Artificial feeding synchronizes behavioral, hormonal, metabolic and neural parameters in mother-deprived neonatal rabbit pups

Nursing in the rabbit is under circadian control, and pups have a daily anticipatory behavioral arousal synchronized to this unique event, but it is not known which signal is the main entraining cue. In the present study, we hypothesized that food is the main entraining signal. Using mother-deprived pups, we tested the effects of artificial feeding on the synchronization of locomotor behavior, plasma glucose, corticosterone, c-Fos (FOS) and PERIOD1 (PER1) rhythms in suprachiasmatic, supraoptic, paraventricular and tuberomammillary nuclei. At postnatal day 1, an intragastric tube was placed by gastrostomy. The next day and for the rest of the experiment, pups were fed with a milk formula through the cannula at either 02:00 h or 10:00 h [feeding time = zeitgeber time (ZT)0]. At postnatal days 5-7, pups exhibited behavioral arousal, with a significant increase in locomotor behavior 60 min before feeding. Glucose levels increased after feeding, peaking at ZT4-ZT12 and then declining. Corticosterone levels were highest around the time of feeding, and then decreased to trough concentrations at ZT12-ZT16, increasing again in anticipation of the next feeding bout. In the brain, the suprachiasmatic nucleus had a rhythm of FOS and PER1 that was not significantly affected by the feeding schedule. Conversely, the supraoptic, paraventricular and tuberomammillary nuclei had rhythms of both FOS and PER1 induced by the time of scheduled feeding. We conclude that the nursing rabbit pup is a natural model of food entrainment, as food, in this case milk formula, is a strong synchronizing signal for behavioral, hormonal, metabolic and neural parameters.     

Effect of rikkunshito on gastric sensorimotor function under distention

Background The herbal medicine rikkunshito is effective for the treatment of gastrointestinal symptoms in patients with functional dyspepsia. Although some basic studies on the effects of rikkunshito have been reported in rats, its effects on human gastric function have not yet been clarified. Psychosocial stress induces visceral hypersensitivity and elements of rikkunshito may reasonably affect or suppress this process. We conducted a study to verify the hypothesis that rikkunshito improves stress‐induced gastric hypersensitivity and/or changes in gastric wall tone. Methods Nine healthy volunteers (five males, four females) participated in the study. The counterbalanced regimen consisted of a 2‐week period of oral administration of 7.5 g day^?1 rikkunshito, then a 2‐week period without treatment. Fundic sensorimotor function was examined using a gastric barostat twice on the day after each period. Virtual reality stress was imposed during the measurements of gastric tone and electrocardiogram. Key Results Stress induced a significant increase in heart rate (P = 0.041), gastric volume (P = 0.008), and phasic volume events (P = 0.049) and a decrease in sensory (P = 0.038), discomfort (P = 0.011), and pain (P = 0.041) thresholds of the stomach. Rikkunshito significantly reduced epigastric fullness (P = 0.037) and perceived stress (P = 0.034) following stimulation of the pain threshold, regardless of stress without the drug. Stress reduced gastric volume at the sensory threshold and increased anxiety at the discomfort threshold, and these responses were significantly inhibited by rikkunshito (P = 0.026, P = 0.022, respectively). Conclusions & Inferences These findings suggest that rikkunshito may improve symptoms and impaired gastric accommodation under distention stimuli of the proximal stomach superimposed by stress.     

Involvement of glutamate in gastrointestinal vago-vagal reflexes initiated by gastrointestinal distention in the rat

