Experimental Helicobacter pylori infection of rhesus macaques (Macaca mulatta)

The aim of the present study was to establish an animal model for Helicobacter pylori (H. pylori) infection at the German Primate Centre in rhesus monkeys (Macaca mulatta). During the experiments the susceptibility of three animals to different H. pylori strains of human origin was tested. In a follow-up study gastric biopsies from three different sites were investigated in regular intervals using microbiological, histological, electron microscopical and molecular biological methods to evaluate the presence of bacterial colonization and the occurrence of gastritis. It was possible to establish a persistent experimental infection. The rather long follow-up period of 18 months offered the possibility to demonstrate a permanent H. pylori infection in the gastric mucosa of the test animals. The three animals have now been successfully colonized with H. pylori for 18 months and presented a chronic active gastritis confirmed by microbiological and histological methods. By molecular typing, the identity of the isolates recovered from the animals was shown. It was possible to demonstrate that one infection strain outcompeted the second one. Taken together, prerequisites exist for making use of an attractive and useful animal model in rhesus monkeys especially for long term observations.     

Immunization with recombinant Helicobacter pylori urease in specific-pathogen-free rhesus monkeys (Macaca mulatta)

Immunization with urease can protect mice from challenge with Helicobacter pylori, though results vary depending on the particular vaccine, challenge strain, and method of evaluation. Unlike mice, rhesus monkeys are naturally colonized with H. pylori and so may provide a better estimate of vaccine efficacy in humans. The purpose of this study was to examine the effectiveness of H. pylori urease as a vaccine in specific-pathogen (H. pylori)-free rhesus monkeys. Monkeys raised from birth and documented to be free of H. pylori were vaccinated with orogastric (n = 4) or intramuscular (n = 5) urease. Two control monkeys were sham vaccinated. All monkeys were challenged with a rhesus monkey-derived strain of H. pylori, and the effects of vaccination were evaluated by use of quantitative cultures of gastric tissue, histology, and measurement of serum immunoglobulin G (IgG) and salivary IgA. Despite a humoral immune response, all monkeys were infected after H. pylori challenge, and there were no differences in the density of colonization. Immunization with urease therefore does not fully protect against challenge with H. pylori. An effective vaccine to prevent H. pylori infection will require different or more likely additional antigens, as well as improvements in the stimulation of the host immune response.     

Determination of the infectious dose of Helicobacter pylori during primary and secondary infection in rhesus monkeys (Macaca mulatta)

We sought to determine the infectious dose of Helicobacter pylori during primary and secondary infection in the rhesus monkey and to determine whether preinoculation acid suppression is necessary to produce colonization. Mixed inoculation with three human-derived strains showed that H. pylori J166 is particularly adapted to colonization of rhesus monkeys, since it outcompeted two other strains. The minimum infectious dose of H. pylori J166 was 10(4) bacteria in specific-pathogen (H. pylori)-free monkeys. Rechallenge of these monkeys after antibiotic therapy was characterized by a 10- to 100-fold decrease in bacterial load compared to primary infection, but with little change in the infectious dose. Acid suppression prior to inoculation was not necessary for colonization to occur. These results provide a basis for future animal experiments using more ecologically relevant conditions of inoculation and suggest that reduction in bacterial load rather than complete protection may be a more realistic goal for H. pylori vaccination.     

Selection for urease activity during Helicobacter pylori infection of rhesus macaques (Macaca mulatta)

Helicobacter pylori strain J166 recovered from experimentally inoculated rhesus monkeys had up to a 250-fold-increased urease activity over that before inoculation. This was found to result from the selection of urease positive J166 clones from a heterogeneous inoculum, which was predominantly urease negative due to a 1-bp insertion in the ureA gene. These results confirm the importance of urease for H. pylori colonization. Strain J166 is particularly well adapted to the rhesus monkey, since it colonized preferentially despite the fact that less than 0.1% of the inoculum was urease positive.     

