Hematology and serum chemistry values of sooty mangabeys (Cercocebus atys): comparison with rhesus monkeys.

BACKGROUND: The sooty mangabey is a vulnerable West African species that naturally harbors simian immunodeficiency virus (SIV) without pathological symptoms. We present normative hematology and serum chemistry values for this species. METHODS: Hematology analytes from 136 females and 96 males and serum chemistry analytes from 57 females and 26 males were studied. RESULTS: Values of several analytes fell outside published reference ranges in the rhesus monkey, a laboratory standard for Old World primates. Erythrocyte-related parameters were higher in mangabeys than in rhesus monkeys, while platelet counts were lower. Mangabeys also had higher gamma-glutamyltransferase levels and lower urea nitrogen levels. Males had higher erythrocyte-associated values than females. Albumin, globulin, albumin/globulin ratio, calcium, and creatinine changed with age in patterns similar to those reported for the rhesus monkey. CONCLUSIONS: The unique blood profile of the mangabey should be taken into account in clinical and experimental studies of this species.

Neutralizing antibody-independent containment of immunodeficiency virus challenges by DNA priming and recombinant pox virus booster immunizations.

Eight different protocols were compared for their ability to raise protection against immunodeficiency virus challenges in rhesus macaques. The most promising containment of challenge infections was achieved by intradermal DNA priming followed by recombinant fowl pox virus booster immunizations. This containment did not require neutralizing antibody and was active for a series of challenges ending with a highly virulent virus with a primary isolate envelope heterologous to the immunizing strain.

Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine.

Heterologous prime/boost regimens have the potential for raising high levels of immune responses. Here we report that DNA priming followed by a recombinant modified vaccinia Ankara (rMVA) booster controlled a highly pathogenic immunodeficiency virus challenge in a rhesus macaque model. Both the DNA and rMVA components of the vaccine expressed multiple immunodeficiency virus proteins. Two DNA inoculations at 0 and 8 weeks and a single rMVA booster at 24 weeks effectively controlled an intrarectal challenge administered 7 months after the booster. These findings provide hope that a relatively simple multiprotein DNA/MVA vaccine can help to control the acquired immune deficiency syndrome epidemic.

Neuronal population of area 4 during the life span of the rhesus monkey.

One right or left area 4 of each of 19 rhesus monkeys, ranging in age from 1 day to 35 years, was processed (frozen sectioned at 30 or 40 microns) for light microscopic analysis to assess age-related changes in the neuronal population. All neurons were examined regardless of their size. In addition, Betz cells were analyzed separately; to be regarded as Betz cells, pyramidal somata had to display a minimum height of 38 microns. A significant loss of approximately one-third was observed in the total number of neurons in maturing monkeys (less than 5.5 years). In contrast, in maturing rhesus monkeys significant increases with age were observed in the mean number of Betz cells, and in the means of Betz cell area, height, width, perimeter, and estimated volume. In adult monkeys (greater than 4.5 years), no age-associated loss of neurons was observed. Also, no loss of Betz cells occurred, although the perimeter, area, and estimated volume of Betz cells decreased slightly, but significantly, with increasing age in adult monkeys. Lipofuscin granules were discernable in Betz cells beginning at the age of 5 years and their number increased with increasing age. In the older rhesus monkeys, the lipofuscin granules were so large and numerous that in some Betz cell somata they displaced the nucleus from its usual location in the center of the cell. No age-related change in thickness of area 4 was found.

Brain weight does not decrease with age in adult rhesus monkeys.

Cross-sectional studies on adult human autopsy material have shown that younger cohorts have heavier brains than older groups. We sought to determine whether a similar pattern is present in the rhesus monkey, a species that serves as a useful model of human brain and cognitive aging. Data were obtained from necropsies of 399 rhesus monkeys (180 females; 219 males), of ages covering the entire adult lifespan of this species. In addition to fresh brain weight, variables considered were age, sex, body weight, heart weight, identity of the prosector, and circumstance of death. Initial bivariate analyses revealed a significant sex difference in brain weight (mean for males: 96.1 g; for females: 86.1 g; p < 0.001), as well as significant correlations of brain weight with body weight (r = 0.20, p < 0.01 for females; r = 0.27, p < 0.001 for males), and heart weight (r = 0.27, p < 0.001 for females; r = 0.38, p < 0.001 for males). Identity of prosector, circumstance of death, and age were not significantly related to brain weight in bivariate analyses. Multiple linear regression, controlling for possible confounding effects of body weight and sex, also suggested that brain weight is stable throughout adulthood in the rhesus monkey.