Vago-vagal reflexes play an integral role in the regulation of gastrointestinal function. Although there have been a number of reports describing the effects of various stimuli on the firing rates of vagal afferent fibers and vagal motor neurons, little is known regarding the neurotransmitters that mediate the vago-vagal reflexes. In the present work, we investigated the role of glutamate in the vago-vagal reflex induced by gastrointestinal distention. Using single-cell recording techniques, we determined the effects of gastric and duodenal distention on the firing rates of gut-related neurons in the dorsal vagal complex, in the absence and presence of glutamate antagonists. Kynurenic acid, a competitive glutamate receptor antagonist, injected into the dorsal vagal complex, blocked the neuronal response of neurons in the dorsal motor nucleus of the vagus and the nucleus of the solitary tract to gastrointestinal distention. Injection of glutamate into the nucleus of the solitary tract produced inhibition of dorsal motor nucleus of the vagus neurons that were also inhibited by gastric and/or duodenal distention. Thus, the distention-induced inhibition of dorsal motor nucleus of the vagus neurons may be mediated by glutamate-induced excitation of gut-related nucleus of the solitary tract neurons. To investigate the role of the various glutamate receptor subtypes in the distention-induced events, we studied the effects of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a selective non-NMDA receptor antagonist, and DL-2-amino-5-phosphonopentanoic acid (DL-AP5), a selective NMDA receptor antagonist. CNQX injected into the dorsal vagal complex either blocked or attenuated the inhibitory response of the neurons in the dorsal motor nucleus of the vagus and nucleus of the solitary tract neurons to gastric and duodenal distention. In contrast, DL-AP5 had less effect, especially in the vago-vagal reflex elicited by gastric distention. The results suggest (1) distention activates vagal afferents in the gastrointestinal tract; (2) the central branches of the vagal afferents from the gut terminate in the nucleus of the solitary tract and release glutamate that mainly act on non-NMDA receptors; (3) glutamate activates the inhibitory neurons in the nucleus of the solitary tract that project to the dorsal motor nucleus of the vagus; and (4) the inhibitory neurotransmitter suppresses the activity of the dorsal motor nucleus of the vagus neurons. For the excitatory neuronal responses of the dorsal motor nucleus of the vagus neurons to gastrointestinal distention, the possible circuit is that the vagal afferents containing glutamate directly activate the receptors on the dendrites of the dorsal motor nucleus of the vagus.     

Vago-sympathetic modulation of gastric mechanoreceptors: Effect of distention and nutritional state

Summary Unit discharge evoked in gastric afferents by tactile stimulation of the frog's stomach was inhibited by electrical stimulation of gastric vagi and facilitated by cervical sympathetic stimulation. The inhibition or the facilitation of the evoked response depended on the mode and parameters of stimulation used. The tactually-evoked activity was also inhibited by gastric distention in well-fed animals (Type-I). This inhibition was released by gastric vagotomy, while cervical sympathectomy had no appreciable effect on the evoked inhibitory response.In Type-II animals (animals kept on chronic food deprivation) the tactually-evoked activity was facilitated, rather than inhibited, by coupling tactile stimulation with gastric distention. This facilitation was abolished by cervical sympathectomy, but was not significantly affected by gastric vagotomy. It appears that the differential modulating control of gastric mechanoreceptor activity is biased by the state of energy balance and is brought about by a dual efferent control system mediated through autonomic nerves, gastric vagal fibers being inhibitory, and cervical sympathetic nerves being facilitatory to the tactile response.This investigation was supported by PL-480 Grant NIH-01-015-1.     

Influence of tegaserod on proximal gastric tone and on the perception of gastric distention in functional dyspepsia

Background Abnormalities in gastric sensorimotor function (hypersensitivity to distention and impaired meal accommodation) have been implicated in the pathophysiology of functional dyspepsia (FD). To study the effect of the 5‐HT₄ agonist tegaserod on sensitivity to gastric distention and gastric accommodation in FD. Methods Thirty FD patients (7 males, mean age 42 ± 2 years) underwent a gastric barostat study on two separate occasions, 2 weeks apart, after 5 days of pretreatment with placebo or tegaserod 6 mg b.i.d. in a double‐blind randomized order. After introduction of the barostat bag, graded isobaric distentions (2 mmHg increments/2 min) were performed to determine gastric compliance and sensitivity to distention. Subsequently, the pressure level was set at intra‐abdominal pressure [minimal distending pressure (MDP)] + 2 mmHg for 90 min, with administration of a liquid meal (200 mL; 300 kcal) after 30 min. Key Results Tegaserod had no influence on MDP (7.9 ± 0.4 vs 7.4 ± 0.4 mmHg) or fasting gastric compliance (44 ± 10 vs 61 ± 6 mL mmHg^?1) and on fasting thresholds for first perception (3.6 ± 0.4 vs 4.2 ± 0.2 mmHg above MDP) or discomfort (9.9 ± 0.7 vs 10.5 ± 0.5 mmHg above MDP). Tegaserod did not alter intra‐balloon volumes before and after the meal [respectively 146 ± 14 vs 120 ± 11 and 297 ± 28 vs 283 ± 29 mL, not significant (NS)], or the amplitude of the meal‐induced gastric relaxation (151 ± 23 vs 162 ± 23 mL, NS). In the subgroup with normal gastric emptying (n = 22), tegaserod significantly enhanced meal‐induced accommodation (126 ± 23 vs 175 ± 29 mL, anova P < 0.001). Conclusions & Inferences Tegaserod does not alter gastric sensorimotor function in FD patients as a group. In the subgroup with normal gastric emptying, tegaserod 6 mg b.i.d enhanced gastric accommodation.     

