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Studies examining hormones throughout pregnancy and lactation in women have been limited to single, or a few repeated, short-term measures of endocrine activity. Furthermore, potential differences in chronic hormonal changes across pregnancy/lactation between first-time and experienced mothers are not well understood, especially as they relate to infant development. Hormone concentrations in hair provide long-term assessments of hormone production, and studying these measures in non-human primates allows for repeated sampling under controlled conditions that are difficult to achieve in humans. We studied hormonal profiles in the hair of 26 female rhesus monkeys (Macaca mulatta, n=12 primiparous), to determine the influences of parity on chronic levels of cortisol (hair cortisol concentration, HCC) and progesterone (hair progesterone concentration, HPC) during early- to mid-pregnancy (PREG1), in late pregnancy/early lactation (PREG2/LACT1), and in peak lactation (LACT2). We also assessed infants' neurobehavioral development across the first month of life. After controlling for age and stage of pregnancy at the first hair sampling period, we found that HCCs overall peaked in PREG2/LACT1 (p=0.02), but only in primiparous monkeys (p

The emergence of social behaviors early in life is likely crucial for the development of mother - infant relationships. Some of these behaviors, such as the capacity of neonates to imitate adult facial movements, were previously thought to be limited to humans and perhaps the ape lineage. Here we report the behavioral responses of infant rhesus macaques (Macaca mulatta) to the following human facial and hand gestures: lip smacking, tongue protrusion, mouth opening, hand opening, and opening and closing of eyes (control condition). In the third day of life, infant macaques imitate lip smacking and tongue protrusion. On the first day of life, the model's mouth openings elicited a similar matched behavior (lip smacking) in the infants. These imitative responses are present at an early stage of development, but they are apparently confined to a narrow temporal window. Because lip smacking is a core gesture in face-to-face interactions in macaques, neonatal imitation may serve to tune infants' affiliative responses to the social world. Our findings provide a quantitative description of neonatal imitation in a nonhuman primate species and suggest that these imitative capacities, contrary to what was previously thought, are not unique to the ape and human lineage. We suggest that their evolutionary origins may be traced to affiliative gestures with communicative functions.

Peer-reared (PR) rhesus monkeys with early maternal separation later exhibit aggressiveness, impaired impulse control, alcohol abuse, and low CSF 5-hydroxyindoleacetic acid. This study compared regional brain serotonin transporter (SERT) binding between nine PR and seven mother-reared rhesus monkeys with [11C]DASB positron emission tomography (PET) imaging. Parametric images of binding potential (BP) (which is proportional toBmax/KD, in whichBmaxis transporter density andKDis dissociation constant) and relative blood flow (R1) were generated by the two-parameter multilinear reference tissue model.R1images were used for coregistration and normalization of PET parametric data to the magnetic resonance imaging template space. Group BP differences were analyzed voxelwise by Student'sttest in SPM2. Region of interest-based parameter values were also calculated to obtain the magnitude of regional BP differences between the two groups. For the PR group, SERT BP was decreased by 10–23% across a range of brain areas consisting of the raphe, thalamus, hypothalamus, caudate and putamen, globus pallidum, anterior cingulate gyrus, and medial temporal regions, including amygdala and hippocampus (cluster-level correctedp= 0.002). For the latter three regions, BP was decreased in the right hemisphere. These results agree with the hypothesis that early maternal deprivation affects the development of the serotonergic system and suggest that decreased serotonergic innervations in the critical brain regions may explain some of the behavioral and biochemical abnormalities in PR monkeys.

The effects of appetitive controllability on behavioral and cortisol reactivity to novelty in 12 infant rhesus monkeys were studied. Surrogate-peer-reared infants had homecage access to food treats contingently via lever pressing ("master") or noncontingently ("yoked") for 12 weeks from postnatal month 2. Masters lever-pressed more, but did not differ in baseline cortisol. At month 5, infants were exposed to a novel environment in social groups and individually. Masters were significantly more active and exhibited significantly lower cortisol reactivity to the novel environment, but only in the individual context. Also, individual differences in operant behavior were positively correlated with behavioral activity and negatively correlated with cortisol reactivity to the novel environment. The results reveal context-specific benefits of contingent stimulation in infancy.

Activity patterning and circadian cycles have proven to be important measures for clinical and translation research. For example, circadian disruption and activity levels that deviate significantly from either baseline or a comparison group may serve as diagnostic criteria for a range of disorders including depression (Jean-Louis et al., 2000), attention deficit disorder (Miller and Kraft, 1994), posttraumatic stress disorder (Glod et al., 1997 a, b), and substance abuse (Johnson and Breslau, 2001). At the same time, individual differences in activity patterns may serve as an early risk marker for those disorders.

Recent research has disclosed marked individual differences in biobehavioural responses to social conflicts exhibited by rhesus monkeys across the life span. For example, approximately 5-10% of rhesus monkeys growing up in the wild consistently exhibit impulsive and/or inappropriately aggressive responses to mildly stressful situations throughout development; those same individuals also show chronic deficits in their central serotonin metabolism. These characteristic patterns of biobehavioural response emerge early in life and remain remarkably stable from infancy to adulthood. Laboratory studies have demonstrated that although these characteristics are highly heritable, they are also subject to major modification by specific early experiences, particularly those involving early social attachment relationships. Moreover, genetic and early experience factors can interact, often in dramatic fashion. For example, a specific polymorphism in the serotonin transporter gene is associated with deficits in early neurobehavioural functioning and serotonin metabolism, extreme aggression, and excessive alcohol consumption among monkeys who experienced insecure early attachment relationships but not in monkeys who developed secure attachment relationships with their mothers during infancy. Because daughters tend to develop the same type of attachment relationships with their own offspring that they experienced with their mothers early in life, such early experiences provide a possible non-genetic mechanism for transmitting these patterns to subsequent generations.