Recognition memory span in rhesus monkeys of advanced age.

Assessment of recognition memory was performed on eight rhesus monkeys of advanced age (25 to 27 years of age) using the delayed recognition span test (DRST). Their performance was compared to that of five young adult animals (5 to 7 years of age) on two stimulus conditions of the DRST: spatial position and color. Both trial unique and repeating series were used for each of the two conditions. As a group, aged monkeys were impaired on both the spatial and color conditions of the DRST, achieving about two-thirds of the span of the young adult group in each condition. Error analyses revealed that monkeys in the aged group also produced more perseverative responses (i.e., displacing the previously correct disk) than did young adults. Together the findings suggest that monkeys of advanced age are impaired on tasks with memory loading demand characteristics.

Executive system dysfunction in the aged monkey: spatial and object reversal learning.

As part of the effort to characterize age-related cognitive changes in executive system function in a nonhuman primate model of human aging, the performance of seven rhesus monkeys, 20 to 28 years of age, was compared to that of five young adult monkeys, 6 to 11 years of age, on spatial and object reversal tasks. No differences in performance were found between the two groups in the initial learning of either task. On spatial reversals, aged monkeys were impaired relative to young adults, but there was no difference in overall performance between the groups on object reversals. Central to this article, a perseverative tendency was noted in the aged group on both spatial and object reversal tasks. Changes in executive system dysfunction may represent an important aspect of age-related cognitive decline.

Brain weight throughout the life span of the chimpanzee.

Studies on human postmortem material report lower brain weights in older than in younger cohorts, whereas there is no apparent change with age in the rhesus monkey. In view of these contrasting results, we examined the pattern of brain weight across the life span in the chimpanzee, one of the closest biological relatives of humans. To place the study in context of the empirical life expectancy of the chimpanzee, we first performed a survival analysis on data from 275 chimpanzees that were maintained in the colony of the Yerkes Primate Center. The survival analysis revealed the maximum life spans of female and male chimpanzees to be about 59 and 45 years, respectively. We examined fresh brain weights from 76 chimpanzees ranging in age from birth to 59.4 years of age. The brains were taken from 9 infants (birth to 1 year of age), 25 juveniles (1-7 years), 13 adolescents (7-15 years), 21 young adults (15-30 years), and 8 old adults (over 30 years). Adult brain weight was achieved by the age of 7 years. The adolescent and young adult chimpanzees had the largest brain weights; in these two age groups combined, the mean brain weight (+/- standard deviation) was 368.1 g (+/-37.3) for females (n = 17) and 405.6 g (+/-39.4) for males (n = 17). This sex difference was statistically significant (P < 0.01). Simple linear regression performed on the combined material from females and males aged 7 years and older revealed a decline in brain weight with advancing age of 1.1 g/year (P < 0.05). When the effect of sex on brain weight was statistically controlled for, the loss of brain weight with age was 0.9 g/year (P = 0.07). These results suggest that brain weight declines moderately with age in the chimpanzee as it does in humans.

Estradiol selectively affects processing of conspecifics' faces in female rhesus monkeys.

Estrogen deficiency following ovariectomy or menopause increases the risk of developing diseases such as osteoporosis and may also lead to memory impairment. Although estrogen replacement therapy (ERT) alleviates many symptoms associated with estrogen loss, it is not clear whether it also benefits cognitive function. The effect of estrogens upon cognition can best be studied in an animal model of human menopause, in which estrogen levels can be experimentally manipulated. Six young ovariectomized female rhesus monkeys (6-9 years old) were tested on a battery of touchscreen-based cognitive tasks, including the Matching-to-Sample (MTS) task with mixed delays and the spatial, object, and face conditions of the Delayed Recognition Span Test (DRST). Monkeys were tested 5 days a week, one task per week, for a total of 8 months, while undergoing treatments with placebo and ethinyl estradiol (EE2) in alternating 28-days blocks. Blood samples were collected to verify EE2 levels. We also observed the monkeys by video monitor during test sessions and recorded locomotor activity and response topology. Performance on the face-DRST, a task that involved selecting the new face in an increasing array of rhesus monkey faces, was impaired by EE2 treatment, as compared to placebo. Other tasks were unaffected by EE2. There was no clear evidence of EE2 effects upon motor activity or anxiety. In order to test the reliability of our findings, we conducted an additional experiment in which the monkeys were again given the face-DRST with different categories of face stimuli for 4 months, while receiving placebo and EE2 in alternating 7-days blocks. They performed each task 4-5 days/week for 4 weeks with (1) the same rhesus monkey faces as in the first experiment, (2) human faces, (3) chimpanzee faces, and (4) novel rhesus monkey faces. Face-DRST performance did not vary as a function of treatment when human or chimpanzee faces were used as stimuli. In contrast, periods of EE2 treatment were associated with a lower performance for both sets of rhesus monkey faces. These findings suggest that EE2 treatment has a detrimental effect on processing faces of conspecifics by female rhesus monkeys. We speculate that estrogens may produce this effect by enhancing emotional reactivity to socially relevant stimuli.