Artificial autonomic reflexes: using functional electrical stimulation to mimic bladder reflexes after injury or disease

Autonomic reflexes controlling bladder storage (continence) and emptying (micturition) involve spinal and supraspinal nerve pathways, with complex mechanisms coordinating smooth muscle activity of the lower urinary tract with voluntary muscle activity of the external urethral sphincter (EUS). These reflexes can be severely disrupted by various diseases and by neurotrauma, particularly spinal cord injury (SCI). Functional electrical stimulation (FES) refers to a group of techniques that involve application of low levels of electrical current to artificially induce or modify nerve activation or muscle contraction, in order to restore function, improve health or rectify physiological dysfunction. Various types of FES have been developed specifically for improving bladder function and while successful for many urological patients, still require substantial refinement for use after spinal cord injury. Improved knowledge of the neural circuitry and physiology of human bladder reflexes, and the mechanisms by which various types of FES alter spinal outflow, is urgently required. Following spinal cord injury, physical and chemical changes occur within peripheral, spinal and supraspinal components of bladder reflex circuitry. Better understanding of this plasticity may determine the most suitable methods of FES at particular times after injury, or may lead to new FES approaches that exploit this remodeling or perhaps even influence the plasticity. Advances in studies of the neuroanatomy, neurophysiology and plasticity of lumbosacral nerve circuits will provide many further opportunities to improve FES approaches, and will provide "artificial autonomic reflexes" that much more closely resemble the original, healthy neuronal regulatory mechanisms.     

Gastric electrical stimulation reduces visceral sensitivity to gastric distention in healthy canines

The aim of this study was to investigate the effects and mechanisms of gastric electrical stimulation (GES) on proximal stomach distention-induced visceral sensitivity. Isobaric gastric distention was performed using a barostat system in 8 normal and 6 vagotomized dogs and animal behaviors were noted and graded. The normal dogs were studied in 4 sessions: control (no GES), short pulse GES, long pulse GES, and dual-pulse GES, and the vagotomized dogs were studied in three sessions: control (no GES), long pulse GES and guanethidine. It was found that: 1) proximal stomach distention-induced behavioral changes were mediated by vagal and sympathetic pathways. The total behavior score (TBS) was 40.6 ± 7.4 in the controls, 15.3 ± 8.9 in vagotomized dogs (P=0.006 vs. control) and 8.8 ± 0.9 in the vagotomized dogs with guanethidine (P=0.04 vs. vagotomy). The behavioral changes were mediated via the vagal pathway at distention pressures below 20 mmHg, but mediated via both the vagal and sympathetic pathways at distention pressures equal to and above 20 mmHg. 2) GES with long pulses or dual pulses but not short pulses reduced the distention-induced behavioral score (P=0.003, P=0.006 and P=0.7, respectively) and the effects of GES of long pulses might be mediated via the vagal and sympathetic pathways. In conclusion, gastric distention-induced visceral sensitivity is mediated via the vagal pathway at low distention pressures but via both vagal and sympathetic pathways at high distention pressures. GES with long but not short pulses reduces distention-induced visceral sensitivity.     