INTRODUCTION Professor Robert B. Cairns was a giant in the field of developmental science. His theoretical vision and his empirical rigor and persistence drove a lifelong research and academic career that uniquely helped shape this emerging, dynamic interdisciplinary field. He was a remarkable teacher, researcher, and scholar who profoundly influenced countless students and colleagues and whose legacy will long be with us. I first got to know Bob Cairns during a mutual stint at the Center for Interdisciplinary Studies (ZIF) at the University of Bielfeld in Germany during the fall and winter of 1977–78. We were both at the ZIF as part of a 9-month-long program entitled “Early Development in Animals and Man” organized by the late ethologist Professor Dr. Klaus Immelmann, who had brought together a group of prominent researchers, representing a wide range of disciplines, who studied developmental phenomena both in humans and in a variety of other mammalian and avian species. I had known about Bob Cairns and his research since my very first days in graduate school at the University of Wisconsin – at that time Jim Sackett was telling all the graduate students at the Primate Laboratory about this guy in Indiana who hauled sheep to his lab in back of his station wagon in order to run studies that demonstrated the power of contiguity conditioning in establishing social bonds.

Functional allelic variation in the transcriptional control region of the serotonin transporter and monoamine oxidase A genes has been associated with anxiety- and aggression-related behavior in humans and, more recently, in nonhuman primates. Here, we have genotyped these polymorphic regions in seven species of the genus Macaca. Macaques exhibit exceptional inter-species variation in aggression-related social behavior as illustrated by recent studies showing overlapping patterns of aggression-based social organization grades and macaque phylogeny. We cloned and sequenced two new alleles of the serotonin transporter gene-linked polymorphic region in Barbary and Tibetan macaques. In addition, we observed that species displaying tolerant societies, with relaxed dominance and high levels of conciliatory tendency, were monomorphic for both the serotonin transporter gene and, with the exception of Tonkean macaques, the monoamine oxidase A gene. In contrast, those species known to exhibit intolerant, hierarchical and nepotistic societies were polymorphic at one or more of these loci. Rhesus (M. mulatta), the most intolerant and hierarchical species of macaques, showed the greatest degree of allelic variation in both genes. Additional investigation of a polymorphic repeat in exon III of the dopamine receptor D4 as well as a repeat/single nucleotide polymorphism in the 3′ untranslated region of the dopamine transporter which have both been implicated in the modulation of complex behavior failed to reveal a relationship between allelic variability and social organization grade. Taken together, these findings suggest that genetic variation of serotonergic neurotransmission may play an important role in determining inter-species differences in aggression related behavior in macaques.

In the present study we examined the relationship among handedness, immune functioning, and behavioural reactivity in rhesus macaques. We used the absolute number of CD4+ (T-helper) and CD8+ (T-suppressor) cells as dependent measures of immune functioning. We derived reactivity profiles from behavioural responses to a threat, and hand preference profiles from a quadrupedal food-reaching test. The results indicate positive correlations between the frequency of right versus left hand reaches and the absolute number of CD4+ cells, and between the frequency of right versus left hand reaches and the degree of human-directed aggression in response to an invasive threat. Immune measures were not associated with the strength of hand preference. These results are consistent with and extend previous findings obtained with rodents to nonhuman primates and provide further support for the view that behavioural lateralisation is associated with immune functioning and behavioural reactivity.

In this research we examined biological and behavioural correlates of handedness in free-ranging adult male rhesus macaques (Macaca mulatta). Specifically, we examined relationships between handedness and cerebrospinal fluid (CSF) concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma concentrations of the hormones cortisol and adrenocorticotropin (ACTH), and multiple indices of social behaviour, including occurrences of proximity to other animals, grooming, submission, and aggression. We determined handedness through systematic observation of animals reaching for food in their unrestricted home environment. The frequency of right- versus left-hand use was significantly positively correlated with CSF 5-HIAA, CSF MHPG, and plasma cortisol concentrations, and with social proximity and the frequency and duration of bouts in which animals received grooming. The frequency of right- versus left-hand use was significantly negatively correlated with the frequency of submissive behaviour, and with the frequency and intensity of bouts in which animals received aggression. We conclude that handedness is associated with an array of biological and behavioural processes in free-ranging adult male rhesus macaques and that left-handedness may be used to identify individuals at increased risk for impaired functioning of the serotonin, norepinephrine, and hypothalamic-pituitary-adrenal systems, and for social isolation and susceptibility to violent attack.

Background: Studies in rodents demonstrate sex differences in neuroendocrine stress axis activity after treatment with alcohol. In abstinent alcoholics, atypical depressives, and individuals with posttraumatic stress disorder, limbic-hypothalamic-pituitary-adrenal (LHPA)-axis activity is often blunted; among females in these patient populations, however, resistance to glucocorticoid feedback and increased pituitary reactivity is observed. Early parental loss is a major life stressor and is a risk factor for both affective disturbances and LHPA-axis abnormalities later in life. We wanted to determine whether sex and early life parental absence would interact to influence alcohol-induced alterations in LHPA-axis activity after exposure to ethanol in macaques. Methods: Animals were reared with their mothers in social groups (MR, n= 94) or without adults in peer-only groups (PR, n= 79). At 5 years of age, they received an intravenous infusion of alcohol (2–2.2 g/kg), and the effects of alcohol, sex, and rearing condition on ACTH and cortisol levels were analyzed by ANOVA. Results: Peer-reared females had higher ACTH levels than did PR males, MR females, and MR males after alcohol infusion. Alcohol-induced cortisol levels were not affected by sex and rearing condition. Conclusions: These findings suggest that there are sex differences in glucocorticoid negative feedback, pituitary responsivity, or release of ACTH secretagogues among individuals exposed to early life stress and emphasize the importance of considering sex effects when studying LHPA-axis dysregulation in alcoholism and other stress-related neuropsychiatric disorders.