Fluctuations in spatial recognition memory across the menstrual cycle in female rhesus monkeys.

Findings are inconsistent regarding whether women's cognitive performance fluctuates across phases of the menstrual cycle, but differences in methodology and the use of reported cycle phase rather than precise hormonal measures may underlie these disparities. Studies in monkeys may help resolve these discrepant findings, since hormonal status can be reliably determined. We tested four young (5-7 years old) female rhesus monkeys daily during one entire menstrual cycle on three cognitive tasks displayed on a computerized touch-screen system: a Matching to Sample task with a 30 s delay (MTS-30s), a Matching to Sample task without delay (MTS-no delay) and the spatial condition of the Delayed Recognition Span Test (spatial-DRST). Blood samples were collected at specific time intervals throughout the cycle and assayed for estradiol and progesterone in order to identify hormonal status. There was a nonsignificant trend for the MTS-30s scores to be better during the follicular and luteal phases, when estradiol levels were low, than during the peri-ovulatory phase, when estradiol levels were at their highest. MTS-no delay performance did not vary as a function of hormonal status. Spatial-DRST scores were significantly better during the follicular and luteal phases than during the peri-ovulatory phase of the cycle. These data in the female rhesus monkey support the hypothesis that spatial memory performance is sensitive to estradiol variations across the menstrual cycle, with better performance associated with low estradiol levels.

Chronic medical conditions and risk of fall injury events at home in older adults.

OBJECTIVE: To evaluate the association between selected chronic medical conditions (CMCs) and fall injury events at home among community-dwelling older persons. DESIGN: Population-based case-control study. SETTING: The general community. PARTICIPANTS: Persons aged 65 and older living at home, excluding those using a wheelchair; 467 cases and 691 control subjects were studied. MEASUREMENTS: The main independent variables were self-reported histories of 10 CMCs: diabetes, high blood pressure, anemia, heart attack, Parkinson's disease, stroke, emphysema, cancer (other than skin), cataracts, and glaucoma. RESULTS: The final multivariate model included variables for age, sex, body mass, dependency in activities of daily living, current exercise (three or more times per week), mental status scores, and three CMCs. Persons with a history of stroke or anemia had an increased risk of a fall injury event: for stroke the adjusted odds ratio (aOR) equalled 1.7 (95% confidence interval (CI), 1.0-3.0); for anemia the aOR equalled 1.5 (95% CI, 1.0-2.2). Those with a history of high blood pressure had decreased risk (aOR = .7, 95% CI 0.5-0.9). CONCLUSIONS: Persons 65 and older with a self-reported history of anemia or stroke are at increased risk of a fall injury event in the home, whereas those with a self-reported history of high blood pressure are at decreased risk.

Cognitive function in aged ovariectomized female rhesus monkeys.

To determine whether ovariectomy exacerbates age-related cognitive decline, the performance of 6 aged monkeys that had been ovariectomized early in life (OVX-Aged) was compared to that of 8 age-matched controls with intact ovaries (INT-Aged) and that of 5 young controls with intact ovaries (INT-Young) in tasks of visual recognition memory, object and spatial memory, and executive function. The OVX-Aged monkeys were marginally more impaired than the INT-Aged monkeys on the delayed nonmatching-to-sample with a 600-s delay. In contrast, they performed significantly better than the INT-Aged controls on the spatial condition of the delayed recognition span test. The hypothesis that prolonged estrogenic deprivation may exaggerate the age-related decline in visual recognition memory will require additional support. However, the findings suggest that long-term ovariectomy may protect against the development with aging of spatial memory deficits.

Age-related brain changes in rhesus monkeys: a magnetic resonance spectroscopic study.

Brain metabolites were measured by proton magnetic resonance spectroscopy in five young (4-10 years of age) and six old (24-30 years of age) adult rhesus monkeys. The two age groups had similar levels of N-acetylaspartate and of choline relative to creatine, but the ratio of myo-inositol/creatine was higher in each old monkey than in any of the young animals. There was no significant relationship between the metabolite ratios and cognitive performance. The findings indicate that a consistent pattern of non-invasively detectable biochemical changes occurs in the brain with ageing. Whether these changes have functional significance in age-related pathologies, or are simply markers of brain ageing will be the subject of future studies.

