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This experiment examined coupling between two circadian pacemakers, one entrained by light and the other by food. Rats were housed in running wheels: one-half on restricted feeding from 0900 to 1100 h whereas the others were free fed. After timed-fed rats developed bursts of running before 0900 h, all rats were given free access to food. A month later, the light-dark (LD) cycles for one-half the rats in each group were delayed by 6 h. After entrainment to the new LD cycles, all rats were probed with 96-h periods of food deprivation. During these probes, unshifted timed-fed rats ran more than their free-fed controls at 0600-1200 h, but delayed timed-fed rats ran more than their controls at 1200-1500 h, i.e., 6 h later than unshifted rats. Next, the unshifted rats were subjected to a 6-h advance in their LD cycle. One month later, all rats were again probed with food deprivation. Delayed timed-fed rats continued to run more at 1200-1500 h than their free-fed controls, but timed-fed and free-fed phase-advanced rats showed similar activity patterns after the phase advance. However, when activity patterns before these probes were subtracted, timed-fed advanced rats showed greater "responses" to food deprivation at 0001-0300 h than their free-fed controls, i.e., 6 h earlier than before the phase advance. Thus LD shifts delayed and advanced the running that was previously associated with food availability and reset the food-entrainable circadian pacemaker.

Previously we showed that rhesus monkeys have ultradian cortisol rhythms with periods of about 90 min that persist during the infusion of large amounts of adrenocorticotropin. The experiments reported here showed that rats exhibit ultradian corticosterone rhythms with a similar period (median period 61 min). However, rat ultradian corticosterone rhythms were distorted by large slow trends that had to be removed before the rhythm could be adequately assessed. The need for sophisticated trend removal suggests that physiological variables that have been described as exhibiting episodic fluctuations (e.g., human cortisol) may actually be periodic and ultradian. The ultradian glucocorticoid rhythm persisted during stress both in monkeys (median period 80 min) and rats (median period 52 min). However, the glucocorticoid stress response appeared to produce large slow trends in both monkeys and rats, indicating that environmental influences may introduce slow trends that make raw data difficult to evaluate. More importantly, the fact that ultradian glucocorticoid rhythms persist during stress provides further evidence of limits on the classical concept that glucocorticoid secretion is tightly and inseparably linked to hormonal events in the hypothalamic-pituitary unit.

Acute experiments were performed on open-chest male mongrel dogs that were anesthetized with thiopental sodium and respired. An average of 10 penetrations per side was used to explore the rostral-caudal organization of the nucleus ambiguus (NA) and the area ventrolateral to it. Atrial pacing was performed on some trials to clarify the occurrence of atrioventricular (AV) block. In addition, the vagi were sectioned in some animals to confirm the peripheral pathway of the observed effects. Finally, the twin-pulse technique was used to classify the neurons underlying the observed effects according to their refractory periods. Stimulation in the area of the NA and lateral to it produced bradycardia and bradyarrhythmias without altering blood pressure. Stimulation of either the left or right NA produced slowing of both atrial and ventricular rates. However, slowing of the atrial rate was greatest with right NA stimulation, whereas slowing of the ventricular rate was predominant with left-side stimulation. The presence of AV block was evident from dropped QRS complexes with and without pacing. Vagotomy demonstrated that these effects were conducted by ipsilateral but not contralateral nerves. Measurement of the refractory periods showed that the neurons underlying both atrial and ventricular slowing were characteristic of B-fibers.

We have developed a rhesus monkey model that enables us to investigate physiological rhythms and circadian effects on performance in an integrated framework. Monkeys worked for 8 h/day on a two-component task (a vigilance trial followed by a discrimination trial) for their daily food aliquot. Concurrently, we recorded activity and temperature rhythms around the clock. To test the model, we studied rhythms and performance during entrainment to a 24-h light cycle and after a 6-h phase advance. Results from this animal model displayed many of the essential characteristics seen in similar human experiments. During stable entrainment, temperature rhythms reached their maximum amplitude in late afternoon, with activity rhythms reaching their maximum amplitude several hours earlier. Performance exhibited consistent task-dependent variations over the course of daily sessions. Speed of discrimination performance was fastest at the beginning of the session, and speed of vigilance performance was fastest several hours later. After a 6-h phase advance, monkeys exhibited transient internal desynchrony with activity resynchronizing faster than temperature. Both vigilance and discrimination were impaired after the phase shift, with vigilance exhibiting larger-magnitude and longer-lasting impairments than discrimination. A second drop in performance was seen 10-14 days after the phase shift. These data replicate and extend earlier work in humans and show that this model can be used in the study of chronobiological questions that would be too expensive or too impractical to do with humans.