Long-lasting modification of reflexes after neonatal nerve injury in the rat

The reflex activity of motoneurones to the extensor digitorum longus (EDL) muscle following sciatic nerve crush during the first 5 days after birth (neonatal crush) or in the adult (adult crush) was studied 3-6 months later, when the axons had reinnervated their target muscles. Electromyograms (EMG) and muscle tension were recorded from the EDL muscle (a physiological flexor) on the injured and uninjured sides. Reflex responses were evoked by stimulation of the common peroneal (CP), the tibial (T) and the sural (S) nerves, ipsilateral and contralateral to the side of injury. In animals which had sustained a neonatal crush, stimulation of branches of the injured sciatic nerve elicited ipsilateral reflex responses that were about 3 times larger than those recorded from the uninjured side or in normal animals. Stimulation of the CP nerve on the uninjured side invariably elicited a contralateral reflex response from the reinnervated muscles, while stimulation of the CP nerve on the injured side either failed to produce a response or produced a very weak reflex response from the control muscles. Reflexes recorded from the reinnervated muscles by stimulation of the tibial and sural branches of the uninjured sciatic nerve were 3-7 times greater than those recorded from the uninjured side or in normal animals. The reflex responses obtained from reinnervated muscles of animals with nerve injury in adulthood were similar to those obtained from control, unoperated adult rats. These results indicate that sciatic nerve injury during a critical development period leads to a permanent enhancement of reflex responses from reinnervated fast flexor muscles not seen after similar injury in adults.     

Neurological reflexes and early motor behavior in rats subjected to neonatal hypoxic-ischemic injury

Severe perinatal hypoxia-ischemia is an important cause of brain injury in both full-term and premature newborns, with a high risk of future behavioral and neurological deficits. The most commonly used animal model of neonatal hypoxia-ischemia is the unilateral ligation of the common carotid artery followed by exposure to hypoxia in 7-day-old rats. In spite of the wide use of this model, lot of contradictions and discrepancies exist between the results obtained by different laboratories regarding behavioral deficits and there are no data regarding the possible delay of the appearance of neurological reflexes and the time-course of reflex performances following neonatal hypoxic-ischemic injury in rats. In the present study we showed that neonatal hypoxia-ischemia retarded the development of somatic growth and several neurological reflexes (ear twitch, grasping, gait and negative geotaxis). Hypoxic animals also displayed retarded performance in righting, geotaxis and gait reflexes. Although hypoxic pups performed worse in most tests for motor coordination, they reached normal levels by 5 weeks of age except in the footfault test. In the open-field, hypoxic animals were generally more active, except at 3 weeks, when activity of normal pups increased enormously as well. Brain areas were significantly reduced in hypoxic animals, but no close correlation was found with behavioral deficits.     

Gastrointestinal factors in hunger and satiety

The evidence for the participation of signals from the gastrointestinal tract in hunger and satiety is reviewed. Various methods of subjecting only certain portions of the gastrointestinal tract to food are described including sham feeding, crossing of the intestines of two animals, and intragastric, intraduodenal and intravenous feeding. These methods have revealed that animals eat more when only the mouth is exposed to food, but consume less when food enters the stomach directly and still less when feeding themselves intravenously. The role of the stomach in satiety is discussed in relation to the results of the many experiments in which intragastric loads were administered. These experiments generally revealed that gastric loads suppressed intake in proportion to their caloric value, but that compensation was not precise. A similar analysis is made of the role of the intestines in satiety. These studies present evidence for osmoreceptors and glucoreceptors, distention, and pressure, all of which may participate in satiety. The numerous effects of vagotomy on food intake are reviewed and an attempt is made to separate afferent from efferent effects and vagal effects from nonspecific surgical injury. The role of other afferents is explored. A brief survey of the most recent studies on humoral factors indicates that cholecystokinin is probably acting as a satiety agent, but its mode of action remains unknown. The changes in the gastrointestinal tract that accompany an increase or decrease in food intake reveal adaptive changes that occur in the organ. The evidence for gastrointestinal factors in satiety of the suckling animal is presented. Finally, a hypothesis is presented in which the various factors that bring a meal to an end are included. Preabsorptive satiety may consist of multiple factors which probably include signals from osmoreceptors and possibly other chemoreceptors in the upper small intestine. The signals from these receptors are neural while other products of digestion stimulate the release of humoral agents, such as cholecystokinin, which may act locally, in the liver, or on the central nervous system. Stretch or distention of the intestines at various locations may also contribute to preabsorptive satiety.     

The clinical use of brainstem reflexes and hand-muscle reflexes.