In spite of significant efforts, the neurobehavioral deficits in infants born from cocaine-abusing mothers have not been clearly defined. In the present study, we examined the presence of these abnormalities in a rhesus monkey model of prenatal cocaine exposure using a nonhuman primate adaptation of the Neonatal Behavioral Assessment Scale (NBAS). Pregnant monkeys (n = 14) received 10 mg/kg cocaine twice a day orally (in fruit treats) from the 40th through 102nd postconception days (PCD40-PCD102), which is the period of cerebral cortical neuronogenesis (approximately second trimester). The control consisted of pregnant monkeys (n = 14) receiving fruit treats only. The animals were allowed to deliver vaginally at term (approximately PCD165). The first testing session was conducted on PCD171 (within the first week after birth); the second testing session was conducted on PCD177 (within the second week after birth); the third test was conducted on PCD183 (within the third week after birth); and the fourth testing session was conducted on PCD189 (within the fourth week after birth). The prenatally cocaine-exposed infants showed deficits in orientation, state control, and motor maturity, which were detectable during the second, third, and fourth testing sessions. The same testing sessions also revealed a significant reduction in the time devoted to toy manipulation, which points to impaired attention. None of these abnormalities were seen during the first testing session. The first session, however, revealed increased tremulousness (one of the indicators of autonomic stability) in the prenatally cocaine-exposed infants. This impairment disappeared by the third testing session. The present findings demonstrate the potential of prenatal cocaine exposure to induce neurobehavioral deficits detectable by NBAS-like testing in primate infants.

Background In humans and macaques, a promoter polymorphism that decreases transcription of the serotonin transporter gene is associated with anxiety. Serotonin transporter gene disruption in rodents produces anxious animals with exaggerated limbic–hypothalamic–pituitary–adrenal (LHPA) responses to stress. We wanted to determine whether serotonin transporter gene promoter variation (rh-5HTTLPR) and rearing condition would interact to influence endocrine responses to stress in infant rhesus macaques. Methods Animals were reared with their mothers (MR, n = 141) or in peer-only groups (PR, n = 67). At 6 months of age, adrenocorticotropic hormone (ACTH) and cortisol levels were determined at baseline and during separation stress. Serotonin transporter genotype ( l/l and l/s ) was determined with polymerase chain reaction followed by gel electrophoresis. Results Cortisol levels increased during separation, and there was a main effect of rearing condition, with decreased cortisol levels among PR macaques. Animals with l/s rh5-HTTLPR genotypes had higher ACTH levels than did l/l animals. Adrenocorticotropic hormone levels increased during separation, and there was a separation × rearing × rh5-HTTLPR interaction, such that PR- l/s animals had higher ACTH levels during separation than did other animals studied. Conclusions These data demonstrate that serotonin transporter gene variation affects LHPA axis activity and that the influence of rh5-HTTLPR on hormonal responses during stress is modulated by early experience.

We examined the relations among cerebrospinal fluid (CSF) monoamine metabolite concentrations, plasma hormone concentrations, aggression, and impulsive risk-taking behavior in a free-ranging population of female rhesus macaques. We selected 44 juvenile female rhesus macaques as subjects from a population of approximately 3000 macaques that inhabit a 475-acre Sea Island. We obtained CSF and blood samples, and recorded behavioral observations over a subsequent 18-month period. Our results indicate an inverse correlation between CSF concentrations of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the frequency of low-intensity restrained aggression typically associated with matrilineal defense of social status. In contrast, previous research with males has shown an inverse correlation between CSF 5-HIAA concentrations and levels of violent unstrained aggression typically associated with traumatic injury and death. We also noted a negative correlation between plasma concentrations of the stress hormone cortisol and the frequency of low-intensity aggressive acts, a finding not reported in our previous studies with males. Further examination revealed a negative correlation between CSF 5-HIAA concentrations and the rate of long dangerous leaps through the forest canopy, suggesting that the relation between low serotonergic functioning and impulsivity may generalize to both female and male primates. These results indicate that females with low CSF 5-HIAA concentrations, like their male counterparts, are at increased risk for impulsive temperament, but that unlike males, females may be buffered from this risk through intersexual differences in life history patterns and social affiliation.

Low platelet monoamine oxidase (MAO) activity is associated with "type 2 alcoholism." MAO activity is also affected by cigarette smoking. Since most alcoholics are smokers, it is difficult to evaluate the possible effect of platelet MAO activity on alcoholism independently of the effects of smoking. The authors investigated the relationship between platelet MAO activity and excessive alcohol consumption in rhesus macaques.Platelet MAO activity and CSF metabolite concentrations were measured. The authors also investigated level of voluntary alcohol intake and social dominance rank.Subjects with low platelet MAO activity consumed alcohol to excess, had low CSF 5-hydroxyindoleacetic acid concentrations, and were less competent socially.These findings show that nonhuman primates that exhibit type 2-like alcohol features display low platelet MAO activity and support the notion that platelet MAO activity is a biologic marker for central serotonergic activity. The results also challenge the hypothesis that low platelet MAO activity in type 2 alcoholism is simply an artifact of smoking.