Captive rhesus monkeys (Macaca mulatta) are commonly infected with Helicobacter cinaedi

Helicobacter cinaedi may cause proctocolitis or bacteremia in homosexual men infected with human immunodeficiency virus or occasionally in other immunocompromised hosts. There are scattered reports of H. cinaedi isolated from a variety of animal hosts, but to date only hamsters have been found to be a common natural reservoir. Microaerophillic cultures of feces from 5 of 16 asymptomatic rhesus monkeys (Macaca mulatta) (31%) were positive for a curved gram-negative rod. A polyphasic taxonomic approach was used to identify the organism as H. cinaedi. These results show that H. cinaedi frequently colonizes asymptomatic captive rhesus monkeys, which may serve as another potential reservoir for human infection.     

Alzheimer's Abeta vaccination of rhesus monkeys (Macaca mulatta)

Recent preliminary data suggest that vaccination with Alzheimer's Abeta might reduce senile plaque load and stabilize cognitive decline in human Alzheimer's disease. To examine the mechanisms and consequences of anti-Abeta-antibody formation in a species more closely related to humans, rhesus monkeys (Macaca mulatta) were vaccinated with aggregated Abeta(1-42). Immunized monkeys developed anti-Abeta titers exceeding 1:1000, and their plasma Abeta levels were 5-10-fold higher than the plasma Abeta levels observed in monkeys vaccinated with aggregated amylin. These data support the use of non-human primates to model certain phenomena associated with vaccination of humans with aggregated Alzheimer's Abeta.     

Coronary arterial ectasia, a predominant type of coronary sclerosis in aged captive rhesus monkeys (Macaca mulatta).

In hearts from aged rhesus monkeys, ranging from 20 to over 30 years, marked coronary arterial ectasia, dilatation, and tortuosity of the entire vessel were observed in 18 animals. Another 7 animals showed a moderate degree of ectatic changes. Dilated arteries showed remarkable thinness of the tunica media with atrophy and attenuation of the muscle cells and increased fibrous tissue. Diffuse or focal intimal fibrous thickening was present in the ectatic arterial wall, but cholesterol deposit, calcification, or the presence of lipid-laden foam cells in the intimal and medial wall was not observed. A focal degeneration and fibrosis of the myocardium were seen in the hearts of 11 cases. Clinically, 2 cases had either spontaneous diabetes mellitus or cardiac decompensation with mitral insufficiency, but the others had no abnormal metabolic or cardiovascular histories. Coronary arterial ectasia accompanied with medial fibrosis appears to be a predominant type of coronary arterial lesion in aged rhesus monkeys under long-term captivity.     

Effects of selective neonatal temporal lobe lesions on socioemotional behavior in infant rhesus monkeys (Macaca mulatta).

Normal infant monkeys and infant monkeys with neonatal damage to either the medial temporal lobe or the inferior temporal visual area were assessed in dyadic social interactions at 2 and 6 months of age. Unlike the normal infant monkeys, which developed strong affiliative bonds and little or no behavioral disturbances, the lesioned monkeys (each of which was observed with an unoperated control) exhibited socioemotional abnormalities and aberrant behaviors. The socioemotional changes predominated at 6 months of age and were particularly severe in monkeys with medial temporal lesions. In both the pattern and time course, the socioemotional deficits produced by the neonatal medial temporal lesions bear a striking resemblance to the behavioral syndrome in children with autism. Further analysis of these lesion-induced abnormalities in nonhuman primates may therefore provide insight into this debilitating human developmental disorder.     

Preferences of female rhesus monkeys (Macaca mulatta) for infantile coloration

While developmental researchers have long noted that infants of many mammalian species, including primates, have characteristic physical features, such as a distinctive coat or skin color, and some authors have further suggested that these features serve to elicit caretaking and solicitous behavior, few systematic investigations of the actual salience of such features for adult conspecifics have been carried out to date. The present series of 3 studies sought to determine whether natal coat and/or facial skin coloration might provide desirable visual stimulation for rhesus monkey adult females. In these studies the faces and/or fur of 6-month-old rhesus monkeys were dyed to simulate the normal coloration of rhesus monkey neonates. Adult females varying in parity and rearing history were then tested for their relative preference between these infantile-colored 6-month-olds and both normally colored 6-month-olds and other differentially colored control stimulus monkeys. Results indicated that regardless of parity or rearing history the adult female subjects exhibited consistent preferences for the stimulus animals with neonatal-like reddish-pink facial skin coloration.     