Brainstem reflexes and hand-muscle reflexes can be elicited and recorded with routine EMG equipment. Not all these reflexes are useful in clinical neurology. But those that are - the subject of this review - exhibit distinct patterns of abnormality that have clinical diagnostic and localizing value in various diseases, including cranial neuropathies, focal lesions within the cervical cord, brainstem, and brain, movement disorders, and pain.     

Lateralized hunger: Ipsilateral attenuation of cortical spreading depression-induced feeding after unilateral 6-OHDA injection into the substantia nigra

Unilateral injections of 6-hydroxydopamine into the substantia nigra in the rat significantly attenuated cortical spreading depression (CSD)-induced eating from the hemisphere ipsilateral but not contralateral to the lesion. The lateralized decrease in elicited feeding was correlated with postlesion body weight loss, striatal catecholamine depletion (dopamine, 94%; norepinephrine, 52%) and amphetamine-induced ipsilateral turning, and can be characterized as an inability of the lesioned nigrostriatal system to maintain the CSD-elicited response rather than a failure to induce it. The interhemispheric control procedure allows us to exclude various general sensory and motor deficits to account for the decrement of feeding, and to attribute the feeding deficit to a reduced nigrostriatal transmission. It is suggested that CSD-induced feeding is due to an activation of integrative sensorimotor systems (especially the nigrostriatal dopamine system), rather than to homeostatic imbalances.     

Tolerability of bolus versus continuous gastric feeding in brain-injured patients

Brain injured patients may exhibit altered gastric emptying; thus, some believe post-pyloric feeding to be tolerated better than gastric feeding. Reliable post-pylorus access can be difficult to obtain, so gastric feeding remains the preferred route for administering nutrition. Feeding intolerance may be associated with increased complications and costs. We sought to compare bolus (B) versus continuous (C) gastric feeding in brain injured patients. This retrospective cohort study was carried out at a neurological/neurosurgical intensive care unit at a Level 1 trauma and tertiary referral center. Our subjects were 152 consecutive patients over two years. Use of B or C feedings was based on clinicians' preferences. Abdominal examination and gastric residuals (> 75 mL over four hours) defined feeding intolerance (FI). Putative risks for FI were compared between the groups. Demographic characteristics were similar between groups B (n = 86) and C (n = 66). Feeding intolerance occurred more often in group B than in group C (60.5% vs. 37.9%, p = 0.009). Group C patients achieved 75% of nutritional goals faster than group B patients (median 3.3 vs. 4.6 days; p = 0.03). Prokinetic agent use was similar between the groups and did not reduce the time to achieve nutritional goals. There was a trend towards a reduction in the incidence of infections in group C (p = 0.05). Independent predictors of FI included: sucralfate (OR 2.3), propofol (OR 2.1), pentobarbital (OR 3.9) or paralytic (OR 3) use; older age (OR 5); days receiving mechanical ventilation (OR 1.2); and admission diagnosis of either intracerebral hemorrhage (OR 2.2) or ischemic stroke (OR 1.9). Continuous gastric feeding is better tolerated than B feedings in patients with acute brain injuries. Use of prokinetic agents did not affect time to achievement of nutritional goals. Use of common medications including sucralfate and propofol were associated with FI.     

Development of gastric slow waves and effects of feeding in pre-term and full-term infants

The aims of this study were to investigate the difference in developmental process of gastric slow waves and the effects of feeding in pre-term and full-term infants. Twenty-six pre-term and 31 full-term infants were enrolled in the study. Gastric myoelectrical activity was recorded using electrogastrography (EGG) from birth to month 6. An increase in the % of 2-4 cpm slow waves was noted in both pre-term (P < 0.01) and full-term infants (P < 0.04) from birth to month 4. The pre-term infants showed a reduced dominant EGG power at certain points of the study. (3) Breast or formula feeding resulted in no difference in the EGG in the full-term infants and showed a difference in the postprandial dominant power of the EGG in the pre-term infants only at month 2 after birth (P < 0.05) but not at other times. The gastric slow wave in pre-term infants is of a significantly reduced amplitude but similar rhythmicity. The method of feeding has no effects on the EGG in full-term infants and minimal effects (may be of non-clinical significance) on the EGG in pre-term infants as the difference was noted only at one time point during the 6-month follow-up study.