In rhesus macaque males, lower than average cerebrospinal fluid (CSF) concentrations of the principle metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA), have been linked to impulsivity, involvement in escalated aggression, failure to elicit consort relationships, production of fewer sperm plugs, and a relatively early age of mortality. Given these potential fitness costs, we performed two studies aimed at elucidating the effects of CSF 5-HIAA on reproduction. Study 1 retrospectively evaluated over a four-year period, the relative reproductive outcome for pairs of adult male rhesus macaques (n = 15) who lived in social groups and who differed in concentrations of CSF 5-HIAA. Study 2 examined the relationship between CSF 5-HIAA and sperm motility and density (n = 12), as a potential mechanism for maintaining variability in CSF 5-HIAA. For Study 1, an average measure from two CSF 5-HIAA samples was calculated for the two males who were present during the time when conception most likely took place (offspring birth date -165 +/- 14 days). Within-pair comparisons of CSF 5-HIAA concentrations between the sire and the non-successful male were drawn for each of the 72 offspring in the study. We found that while sires were typically the male with relatively higher CSF 5-HIAA within the pair, there were no absolute differences in CSF 5-HIAA between males who sired at least one offspring (sires) and those who failed to reproduce (non-sires). Furthermore, while absolute age was not predictive of reproductive outcome, sires with relatively high CSF 5-HIAA also tended to be also relatively older than their competitors. By contrast, for the males with relatively low CSF 5-HIAA who reproduced, sires were relatively younger than the non-sires. These differences in reproductive outcome for males differing in CSF 5-HIAA could not be explained by variability in sperm quantity or quality as we did not find evidence of a relationship between CSF 5-HIAA and either sperm measure. The results of this study suggest that as serotonergic function affects many aspects of behavior and survivorship, it might also be associated with reproductive outcome and different life-history strategies for males differing in concentrations of CSF 5-HIAA.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is highly concentrated in CNS tissues. Although breast milk contains the fatty acids DHA and arachidonic acid, infant formulas marketed in North America do not contain these nutrients. The potential deleterious effects of rearing infants with formulas devoid of these nutrients was assessed by comparing nursery-reared rhesus macaque infants (Macaca mulatta) fed standard formula with infants fed standard formula supplemented with physiologically relevant concentrations of DHA (1.0%) and arachidonic acid (1.0%). Neurobehavioral assessments were conducted on d 7, 14, 21, and 30 of life using blinded raters. The 30-min assessment consisted of 45 test items measuring orienting, temperament, reflex capabilities, and motor skills. Plasma concentrations of DHA in standard formula-fed infants were significantly lower than those fed supplemented formula or mother-raised (breast-fed) infants; however, infants fed the supplemented formula exhibited higher arachidonic acid levels than either mother-reared infants or infants fed standard formula. Infant monkeys fed the supplemented formula exhibited stronger orienting and motor skills than infants fed the standard formula, with the differences most pronounced during d 7 and 14. This pattern suggests an earlier maturation of specific visual and motor abilities in the supplemented infants. Supplementation did not affect measures of activity or state control, indicating no effect on temperament. These data support the assertion that preformed DHA and arachidonic acid in infant formulas are required for optimal development.

Early life stress (ELS) is associated with increased vulnerability for diseases in later life, including psychiatric disorders. Animal models and human studies suggest that this effect is mediated by epigenetic mechanisms. In humans, epigenetic studies to investigate the influence of ELS on psychiatric phenotypes are limited by the inaccessibility of living brain tissue. Due to the tissue-specific nature of epigenetic signatures, it is impossible to determine whether ELS induced epigenetic changes in accessible peripheral cells, for example, blood lymphocytes, reflect epigenetic changes in the brain. To overcome these limitations, we applied a cross-species approach involving: (i) the analysis of CD34+ cells from human cord blood; (ii) the examination of blood-derived CD3+ T cells of newborn and adolescent nonhuman primates (Macaca mulatta); and (iii) the investigation of the prefrontal cortex of adult rats. Several regions in MORC1 (MORC family CW-type zinc finger 1; previously known as: microrchidia (mouse) homolog) were differentially methylated in response to ELS in CD34+ cells and CD3+ T cells derived from the blood of human and monkey neonates, as well as in CD3+ T cells derived from the blood of adolescent monkeys and in the prefrontal cortex of adult rats. MORC1 is thus the first identified epigenetic marker of ELS to be present in blood cell progenitors at birth and in the brain in adulthood. Interestingly, a gene-set-based analysis of data from a genome-wide association study of major depressive disorder (MDD) revealed an association of MORC1 with MDD.

A recent change in standard pediatric practice on immunization of young infants has involved the administration of two injections during the same office visit as opposed to one injection per office visit. In the past, infants received a single injection at 2, 4, and 6 months of age, to immunize against diphtheria, tetanus, and pertussis. Now, young infants also receive a second injection, to immunize against Haemophilus influenzae type b. This change in procedure raises the question whether two injections during the same visit might be too stressful for young infants. A clear demonstration that two injections are no more stressful than one could provide sufficient evidence to allow pediatricians to feel confident that this new procedure is appropriate.

Nonhuman primates offer unique opportunities to study the effects of genes, environments, and their interaction, on physiology and complex behavior. We examined genotype and early environment contributions to CNS function in a large sample of rhesus monkeys. In humans, length variation of the serotonin (5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) that results in allelic variation in 5-HTT expression is associated with decreased serotonergic function and 5-HT-mediated psychopathology. We report that an analogous variation of the gene's regulatory region in monkeys interacts with early experience to affect central 5-HT functioning. Monkeys with deleterious early rearing experiences were differentiated by genotype in cerebrospinal fluid concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid, while monkeys reared normally were not. These findings demonstrate an environment-dependent effect of the rh5-HTTLPR genotype on CNS 5-HT function and suggest nonhuman primates may provide an important avenue for investigating gene/environment interactions using candidate genes for physiological and behavioral traits.