Tubuloreticular structures in rectal biopsies of SIV-infected rhesus monkeys (Macaca mulatta)

Tubuloreticular structures (TRS) are considered to be a specific ultrastructural marker for AIDS in various organs. Experimental SIV infection in rhesus macaques is the most appropriate animal model of HIV infection. In 8 rhesus monkeys, experimentally infected with SIVmac251/MPBC, rectum biopsies were taken prior to and post infection (day 3; 1, 2, 4, 12 weeks p.i.) and were investigated by transmissionelectron microscopy to determine incidence and extent of tubuloreticular structures as well as affected cells. From the first week p.i. on TRS were found in all experimental animals as tubuli with a diameter of 20-30 nm. The tubuli were arranged in regular paracristalline formations and formed intracytoplasmatic heterogenous, polymorph accumulations, which were localized close to the endoplasmatic reticulum. In the rectal lamina propria macrophages, endothelial cells, plasma cells, lymphocytes, fibroblasts, and neutrophilic granulocytes were the affected cell types. In 5 control biopsies TRS were detected, too, but, in contrast to SIV-infected animals, they appeared only singular and very small. The results indicate that TRS are a characteristic morphologic criteria of intestinal SIV infection. They appear in very early stages of the infection. In the rectum, they can be detected as bigger, conspicuous, and abundant formations in several cells and have a restricted diagnostic and prognostic validity.     

Maternal cradling and infant nipple preferences in rhesus monkeys (Macaca mulatta)

This study investigated lateral biases in nipple preferences, maternal cradling, carrying, and retrieval in 41 rhesus macaque (Macaca mulatta) mother–infant dyads living in two captive social groups. Observations were made during the first 6 weeks of infant life using a combination of scan sampling and ad-libitum sampling techniques. Infants exhibited a significant left-nipple preference in the first weeks of life but the bias decreased with infant age. Mothers showed a left-arm bias in carrying their infants but no significant lateral bias in cradling or retrieval. Our results suggest that the left-side cradling bias reported in studies of humans and some other primates reflects a bias in the infant's nipple preference rather than in maternal behavior. The infants' preference for the left nipple is consistent with both Salk's (1960) heartbeat hypothesis and with more recent hypotheses linking this lateral bias with brain asymmetry and hemispheric specialization for mother–infant communication. © 1998 John Wiley & Sons, Inc. Dev Psychobiol 32: 305–312, 1998     

Rearing environment and hypothalamic-pituitary-adrenal regulation in young rhesus monkeys (Macaca mulatta)

A mammal's early social environment has important regulatory effects on its behavior and physiology, and this is especially true for regulation of the hypothalamic-pituitary-adrenal (HPA) system. The present study was designed to test hypotheses that various aspects of the social environment are important influences on HPA regulation. Seven hundred seventy eight, 3- to 4-month-old rhesus monkeys were studied as part of a standardized, 24-hr biobehavioral assessment program, which included blood sampling to determine plasma cortisol concentrations. Results indicate that nursery-rearing results in a reduced cortisol set-point for the HPA system, and, for nursery-reared (NR) animals, more peer exposure during infancy is associated with a higher set-point. Age and sex differences during this period were evident but small in magnitude. These data demonstrate the important regulatory role of the social environment on nonhuman primate physiology and suggest caution in assuming that differences between individuals' cortisol levels reflect only differences in perceptions of the "stressfulness" of events.     

