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Background: There has been considerable focus on the adolescent stage of development in the study of alcohol use and the etiology of alcohol-related problems. Because adolescence is a process of dynamic change rather than a discrete or static stage of development, it is important to consider ontogenetic changes in the response to ethanol within the adolescent time period. In rodents, levels of ethanol-induced motor impairment have been shown to increase from early to late adolescence. This study investigated associations between behavior following acute ethanol administration and age, rearing condition (mother-reared vs nursery-reared), and serotonin transporter (rh5-HTTLPR) genotype in a sample of alcohol-naïve adolescent rhesus macaques. Methods: Rhesus macaques ( n=97; 41 males, 56 females), ranging in age from 28 to 48 months, were administered intravenous (IV) doses of ethanol (2.2 g/kg for males, 2.0 g/kg for females) twice in 2 separate testing sessions. A saline/ethanol group ( n=16; 8 males, 6 females) was administered saline in 1 testing session and ethanol in the second session. Following each IV injection, subjects underwent a 30-minute general motor behavioral assessment. Behavior in the saline/ethanol group was compared between the saline and ethanol-testing sessions using analysis of variance. Behavioral data for the larger study sample were averaged between the 2 testing sessions and summarized using factor analysis. Rotated factor scores were used as dependent variables in multiple regression analyses to test for relationships between behavior and age, rearing condition, and rh5-HTTLPR genotype. Results: During the ethanol-testing session, behaviors indicative of motor impairment (stumbles, falls, sways, bumping the wall, and unsuccessful jumps) were frequently observed in the saline/ethanol group, while they did not occur under the saline-testing session. Factor analysis of behavior following ethanol administration in the larger study sample yielded 3 factors: Ataxia, Impaired Jumping Ability, and Stimulation. Significant negative correlations between age and Ataxia were found for both males and females. Females also exhibited positive correlations between age and Impaired Jumping Ability and age and Stimulation. No significant correlations were found with either rearing condition or rh5-HTTLPR genotype. Conclusions: These findings suggest that ontogenetic changes during adolescence in the behavioral response to ethanol differ between rodents and primates. Furthermore, sex differences in the behavioral response to ethanol appear to develop during adolescence. [ABSTRACT FROM AUTHOR]

BACKGROUND: The etiology of alcoholism and alcohol abuse, like many other complex diseases, is heterogeneous and multifactorial. Numerous studies demonstrate a genetic contribution to variation in the expression of alcohol-related disorders in humans. Over the past decade, nonhuman primates have emerged as a valuable model for some aspects of human alcohol abuse because of their phylogenetic proximity to humans. Long-term, longitudinal studies of rhesus macaques (Macaca mulatta) have provided much insight into environmental influences, especially early life experiences, on alcohol consumption and behavior patterns that characterize alcohol intake later in life. It is not known, however, whether there is a genetic component as well to the variation seen in alcohol consumption in rhesus macaques. A significant genetic component to variation in alcohol consumption in rhesus macaques would show for the first time that like humans, for nonhuman primates additive genetic influences are important. Moreover, their use as a model for alcohol-related disorders in humans would have even greater relevance and utility for designing experiments incorporating the expanding molecular genetics field, and allow researchers to investigate the interaction among the known environmental influences and various genotypes. METHODS: In this study, we investigate factors contributing to variation in alcohol consumption of 156 rhesus macaques collected over 10 years when subjects were adolescent in age, belonging to a single extended pedigree, with each cohort receiving identical early rearing backgrounds and subsequent treatments. To measure alcohol consumption each animal was provided unfettered simultaneous access both to an aspartame-sweetened 8.4% (v/v) alcohol-water solution, the aspartame-sweetened vehicle, and to water for 1 hour each day during the early afternoon between 13:00 and 15:00 in their home cages for a period of 5 to 7 weeks. We use multiple regression to identify factors that significantly affect alcohol consumption among these animals and a maximum likelihood program (ASReml) that, controlling for the significant factors, estimates the genetic contribution to the variance in alcohol consumption. RESULTS: Multiple regression analysis identified test cohort and rearing environment as contributing to 57 and 2%, respectively, of the total variance in alcohol consumption. Of the remaining 41% of the variance about half (19.8%) was attributable to additive genetic effects using a maximum likelihood program. CONCLUSION: This study demonstrates that, as in humans, there are additive genetic factors that contribute to variation in alcohol consumption in rhesus macaques, with other nongenetic factors accounting for substantial portions of the variance in alcohol consumption, Our findings show the presence of an additive genetic component and suggest the potential utility of the nonhuman primate as a molecular genetics tool for understanding alcohol abuse and alcoholism. [ABSTRACT FROM AUTHOR]