Plasma concentrations of adrenal, thyroid, and testicular hormones were measured at 4-h intervals around the clock in male hamsters on long (14:10-h light-dark cycle) and short (10:14-h light-dark cycle) days. Plasma corticosterone, cortisol, thyroxine (T4), triiodothyronine (T3), and testosterone rhythms were present on long days. The only one of these hormones to have a significant rhythm on short days was cortisol, but even its amplitude was suppressed compared with the cortisol rhythm on long days. Short days also lowered mean plasma levels of cortisol, T4, T3, and testosterone. Finally, short days raised the ratio of corticosterone to cortisol and lowered the ratio of T4 to T3. Both ratios had significant rhythms on long days but not on short days. Because of the many interactions among adrenal, thyroid, and testicular hormone axes, it is unclear whether the primary effect of short days is on one of these endocrine systems or on another factor that has separate effects on each of the hormone rhythms that was measured. Nonetheless, it is clear that a major effect of short day lengths in hamsters is to suppress hormone rhythms. Explanations of photoperiodic effects that depend on endocrine mediation should take this into account.

Plasma growth hormone (GH), cortisol, and glucose were measured every 20 min in the last 2 h of a 12-h dark cycle and the first 4 h of a 12-h light cycle in eight environmentally limited rhesus monkeys; additionally, ongoing behavior was scored every 20 min in the last 4 h when the lights in the booths housing the monkeys were on. Episodic fluctuations in levels of GH, cortisol, and glucose occurred. Onset of booth illumination was associated with a significant number of GH secretory bursts (6 of 18), and more than twice as many bursts per hour occurred in the light than in the dark (L:D = 0.44:0.19). The onset of illumination was also associated with significant increases in glucose for the eight animals. In addition, plasma glucose increased concurrently with the onset of 13 of 18 bursts of GH secretion. Monkeys were rated as significantly more alert or aroused when plasma levels of GH and glucose were increasing than when they were decreasing. In contrast plasma cortisol showed small, rhythmic fluctuations over time that did not correlate with booth illumination or degree of behavioral arousal. This latter finding challenges the traditional assumption that cortisol is a sensitive index of behavioral arousal.

The volume and composition of the gastric contents as well as the rates of gastric emptying and secretion were determined simultaneously in conscious chair-adapted monkeys. These determinations were made during fasting and after a liquid meal, thereby allowing studies of the physiologic variables which regulate gastric emptying and gastric secretion. Administration of a water meal is followed by a complex pattern of changes in rates of secretion as well as the fractional rate of emptying. During administration of a 100-ml water meal (pH 7.4), intragastric volume increased while acid concentration decreased; both then returned to fasting values 50 min later. The fractional rate of emptying increased fivefold during administration of the water meal, returned to basal values after 30 min, and then increased again, indicating that gastric emptying cannot be characterized as a simple first-order process with a constant coefficient. The pattern of the change in the rate of water secretion was similar to that for fractional gastric emptying. In contrast, after the meal, gastric acid secretion increased steadily and did not become maximal until 20 min.

Infusion of progressively more acidic fluids into the stomachs of rats stressed by immobilization had disparate effects on gastric erosive disease despite their producing a stepwise fall in venous pH. At the highest concentration infused, disease was exacerbated. However, at lower concentrations, disease was ameliorated. The acidity of the infusate altered the incidence but not the magnitude of the duodenal disease that accompanies stress. When bicarbonate was given parenterally, systemic pH was normalized but gastric disease still developed. Thus the level of mucosal pH does not reliably predict whether or not gastric disease will develop. When a series of progressively more basic fluids was infused into the stomachs of stressed rats, gastric disease was lessened in only those rats infused with the highest concentration of bicarbonate. Increasing the pH of the infusate in a stepwise fashion produced a stepwise diminution of duodenal disease incidence with no effect on duodenal disease severity. When the stressed rat's mucosa was stimulated to secret acid by the parenteral injection of secretagogues, gastric disease severity was the same as in control animals given saline. Although secretagogue infusion did not affect the incidence of stress-induced duodenal disease, it significantly exacerbated the magnitude of the elicited disease. These experiments suggest that luminal acid plays a negligible role in the onset of stress-induced gastric disease but may be important in determining the severity of the gastric disease once it has begun. Conversely the amount of luminal acid correlates with the incidence of stress-induced duodenal disease but does not seem to play a role in determining the severity of the duodenal disease after it has begun.