This research examined hand preference and postural characteristics of aimed throwing in capuchin monkeys and humans. We sought to directly compare the throwing performances of these primates, particularly the extent to which target distance influences hand preference, throwing posture, and throwing accuracy. For both species we found positive correlations between target distances for throwing accuracy, direction and strength of hand preference, percentage of bipedal vs tripedal throws, and percentage of overarm vs underarm throws. Throwing accuracy did not vary as a function of right vs left hand use although for monkeys throwing accuracy was positively associated with hand preference strength. We noted a sex difference among humans as males threw more accurately than did females. Between-species analysis indicated that humans exhibited greater right- vs left-hand use, greater hand preference strength, a greater relative percentage of bipedal vs tripedal throws, and a lower relative percentage of overarm vs underarm throws than did monkeys. We believe that the capuchin monkey is an informative nonhuman primate model of aimed throwing in humans and that research examining the throwing behavior of capuchins provides insight into the neurological and behavioral characteristics that underlie coordinated multi-joint movements across the primate order.

Men with low CNS serotonin turnover, as measured by cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations, exhibit aberrant circadian activity patterns characterized by disrupted sleep rhythms and daytime hyperactivity. To assess whether similar patterns are found in nonhuman primates we examined the relationships between CSF 5-HIAA and nighttime activity in free-ranging monkeys. CSF samples were obtained from 16 adult male rhesus macaques living on a 475 acre, heavily forested sea island. Each subject was captured, fitted with a radio-telemetry motion-detector collar, and then released back into its group. A receiver placed near the sleeping trees of the study subjects recorded activity between 2100 hrs and 0600 hrs. Trained observers recorded behavioral data during the day. The animals followed a typical diurnal activity pattern, as they were active 74% of the sampled time during the day and 37% of the sampled time during the night. CSF 5-HIAA concentrations were inversely correlated with total duration of nighttime activity as well as mean duration of all active events. Nighttime activity was inversely correlated with daytime activity. CSF 3-methoxy-hydroxyphenylglycol (MHPG) concentrations were positively correlated with total nighttime activity, and inversely correlated with daytime sleep frequency. We conclude that male rhesus with low CSF 5-HIAA concentrations have higher total nighttime activity, longer mean periods of nighttime activity, and sleep more during the day than do males with high CSF 5-HIAA concentrations. This suggests that low serotonergic neurotransmission is associated with aberrant diurnal activity, as evidenced by a disruption of nighttime sleep patterns and a compensatory higher rate of inactivity during the day.

A cohort of free-ranging rhesus monkeys has been followed since birth in 1994 on the island of Cayo Santiago, Puerto Rico. At 3 years of age, subjects were trapped and blood samples were collected after capture and prior to release the following day. Blood samples were processed for natural cytotoxicity toward xenogeneic tumors, phenotyping, and plasma hormones. Intestinal parasites were determined from fresh stool samples collected during trapping. Data were also available from the previous year for antibody titers to latent viruses prevalent in this population. Behavioral traits of each monkey were characterized using a previously developed trait scale for rhesus monkeys. Natural cytotoxicity toward both K562 and Raji targets declined from capture until release the following day. Plasma cortisol rose and plasma prolactin and growth hormone fell during the period of captivity; a rise in insulin was significant. It was expected that individual differences in behavioral traits might predict immune and hormone levels at the time of capture or changes in these parameters during the capture period. Although behavioral adjectives tended to cluster along three orthogonal dimensions (Insecurity, Irritability, and Sociability), they bore no relationship to the physiological parameters collected acutely (in vitro immune and endocrine parameters). The individual difference markers of gender and maternal rank were not related to the magnitude of the observed changes in these in vitro parameters, either. However, an in vivo measure (CMV titer) was related to individual differences in Irritability. It was concluded that the magnitude of the stress associated with capture overwhelmed the individual difference effects.

Previous studies comparing plasma cortisol levels in mother-reared and nursery-reared rhesus monkey infants under baseline and stress conditions have reported conflicting findings. Differences in subject age, procedures, and specific rearing history may account for many of the discrepant findings. In the present study, mother-reared infants from large social groups, peer-only reared animals, and infants reared with surrogates and limited peer contact were studied in different test conditions across the first 6 months of life. Infants were sampled under three conditions: following a neonatal assessment at Days 14 and 30, immediately upon capture on Day 60, and after 30-min isolation periods on Days 90, 120, and 150. Mother-reared infants exhibited higher cortisol levels on Days 14 and 30 than did both types of nursery-reared infants. In addition, Day 60 basal values of mother-reared infants were higher than those of both peer-reared and surrogate/peer-reared infants. However, on Days 90, 120, and 150, both mother-reared and peer-reared infants exhibited higher cortisol levels in response to separation and 30-min isolation than did the surrogate/peer-reared infants. These differences may reflect group-specific variations in physical environment, capture time, feeding regimen, or diurnal HPA axis rhythms.

Two studies were conducted to examine the effects of oral L-tryptophan (TRP) supplementation as a treatment for self-injurious behavior (SIB) and to investigate behavior and central serotonin turnover of male rhesus monkeys. In Study One, TRP was administered to seven individually housed rhesus monkeys with a recent history of spontaneous SIB. While the monkeys were on TRP treatment (100 mg/kg twice a day), cisternal cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid increased markedly (p=.0013) above baseline (baseline mean=207.6 pmol/ml ± 39; TRP mean=320.3 pmol/ml ± 83.4) , and the duration of self-biting behavior decreased below baseline (p=.03) . In Study Two, 14 individually housed rhesus monkeys without a history of SIB were placed on three different doses of TRP in random order (50, 100, and 200 mg/kg twice a day). TRP had no effect on any behavioral or biochemical variables in the normal monkeys. Conclusions: Supplemental tryptophan in well-tolerated doses reduced self-biting and increases serotonin turnover rate in male monkeys with a recent history of SIB. The same doses of TRP do not affect behavior or serotonin metabolism in male monkeys without a history of SIB.