Behavioral inhibition (BI), a temperamental trait first described by Jerome Kagan, is characterized by wariness to unfamiliar persons and novel situations. BI is a moderately stable trait, with biological and genetic underpinnings. Kagan's methodology for assessing BI is widely used in humans. Although this paradigm could be readily translated for use in nonhuman primates, thereby increasing generalizability from nonhuman primates to humans and fortifying evidence that BI is evolutionarily conserved, researchers have not done so. To address this, this study utilized a modified version of Kagan's paradigm to assess behaviors and biological markers of BI in nonhuman primates. Over the first 5 weeks of life, nursery-reared rhesus monkeys ( Macaca mulatta; N = 12) were rated using the standardized Infant Behavior Assessment Scale for nonhuman primates on measures related to BI (consolability, irritability, struggle, and predominant state). Three months later, behavioral assessments were made in relation to a novel playroom, an unfamiliar peer, and a variety of attention-grabbing, unfamiliar stimuli, followed by the introduction of a human stranger. Behaviors from Kagan's studies of BI in toddlers (freezing, exploration, and latency to approach) and physiological measures related to BI (heart rate) were assessed. Random effects models showed that subjects rated high in temperamental BI spent less time exploring the environment and socializing with peers and more time freezing (an indication of anxiety in rhesus monkeys). These findings suggest that Kagan's paradigm is readily adapted for use in nonhuman primates and support the utility of rhesus monkeys as translational models for assessing the causes and consequences of human BI. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Aberrant functioning of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of conditions such as depression, anxiety disorders, and post-traumatic stress disorder. Early-life adversity and genetic variation can interaction to disrupt HPA axis regulation, potentially contributing to certain forms of psychopathology. This study employs a rhesus macaque model to investigate how early parental neglect interacts with a single nucleotide polymorphism within the promoter region of the corticotropin-releasing hormone (CRH-248) gene, impacting the development of the HPA axis. For the initial six months of life, 307 rhesus monkey infants ( n  = 146 females, n  = 161 males) were either reared with their mothers (MR) in conditions emulating the natural environment (control group) or raised without maternal care in groups with constant or 3-hours daily access to same-aged peers (NR). Blood samples collected on days 30, 60, 90, and 120 of life under stressful conditions were assayed for plasma cortisol and adrenocorticotropic hormone (ACTH) concentrations. Findings revealed that NR subjects exhibited a significant blunting of both ACTH and cortisol concentrations. Notably, there was a gene-by-environment interaction observed for ACTH and cortisol levels, with NR subjects with the polymorphism displaying higher ACTH concentrations and lower cortisol concentrations. To the extent that these results generalize to humans, they suggest that early parental neglect may render individuals vulnerable to HPA axis dysfunction, a susceptibility that is modulated by CRH-248 genotype-a gene-by-environment interaction that leaves a lasting developmental signature.

Studies show that maternal behaviors are mediated by the bivariate serotonin transporter (5-HTT) genotype, although the findings are mixed, with some studies showing that mothers with the s allele exhibit increased maternal sensitivity, while other studies show that mothers with the s allele show decreased maternal sensitivity. Nonhuman primate studies offer increased control over extraneous variables and may contribute to a better understanding of the effects of the 5-HTT genotype on maternal sensitivity. This study assesses the influence of 5-HTT genotype variation on maternal sensitivity in parenting in 125 rhesus macaque mothers (Macaca mulatta) during the first three-months of their infants' lives, an age well before typical infants undergo weaning. Mothers were genotyped for the 5-HTT genotype and maternal behaviors were collected, including neglectfulness, sensitivity, and premature rejections during undisturbed social interactions. Results showed that mothers homozygous for the s allele rejected their infants the most and restrained their infants the least, an indication that mothers with the s allele are more likely to neglect their infants' psychological and physical needs. These findings suggest that, at an age when an infant's needs are based on warmth, security, and protection, mothers with an s allele exhibit less sensitive maternal behaviors. High rates of rejections and low rates of restraints are behaviors that typically characterize premature weaning and are inappropriate for their infant's young age. This study is an important step in understanding the etiology of variability in maternal warmth and care, and further suggests that maternal 5-HTT genotype should be examined in studies assessing genetic influences on variation in maternal sensitivity, and ultimately, mother-infant attachment quality., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Wood et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