Age-related decline in DHEAS is not related to cognitive impairment in aged monkeys.

To determine whether endogenous DHEAS level is related to cognitive performance in the rhesus monkey, we tested 9 young and 14 old monkeys on the acquisition and the 120 s delay condition of the delayed non-matching to sample and on the spatial delayed recognition span test. A single summary measure of cognitive ability, the cognitive performance index (CPI), was derived from these three tests. As expected, the mean level of DHEAS as well as the CPI declined with age. DHEAS level, however, was not significantly correlated with CPI, after controlling for the relationship of age to these two variables. Further, impaired and unimpaired aged monkeys did not differ in DHEAS level. These findings suggest that DHEAS is not independently associated with age-related cognitive decline in the rhesus monkey.

Patterns of cognitive decline in aged rhesus monkeys.

Although cognitive decline has been well established as a consequence of aging in non-human primate models, the prevalence or frequency of impairment for specific age ranges has not been described. The first aim of this study was to estimate prevalence of cognitive impairment on each of the six tests of cognitive performance by comparing the performance of early-aged (19-23 years old), advanced-aged (24-28 years old), and oldest-aged (29+ years old) monkeys to that of young adults (< 15 years old). The second aim was to derive a single overall measure of cognitive performance to help classify behavioral function in our aged monkeys. Accordingly, we obtained performance measures for these age groups on six behavioral measures: (1) acquisition of the delayed non-matching-to-sample task (DNMS); (2) performance of the DNMS with a delay of 120 sec; (3) the spatial condition of the delayed recognition span test (DRST); (4) the color condition of the DRST; (5) spatial reversal learning; and (6) object reversal learning. Early-aged monkeys displayed prevalence rates of impairment significantly greater than zero on all tasks except the DRST-color. The highest prevalence of impairment was observed in this age group in a task measuring spatial memory (DRST). Significant trends toward progressively higher impairment rates in advanced-aged and oldest-aged monkeys were observed for DNMS-acquisition, DRST-color and spatial reversal learning tasks. A linear transformation of standardized scores on the six cognitive tests was derived by means of principal components analysis (PCA). The first PCA (PCA1) included data from 30 monkeys with available data on all six measures, and yielded a composite measure which declined linearly with increasing age (r = -0.74). A second PCA (PCA2) was performed on data from 53 monkeys for which three test scores (DNMS-acquisition, DNMS-120s delay, and DRST-spatial condition) were available. The composite score derived from this analysis was highly correlated (r = 0.93) with the composite score from PCA1, suggesting that a score based on only three tests may provide an adequate classification of global cognitive ability.

Anatomical specificity within rat striatum for the dopaminergic modulation of DRL responding and activity.

The direct application of microgram quantities of crystalline dopamine, D-amphetamine, or scopolamine to the ventral anterior region of the neostriatum of rats decreased response efficiency on a 'differential reinforcement of low rate' 10 sec schedule of reinforcement. Similar applications to the dorsal globus pallidus or posterior striatum either did not alter or increased response efficiency. A comparison of dose-response functions for injections of dopamine in solution into ventral anterior, central and posterior striatum confirmed that only injections into ventral anterior striatum (VAS) decreased response efficiency on the DRL schedule. The same striatal map was found for the dopamine-induced increase in spontaneous locomotor activity in tilt boxes. It was concluded that dopaminergic transmission in ventral anterior striatum, in contrast to the other striatal and pallidal sites tested, is involved in the modulation of behavioral arousal.

Selective enhancement of the lordotic component of female sexual behavior in rats following destruction of central catecholamine-containing systems.

Ovariectomized female rats received two intraventricular injections of 200 microgram of 6-hydroxydopamine (6-OHDA), a treatment which produced 66% depletion of telencephalic norepinephrine and 53% depletion of telencephalic dopamine. Compared to vehicle-injected controls, 6-OHDA-treated animals showed increased lordosis scores when treated with ovarian hormones. This effect was potentiated by additional treatment with 100 mg/kg alpha-methyl-p-tyrosine (AMT), a catecholamine synthesis inhibitor. Besides showing increased frequency and intensity of lordosis, animals treated with both 6-OHDA and AMT retained the lordotic posture significantly longer after the male dismounted than animals given either treatment alone or vehicle controls. The enhancement of lordosis following CA depletion was not prevented by a series of dexamethasone treatments which caused a marked suppression in adrenal steroid (corticosterone) levels. This suggests that normal adrenal function is not a prerequisite for the observed enhancements. It was concluded that the lordotic response is inhibited by the activity of a catecholamine system. Soliciting behavior (hop-darting) was not enhanced by any treatment, suggesting that catecholamine activity has an inhibitory influence on the stop component of sexual behavior, but not on the whole copulatory pattern.

