health care coverage to the uninsured.

Changes in use of health services by the uninsured, when covered after health reform, are a key to the costs of reform. From data on persons under age sixty-five in the 1989 National Health Interview Survey, we estimated their expected use of hospitals (excluding obstetric deliveries) and doctor visits, adjusting for age, sex, and self-reported health status. If uninsured persons obtained private coverage distributed by the plan type of other persons in their home regions, nonobstetric hospital days for the formerly uninsured would increase 28 percent, and their visits to physicians' offices would increase 52 percent. If instead the uninsured enrolled entirely in group- or staff-model health maintenance organizations (HMOs) in their home regions, their nonobstetric hospital days would actually decrease 17 percent, and their visits to physicians' offices would increase 60 percent.

Mesopontine contribution to the expression of active 'twitch' sleep in decerebrate week-old rats.

Myoclonic twitching is a ubiquitous feature of infant behavior that has been used as an index of active sleep. Although the active sleep of infants differs in some ways from the REM sleep of adults, their marked similarities have led many to view them them as homologous behavioral states. Recently, however, this view has been challenged. One avenue for resolving this issue entails examination of the neural substrates of active sleep. If the neural substrates of active sleep were found to be similar to those of REM sleep, then this would support the view that the two states are homologous. Therefore, in the present study, decerebrations were performed in the pons and midbrain to determine whether the mesopontine region is important for the expression of active sleep in infants, just as it is for the expression of REM sleep in adults. It was found that, in comparison to controls, caudal pontine decerebrations reduced myoclonic twitching by 76%, rostral pontine decerebrations reduced twitching by 40%, and midbrain transections had no significant effect on twitching. Moreover, analysis of the temporal organization of twitching indicated that pontine decerebrations predominantly affected high-frequency twitching while leaving unaffected the low-frequency twitching that is thought to be contributed by local spinal circuits at this age. These results indicate that the mesopontine region plays a central role in the expression of active sleep in infant rats.

Pontine and basal forebrain transections disinhibit brown fat thermogenesis in neonatal rats.

Bignall, Heggeness and Palmer (1975) were the first to demonstrate increases in metabolic heat production following midpontine transection in neonatal rats. Subsequent work in adult rats has shown that this procedure disinhibits thermogenesis by brown adipose tissue (BAT). Bignall and his colleagues also found that hypothalamic ablation did not result in increased thermogenesis in 5-day-olds, leading them to conclude that thermoregulation depends on more caudal structures at that age. We have also found that midpontine transection disinhibits BAT thermogenesis and, furthermore, have extended that finding to newborn pups. When transections were made in the basal forebrain, however, we also found profound and rapid increases in brown fat thermogenesis. These results suggest the presence of at least two sources of inhibition of BAT thermogenesis in newborn rats: one located in the rostral pons-caudal midbrain and one located in the basal forebrain.

Comments on HCFA hospital death rate statistical outliers. Health Care Financing Administration.

In March 1986, the Health Care Financing Administration (HCFA) released ten lists of death-rate "outlier" hospitals, one for all 1984 Medicare discharges and nine for specific DRGs. Recent Medicare hospital discharge abstracts have substantially undercounted in-hospital deaths, with large variations by state. Apart from the proportion of a hospital's cases in 80 DRGs, the predictive models had no measures of case severity based on diagnosis or procedure. Having DRG 123 (all deaths from acute myocardial infarction) as an independent variable in the all-death regression model probably accounted for much of its high r2. Inclusion of an independent variable for average length of stay (ALOS) favored hospitals in higher ALOS states by higher predicted death rates. Model bias also favored lower-risk hospitals. Small numbers of predicted deaths for specific DRGs limited low-volume hospitals on these outlier lists to those with high ratios of actual to predicted deaths. On six of the nine DRG-specific outlier lists, a total 1,222 hospitals had unfavorable residuals, while only 8 were favorable. Ten recommendations are given to increase reliability of future outcome analyses.

Prostaglandin E2 accelerates sexual behavior in male rats.

Sexual behavior in male rats is accompanied by an increase in body temperature of 18 degrees C. It has been suggested that this increase may be, at least in part, a febrile response mediated by the endogenous central release of prostaglandins of the E series (PGE). This putative release of PGE could also affect the expression of sexual behavior, a possibility that was tested in the present experiment. PGE2 was infused into the cerebral aqueduct and sexual behavior and hypothalamic temperature were monitored. PGE2 infusion raised hypothalamic temperature and decreased the postejaculatory interval and ejaculation latency. The exact cause of this acceleration of sexual behavior cannot as yet be determined.