It is widely held that the central monoamine neurotransmitters modulate alcohol intake. Few studies, however, directly assess the relationship between baseline and alcohol-induced monoamine turnover, as well as the change from baseline, as predictors of alcohol intake. Using a nonhuman primate model, this study investigates baseline, alcohol-induced and alcohol-induced change in monoamine activity and their relationship with alcohol intake. Alcohol-naïve, adolescent rhesus macaques (Macaca mulatta, N = 114) were administered a standardized intravenous bolus of alcohol solution (16.8%, v/v) on two occasions, approximately 1 month apart. One month prior to and 1 h following each alcohol infusion, cisternal cerebrospinal fluid (CSF) was obtained and assayed for monoamine metabolite concentrations. Approximately 6-7 months later, subjects were allowed unfettered access to an aspartame-sweetened alcohol solution (8.4%, v/v) for 1 h/day, 5 days/week, over 5-7 weeks. Results showed strong positive correlations between baseline and post-infusion CSF monoamine metabolite concentrations, indicating a trait-like response. Low baseline and post-infusion serotonin and dopamine metabolite concentrations and a smaller change in serotonin and dopamine metabolites from one infusion to the next were associated with higher alcohol intake. Low baseline and post-infusion norepinephrine metabolite concentrations predicted high alcohol intake, but unlike the other monoamines, a greater change in norepinephrine metabolite concentrations from one infusion to the next was associated with higher alcohol intake. These findings suggest that individual differences in naturally occurring and alcohol-induced monoamine activity, as well as the change between exposures, are important modulators of initial alcohol consumption and may play a role in the risk for excessive alcohol intake., (© 2022 Society for the Study of Addiction. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

While non-suicidal self-injury (NSSI) occurs in the general population at a surprisingly high rate, with higher rates among certain clinical  populations, its etiology is not well-understood. Consequently, the DSM-5 lists NSSI as requiring further research. This study utilizes a translational model of naturally-occurring NSSI to assess the role of early parental neglect and variation in the serotonin transporter genotype (5-HTT) in the etiology of NSSI. Subjects (N = 161) were rhesus macaques (Macaca mulatta) reared in one of three conditions (mother-reared (MR), peer-reared (PR), or surrogate peer-reared (SPR)), and classified as NSSI (n = 18) or non-NSSI (n = 143). Subjects were genotyped for 5-HTT and their behaviors were recorded during an ecologically-meaningful, stress-evoking, intruder paradigm. Two weeks prior to testing, blood samples were obtained and assayed for plasma cortisol and adrenocorticotropic hormone (ACTH) concentrations. NSSI subjects were more likely to be SPR, paralleling human studies showing that individuals that exhibit NSSI tend to have experienced abuse or neglect early in life. Results also indicated that variation in the 5-HTT genotype differentiated the NSSI subjects. NSSI subjects that were homozygous for the L allele exhibited high plasma ACTH and high rates of stress-induced stereotypies; whereas NSSI subjects with the s allele exhibited impulsive behaviors, including frequently approaching the potentially dangerous intruder, high rates of aggressive vocal threats, and more activity. These results suggest that there may be different 5-HTT genotype-mediated NSSI typologies and that both early experiences and variation in the 5-HTT genotype may be important factors in understanding the etiology of NSSI., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

A variety of studies show that the s-allele of the serotonin transporter genotype (5-HTT) is related to aggression. However, influences of sex and 5-HTT genotype of both subject and opponent have not received as much attention in aggression research. Using a nonhuman primate model, the present study explores differences in rates of aggression exhibited by 201 group-housed male and female rhesus monkeys (Macaca mulatta; 122 females; 79 males) exposed to an unfamiliar age- and sex-matched stranger while in the presence of other same-sex members of their social group. The study also assesses whether the rates of aggression increase when the home-cage resident, the unfamiliar stimulus animal, or both possess the short (s) allele of the 5-HTT. Results showed that, when compared to females, males exhibited higher rates of physical aggression toward the stranger, and when both the male resident and the male stranger possessed the s-allele, rates of physical aggression toward the stranger increased five-fold. Resident females also engaged in higher rates of physical aggression when they possessed the s-allele, although unlike the males, their physical aggression was directed toward familiar same-sex members of their social group. The findings of this study indicate that rates of physical aggression are modulated by 5-HTT resident and stranger suggest a role of sexual competition in the phenotype of the 5-HTT genotype. Importantly, when two males with impulse deficits, as a function of the s-allele, are placed together, rates of violence exhibited by the dyad escalate substantially., (Copyright © 2021. Published by Elsevier Inc.)