Dissociation of active from immobility components of sexual behavior in female rats by central 6-hydroxydopamine: implications for CA involvement in sexual behavior and sensorimotor responsiveness.

Ovariectomized female rats were given a hormone treatment (2 X 8 micrograms/kg estradiol benzoate) that normally supports only low levels of lordosis responding and no soliciting behavior in tests with sexually active males. When subjected to an intraventricular 6-hydroxydopamine (6-OHDA) procedure (with pargyline pretreatment) that produced 85% and 95% depletions of caudate dopamine and cortical norepinephrine respectively, these females exhibited a dramatic increase in the intensity and frequency of lordotic responding but no soliciting behavior over 3 weekly tests. The increase in lordosis was not due to a drug- or stress-induced release of adrenal progesterone, since dexamethasone suppressed the progesterone levels, as documented by radioimmunoassay, but not the higher receptivity of 6-OHDA treated females. In other ovariectomized females given a hormone regimen (2 X 50 micrograms/kg estradiol benzoate plus 500 micrograms progesterone) that supported maximal levels of lordosis and soliciting, the same 6-OHDA treatment prolonged the average duration of lordosis while actually decreasing the incidence and duration of soliciting. The hypothesis is put forward that the differential effects of interfering with catecholamine, and more likely dopamine function on the soliciting and lordosis components of female sexual behavior might best be understood as a dissociation between mutually antagonistic behavior patterns such that responsiveness involving active orientation and forward locomotion is suppressed, whereas responses requiring immobility are augmented.

Differential rearing affects corpus callosum size and cognitive function of rhesus monkeys.

This study investigated the effects of different rearing conditions on neural and cognitive development of male rhesus monkeys (Macaca mulatta). Infants raised individually in a nursery from 2 to 12 months of age (NURSERY, n=9) were compared to age-matched infants raised in a semi-naturalistic, social environment (CONTROL, n=11). Various brain regions were measured by MRI. Although overall brain volumes did not differ between NURSERY and CONTROL animals, corpus callosum (CC) size, measured in mid-sagittal sections, was significantly decreased in the NURSERY group. Group differences were most evident in the posterior aspects of the corpus callosum and appeared to result from changes in the number of cross-hemispheric projections rather than from a decrease in cortical gray matter volume. The decrease in corpus callosum size in the NURSERY animals persisted after 6 months of social housing in a peer-group. Rearing group differences were not found in other structures analyzed, including the hippocampus, cerebellum and anterior commissure. In cognitive testing, NURSERY animals had more difficulty acquiring the delayed non-matching to sample (DNMS) task, but showed no deficits in subsequent memory performance when a 2 or 10 min delay was imposed. The NURSERY infant monkeys were also impaired in object, but not in spatial, reversal learning, although there were no differences in a simple object discrimination task. The cognitive deficits exhibited by the NURSERY animals were significantly correlated with the alterations found in the CC. In summary, rearing environment was associated with sustained differences in cross-hemispheric projections, white matter volume and cognitive performance.

Neuroleptics increase striatal catecholamine metabolites but not ascorbic acid in dialyzed perfusate.

To determine the effects of dopamine receptor blockade upon oxidizable components of striatal extracellular fluid, high-performance liquid chromatography (HPLC) with electrochemical detection was used to assay levels of ascorbic acid, dihydroxyphenylacetic acid (DOPAC) homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) in perfusates obtained from unanesthetized rats following i.p. administration of haloperiodol (1.0 mg/kg) or clozapine (20 mg/kg). Striatal push-pull perfusion was performed by passing artificial CSF between two pulled glass micropipets, encapsulated by a hollow, semipermeable cellulose fiber, thereby limiting recovery to compounds under mw 5000. Samples were directly injected into a C-18 column at half-hour intervals before and after neuroleptic administration. Haloperidol administration resulted in increases in extracellular DOPAC and HVA while failing to alter 5-HIAA or ascorbic acid levels. Similar results were found with clozapine, except for a more variable individual response to the drug; clozapine also produced a small increase in 5-HIAA levels. Animals given a saline injection did not show increases in any of these compounds. These data confirm the involvement of extracellular dopamine metabolites in the electrochemical signal increases observed in vivo following dopamine receptor blockade and provide evidence that extracellular ascorbic acid in the striatum is insensitive to peripheral neuroleptic administration.