Hand preference for quadrupedal and bipedal reaching in humans and rhesus macaques (Macaca mulatta) was examined, and the data were compared with postural reaching data that have been reported for 8 other primate species. Population-level biases were found toward use of the right hand for quadrupedal and bipedal reaching in humans and use of the left hand for quadrupedal reaching in rhesus macaques. Rhesus macaques showed a significant shift toward greater use of the right hand for bipedal vs. quadrupedal reaching. Comparisons with other species showed significant variance in the direction and strength of hand preference across reaching postures. The study noted right-hand biases for bipedal reaching in humans, great apes, and tufted capuchins and shifts toward greater use of the right hand for bipedal vs. quadrupedal reaching in great apes, tufted capuchins, and rhesus macaques. These results suggest that posture alters both the direction and strength of primate hand preference and that bipedalism may have facilitated species-typical right-handedness in humans.

This research examined token-mediated tool-use in a tufted capuchin monkey (Cebus apella). We conducted five experiments. In experiment 1 we examined the use of plastic color-coded chips to request food, and in experiments 2–5 we examined the use of color-coded chips to request tools. Our subject learned to use chips to request tools following the same general pattern seen in great apes performing analogous tasks, that is, initial discrimination followed by an understanding of the relationship among tokens, tools, and their functions. Our findings are consistent with the view that parallel representational processes underlie the tool-related behavior of capuchins and great apes.

Systematic scientific study of the effects of trauma on humans has always faced formidable methodological challenges and both ethical and practical obstacles. The most scientifically rigorous study designs—prospective longitudinal experiments, preferably double-blind in nature—are virtually nonexistent, appropriately precluded by the ethical standards of every civilized society. Instead, some reliance on retrospective data inevitably occurs, at least for part of the period under study (e.g., the time prior to the beginning of the trauma). Practical considerations also hinder prospective studies of the long-term consequences of trauma, especially those that involve life-span or multigenerational perspectives. It simply takes too long for humans to grow up (and old) for such prospective longitudinal studies to be feasible in most cases. As a result, retrospective reports provide the basis for much of our current knowledge base regarding long-term consequences of trauma.

This study examines sexual behavior, serotonin turnover in the central nervous system, and testosterone in free-ranging non-human primates. Study subjects were 33 young adult male rhesus macaques (Macaca mulatta) living in naturalistic social groups on a 475-acre South Carolina barrier island. Blood and cerebrospinal fluid (CSF) samples were obtained during random trappings, and the subjects were located for observation by radio telemetry. Quantitative behavioral samples totaling 203 observation hours were taken during two mating seasons (September through January) in 1994 and 1995. Control observations (65 h) on 13 subjects were also taken during the non-mating seasons in 1994 and 1995. The results indicate that CSF 5-hydroxyindoleacetic acid (5-HIAA), CSF testosterone, and plasma testosterone concentrations increase significantly during the mating season. During the mating season, there were significant increases in high intensity aggression, low intensity aggression, grooming behavior, and heterosexual mounting. In the mating season, CSF 5-HIAA was significantly correlated with several sociosexual behaviors: consorts per hour, heterosexual mounts per hour, and inseminations per hour. In contrast to previous findings from the non-mating season, CSF 5-HIAA was not correlated with any measures of aggression or sociality, although during consorting, CSF 5-HIAA was positively correlated with grooming. From these findings, we conclude that the lack of correlation between intense and severe aggression and CSF 5-HIAA in the mating season may reflect the use of high intensity aggression in 'normative' male-male competition over access to reproductively active females. We also conclude that CNS serotonin turnover is positively correlated with sexual competence, i.e. males with low CSF 5-HIAA concentrations are less sexually competent than males with higher concentrations.

A colony-born male rhesus monkey neonate was assigned to an ongoing protocol assessing behavioral and physiologic development in nursery-reared infants. It was sacrificed at day 20 because of poor weight gain, inability to self-feed, and generalized weakness. An asymmetric internal hydrocephalus was the only notable gross finding at necropsy. A retrospective analysis was performed comparing physical and behavioral measures for it with values for age-matched nursery-reared peers. Weight gain and formula intake lagged behind others in its cohort. The affected macaque spent more time in sleep and awake/quiet states and less time in an awake active state than did its peers. Behaviors during a neonatal temperament/reflex examination were indicative of high levels of irritability, poor muscular tone, nonexistent voluntary motor activity, and slower overall responding. In addition, asymmetric responses for some motor items were observed. However, vestibular/ocular reflexes appeared normal. The occasional observation of hydrocephalus in infants, as well as its prevalence throughout the primate order, indicates that hydrocephalus should be considered in the differential diagnosis for infants with feeding difficulties and motor dysfunction.

The idea that early experiences disproportionately influence adult behaviour has long been a fixture of mainstream developmental theory. Although unambiguous empirical support for this view at the human level is surprisingly sparse, compelling evidence from animal studies abounds. Recent studies with rhesus monkeys have demonstrated dramatic short- and long-term effects of differential early social experiences on both behavioural and physiological functioning. Early social relationships with mothers or other caregivers appear to provide especially powerful determinants of behavioural propensities throughout the lifespan.