Associative processes in differentially reared rhesus monkeys (Macaca mulatta): blocking

Nine isolate and 6 socially reared adult rhesus monkeys were examined in a standard blocking procedure. A tone was paired with a startle stimulus (US) during Phase 1. A tone-light compound CS was paired with a US during Phase 2. In Phase 3, the light was presented alone to test for blocking. Results showed that learning about the light was blocked in social controls, but not in isolates. These data suggest isolates processed information atypically, in that they developed an association to a redundant cue. A second group of isolates (n = 3) underwent the identical procedures. However, conditioned reactions to the tone were extinguished before testing. Test responding was significantly reduced in this group, that is, blocking was obtained. These data suggest the within-compound association developed during Phase 2 mediated the isolate blocking deficit. Together, these findings imply long-term intellectual consequences of early social impoverishment. Such deficits may be mediated by alterations in central dopamine systems.     

The effects of bilateral lesions of the amygdala on dyadic social interactions in rhesus monkeys (Macaca mulatta).

The role of the amygdala in dyadic social interactions of adult rhesus monkeys (Macaca mulatta) was assessed after bilateral ibotenic acid lesions. Social, nonsocial, and spatial behaviors of amygdalectomized and control monkeys were assessed in 3 dyadic experiments: constrained, unconstrained, and round robin. Lesions produced extensive bilateral damage to the amygdala. Across all experiments, the amygdalectomized monkeys demonstrated increased social affiliation, decreased anxiety, and increased confidence compared with control monkeys, particularly during early encounters. Normal subjects also demonstrated increased social affiliation toward the amygdalectomized subjects. These results indicate that amygdala lesions in adult monkeys lead to a decrease in the species-normal reluctance to immediately engage a novel conspecific in social behavior. The altered behavior of the amygdalectomized monkeys may have induced the increased social interactions from their normal companions. This is contrary to the idea that amygdalectomy produces a decrease in social interaction and increased aggression from conspecifics.     

Influence of maternal proximity on behavioral and physiological responses to separation in infant rhesus monkeys (Macaca mulatta).

The effects of maternal proximity on the behavioral and physiological responses of infant rhesus macaques during 4 days of total or adjacent separations from the mother were studied. The 6 infants tested showed behavioral responses that differentiated the two separation conditions. Major differences were found in the quantity and quality of vocalizations, the occurrence of cage-biting and cage-shaking behavior, object exploration, and hunched and freezing postures. In particular, the structure of coo vocalizations clearly discriminated between the presence or the absence of the mother during separation. Cerebrospinal fluid (CSF) concentrations of dopamine and serotonin metabolites did not discriminate between the two separation conditions but showed a transient elevation at 24 hr after separation and were not different from baseline by 96 hr after separation. In contrast, both the plasma cortisol and the CSF norepinephrine metabolite responses tended to be greater and to persist for a longer period of time when infants were totally isolated. The results are discussed within the context of attachment and coping theories.     

Trajectory-selective neuronal activity in the motor cortex of rhesus monkeys (Macaca mulatta)

Neuronal activity recorded in the primate motor cortex reflected movement parameters in addition to the distance and direction of a target. These neurons may reflect the selection, from memory, of a detailed movement trajectory to be executed in response to visuospatial instructions.     

Decrease in nasal temperature of rhesus monkeys (Macaca mulatta) in negative emotional state

We established an infrared thermographic system for the detection of emotion-related temperature changes in rhesus monkeys (Macaca mulatta). We continuously measured temperatures of various facial regions of four rhesus monkeys during the presentation of a potentially 'threatening' person, i.e., a person in a laboratory coat with a catching net, who entered the experimental room and approached the monkeys. The temperatures were also measured before and after the presentation of the 'stimulation period.' The temperature of the nasal region decreased significantly within 10-30 s, and continued to decrease throughout the stimulation period. During this period, the monkeys frequently expressed silent bared-teeth face, staring open-mouth face, and lip-smacking, all of which were expressions of a negative emotion. Assuming that the monkeys experience the negative emotion when viewing the potentially threatening stimulus, we conclude that the decrease in nasal skin temperature is relevant to the alteration of the emotional state. The present findings suggest that nasal temperature can be a reliable and accurate indicator of a change from neutral to negative in emotional state of non-human primates.