This study investigated relationships between withdrawal behaviors in rhesus macaques and changes in monoamine metabolite and endocrine concentrations during repeated psychosocial stress. Rhesus monkeys (N = 71) experienced maternal separation in which four separations took place during four consecutive weeks. Behavioral observations were made, as well as plasma concentrations of cortisol and cerebrospinal fluid concentrations of the serotonin, dopamine, and norepinephrine metabolites were obtained. Animals were assigned to high, moderate, and low withdrawal groups, defined using baseline durations of withdrawal behaviors. Highly withdrawn animals showed less reduction than nonwithdrawn animals in serotonin metabolite concentrations over repeated separations. Highly withdrawn macaques also failed to significantly reduce cortisol concentrations across separation weeks. More adaptation in central serotonin functioning and cortisol concentrations was seen in nonwithdrawn primates than in highly withdrawn primates; these findings have implications for increased risk of developing anxiety disorders in highly inhibited children.

We studied the potential roles of testosterone and serotonin in various forms of aggressive and violent behaviors by measuring each biochemical and behaviour in free-ranging adolescent male nonhuman primates. Our results showed that (1) CSF free testosterone concentrations were positively correlated with overall aggressiveness, but not with measures of impulsivity. (2) CSF 5-HIAA concentrations were negatively correlated with impulsive behavior, and severe, unrestrained aggression, but not with overall rates of aggression. High rates of impulsive behavior were positively correlated with severe, unrestrained aggression, but not overall rates of aggression. (3) Dimensional analyses showed that while subjects with low CSF 5-HIAA exhibited high rates of aggression, high CSF testosterone further augmented rates and intensity of aggression in subjects with low CSF 5-HIAA. We conclude that high CSF free testosterone concentrations are associated with competitive aggression, while low CSF 5-HIAA concentrations are associated with severe aggression which results from impaired impulse control, and perseverance.

This research examined hand preference for a bimanual task in 45 tufted capuchin (Cebus apella) and 55 rhesus macaque (Macaca mulatta) monkeys. Investigators presented subjects with plastic tubes lined with food and noted which hand the animals used to hold the tubes and which hand the animals used to remove the food. Several significant findings emerged from this investigation. First, rhesus macaques, but not tufted capuchins, exhibited a population-level bias toward use of the right hand (although the difference in direction of hand preference between species was not significant). Second, capuchins exhibited greater hand preference strength than did macaques. Third, among capuchins, but not among macaques, hand preference strength was greater for adults than for immatures. Finally, both species used their index digit to remove food most frequently when compared with other digits. Findings of hand preference direction and strength in this study were compared with other findings noted for chimpanzees which performed a bimanual tube task in a previous study. The authors conclude that using the same procedure to compare hand preference across species represents a powerful research tool that can lead to a more complete understanding of the evolution and ontogenesis of primate handedness.

The purpose of this study was to develop an animal model for behavioral features of type II, early-onset alcohol abuse. To perform this research, cerebrospinal fluid (CSF) monoamine metabolite concentrations and home-cage social behaviors of 29 rhesus macaque subjects were examined in a 4-year longitudinal study. Half of the monkeys were reared for their first 6 months with their mothers, and the other half were reared without adults, instead with access only to monkeys of similar age. When the subjects were 6 months old, and again when they were 50 months old, they underwent a series of four, 4-day social separations. We obtained cisternal CSF before and during the first and last separation of each series to quantify 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylgycol (MHPG), and homovanillic acid concentrations. After the 6-month separations, subjects were placed into social groups, and social dominance rankings were assessed. Before and after the 50-month separations, social dominance rankings were evaluated again, and home-cage aggression and social behavior data were collected. Over the 3 1/2 years between CSF samplings, records were maintained of subjects' removal from their social groups for excessive aggression or treatment for wounding. Our results showed that among infants, reduced CSF 5-HIAA was correlated with low social dominance. As young adults, subjects from both rearing groups with low CSF 5-HIAA and MHPG concentrations exhibited reduced rates of social interaction and low social dominance rankings. In addition, peer-reared subjects with low CSF 5-HIAA concentrations exhibited inept social behaviors, and were frequently removed from their social groups for excessive aggression and deviant social behaviors. From these results, we conclude that the peer-rearing paradigm aggravates the untoward social consequences associated with low CSF 5-HIAA concentrations over and beyond reducing CSF 5-HIAA concentrations, suggesting that early experiences may contribute to CNS serotonin changes that increase the disposition to type II-related behaviors. Language: en

Developmental, biochemical, and behavioral concomitants of excessive alcohol consumption were investigated using a nonhuman primate model. The variables of interest were: (1) interindividual stability of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) from infancy to adulthood, (2) effect of parental deprivation early in life on adult CSF 5-HIAA concentrations; (3) correlations between CSF 5-HIAA and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations and alcohol consumption; and (4) correlation between the frequency of competent social behaviors and alcohol consumption. Twenty-nine rhesus macaques were reared for their first 6 months either with their mothers or without adults in peer-only conditions. At 6 and 50 months of age, each subject underwent a series of four, 4-day social separations. Cisternal CSF was sampled before and during the first and last separations; concomitantly, observational data were collected on social dominance behavior in the home-cage. When they reached 50 months of age, the monkeys were provided free access to a palatable alcohol solution daily for 1-hr periods before, during, and after the social separations. Before and after the 50-month separations, data were collected on all types of social behavior in the home-cage. Results showed that peer-reared subjects consumed more alcohol than mother-reared subjects during baseline conditions. Mother-reared subjects, however, increased their rates of consumption to equal peer-reared subjects' rates of consumption during the conditions of a social separation stressor. Peer-reared subjects also exhibited lower CSF 5-HIAA concentrations in infancy and adulthood than their mother-reared counterparts. With rearing condition held constant, interindividual differences in CSF 5-HIAA, MHPG, and homovanillic acid were stable from infancy to adulthood, and high rates of alcohol were consumed by the young adult monkeys with low CSF 5-HIAA and MHPG concentrations, particularly when the CSF was obtained during the social separations. High rates of alcohol consumption were also observed in subjects with infrequent social interactions and less competent social behaviors. In contrast to the human data, we found no gender differences in rates of alcohol consumption, nor in the correlations between alcohol consumption and the other variables. With some exceptions, findings from the study are generally consistent with predictions from Cloninger's type II model of excessive alcohol consumption in men with low CSF 5-HIAA, who also exhibit impaired impulse control and violent and antisocial behaviors.

Few studies have investigated longitudinally interindividual stability of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations in adult nonhuman primates across time and between baseline and stressful conditions. Furthermore, whereas studies with male macaques consistently have reported a significant, negative correlation between CSF 5-HIAA and rates of spontaneous aggression, wounding, and severe aggression, very few studies have examined this relationship in adult female nonhuman primates. Even fewer studies have investigated correlations between CSF 5-HIAA and competent social behavior, such as social dominance, in female monkeys. In the present study, two social groups of adult rhesus monkeys (Macaca mulatta) were formed by placing 16 females (aged 42 to 180 months, mean age: 68 months) in one of two indoor-outdoor enclosures with one or two adult males. CSF norepinephrine (NE), monoamine metabolites, and behavioral data were collected systematically over a 24-week period. In week 5 of the study, one additional female, not familiar to any of the other subjects, was added to each social group. Thereafter the groups were left undisturbed, and data characterizing spontaneous aggressive wounding and severe wound injuries in the females were collected for an additional year. The results showed that both group introduction and the addition of a new subject into each group resulted in increased monoamine turnover in the animals within the social groups. Interindividual differences in CSF concentrations of each of the monoamine metabolites and NE were highly stable from the baseline period to the stress samplings, and between stress samplings. Females with low CSF 5-HIAA exhibited higher rates of spontaneous aggressive wounding, and they were more likely to be removed from their social groups for aggressive wounding and/or treatment of injuries. CSF NE concentrations also were negatively correlated with rates of spontaneous aggression. In contrast, competitive aggression, i.e. noninjurious aggression used to maintain social dominance ranking, was not correlated with CSF 5-HIAA or NE. Females with above average CSF 5-HIAA prior to and following group formation were more likely to attain and maintain a high social dominance ranking within their social group than females with below average CSF 5-HIAA. The present findings indicate that CNS monoamine functioning in adult female rhesus macaques is traitlike, showing a high degree of interindividual stability across time and setting. These findings also suggest a role for serotonin in controlling impulses that regulate aggression and that competent social behavior among nonhuman primates may require average or above average serotonin functioning.

Objective: Considerable evidence suggests that low concentrations ofs-hydroxyindoleacetic acid (5-HIAA) in CSF are associated with a history ofaggressive behavior in both human and nonhuman primates. The purpose ofthis investigation was to examine the relationships among CSF 5-HIAA concentration, history ofaggressive behavior, and cerebral glucose metabolism in a group of nonhuman primates whose CSF 5-HIAA had been sampled several times over the preceding 2 years and whose social behavior had been observed since birth. Method: The subjects were nine adult male rhesus monkeys studied under isoflurane anesthesia. Cerebral glucose utilization was measured by [‘8FJfluorodeoxyglucose positron emission tomography. Aggressiveness ratings were made by a primatologist who had had frequent contact with the animals over several years. Results: There was a significant negative correlation between ratings ofaggressive behavior and CSF 5-HIAA concentrations. There was also a negative correlation between the dose of pentobarbital required to induce anesthesia and level of CSF 5-HIAA. Moreover, there were significant negative correlations between CSF 5-HIAA levels and both whole brain glucose utilization and regionalgiucose utilization in the orbital-frontal cortex. Conclusions: These results suggest that both increased aggressiveness and low concentrations of CSF 5-HIAA are associated with higher brain glucose metabolism in rhesus monkeys under standardized anesthesia. Aggressive nonhuman primates with low CSF 5-HIAA concentrations may have “innate “ tolerance toward functionaly-aminobutyric acid A receptor agonists such as pentobarbital, isoflurane, and possibly alcohol. (Am J Psychiatry 1995; 152:1782-1787)

Objective: The purpose ofthis study was to examine the relationship between behavior and serotonin by using a nonhuman primate model of aggression and impulse control. Method: During a routine capture and medical examination, 26 adolescent male rhesus macaques (Macaca mulatta) were selected as subjects from a free-ranging population of 4,500 rhesus monkeys inhabiting a 475-acre sea island. Physiological data were obtained from 22-23 of the subjects. Blood and CSF samples were obtained, and each subject was fitted with a radio transmitter collar for rapid location. The subjects were released into their social groups, and quantitative behavioral observations were made over a 3-month period. Results: CSF 5-hydroxyindoleacetic acid (5-HIAA) concentrations were inversely correlated with “escalated” aggression, i.e., a measure ofmore intense or severe aggression as defined by the ratio of chases and physical assaults to all aggressive acts. CSF 5-HIAA concentrations were significantly lower in those subjects who showed evidence ofphysical wounding than in subjects with no wounds. Low CSF 5-HIAA concentrations were also correlated with greater risk-taking as determined by an analysis of leaping behaviors in the forest canopy. The ratio of long leaps (leaps that traversed the longest distances at dangerous heights) to all leaps was negatively correlated with CSF 5-HIAA concentrations. Conclusions: Adolescent male rhesus macaques with low CSF 5-HIAA concentrations are at risk for 1) exhibiting more violent forms of aggressive behavior and 2) loss of impulse control as evidenced by greater risk taking during movement through the forest canopy. (Am J Psychiatry 1 994; 15 1:1485-1491)