A μ-opioid receptor (OPRM1) single-nucleotide-polymorphism, found in both humans and rhesus macaques mediates the mother-infant attachment bond. Because mothers treat their sons and daughters differently, it is somewhat surprising that the role of infant sex has not been assessed in the context of a maternal-OPRM1-genotype-by-infant-sex interaction. The present study investigates the effect of maternal-OPRM1-genotype and infant sex on mother-infant behaviors. Over the first 6 months of offspring life, mother-infant behavioral data assessing attachment quality was collected twice weekly from a large number of rhesus monkey mother-infant pairs ( N = 161 dyads; n = 64 female infants, n = 97 male infants). Mothers were genotyped for OPRM1 variation. Factor analysis of the observed behaviors showed two factors: Attachment (maternal-infant cradling, rejections, and infant approaches and leaves), and Maternal Restraints (mother restrains infant, preventing exploration). Further analyses showed a two-way, maternal-genotype-by-infant-sex interaction for both factors. For Attachment, mothers with the CC genotype cradled and restrained (Maternal Restraints) their female infants more and rejected them less, when compared to female infants of CG mothers. Perhaps as a consequence, female infants of CC genotype mothers approached and left their mothers less often, when compared to female infants of CG mothers, likely an indication that female infants from mothers with CG genotype play a greater role in maintaining the mother-infant bond than do female infants from CC genotype mothers. This finding may also indicate a more secure attachment in infants from CC genotype mothers. Unlike female infants, on average, the mother-infant relationship of dyads with a male infant was largely undifferentiated by maternal genotype. These findings suggest that, in contrast to female infants from CG mothers, CC mothers and their female infants appear to have a closer mother-infant relationship which may portend close life-long bonds, as mothers and female offspring remain together throughout life. Male offspring appear to have a more aloof mother-infant bond regardless of OPRM1-genotype. The results of this study indicate that maternal-OPRM1 variation mediates mother-infant attachment behaviors for female infants and has less effect for male infants. This suggests that offspring sex should be included in studies investigating the effect of maternal-OPRM1 genotype on the mother-infant attachment relationship., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wood, Baron, Schwandt, Lindell, Barr, Suomi and Higley.)

Objective: Adopted children tend to show an increased risk for a variety of psychopathological outcomes, even when adoption occurs at birth, which some suggest is a result of nonrandom assignment of adoptees and parents. This study uses a nonhuman primate model, in which adoptions were randomly assigned, to investigate the behavioral and physiological outcomes associated with at-birth adoption., Method: Immediately following birth, rhesus monkey infants were randomly assigned to be reared by either their biological mother (n = 113) or by an unrelated, lactating, adoptive mother (n = 34). At 6 months of age, infant behavior and physiology were assessed during a stressful series of mother-infant separations. Four years later, stress-related behaviors were measured following confrontation by an unfamiliar intruder, an ecologically meaningful stressor., Results: When compared to infants reared by their biological mothers, adopted infants exhibited more behavioral withdrawal and higher plasma adrenocorticotropic hormone (ACTH) concentrations in response to separation. These behavioral differences persisted 4 years later during a stressful intruder challenge, with adoptees exhibiting more behavioral withdrawal, stereotypies, and impulsive approaches of the potentially aggressive intruder., Conclusion: Compared to infants reared by their biological mothers, adopted infants exhibited more behavioral inhibition, impulsivity, and higher ACTH concentrations, even when subjects were randomly assigned to be adopted or to remain with their biological mother. To the extent that these findings generalize to humans, they suggest that the overall risk for psychopathology in adopted individuals persists even after random assignment to adoption conditions., (Copyright © 2021 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Temperament is an individual's nature and is widely believed to have a heritable foundation. Few studies, however, have evaluated paternal and maternal contributions to the triadic dimensions of temperament. Rhesus monkeys are widely utilized to model genetic contributions to human development due to their close genetic-relatedness and common temperament structure, providing a powerful translational model for investigating paternal and maternal genetic influences on temperament. The temperament of rhesus monkey infants born to 19 different sires and 50 different dams was assessed during the first month of life by comparing the temperament of paternal or maternal half-siblings reared with their mothers in species-normative conditions or reared in a neonatal nursery. Factor scores from three dimensions of temperament were obtained (Orienting/Regulation, Negative Affectivity, and Surgency/Extraversion) and ANOVAs were used to assess genetic effects. For paternal half-siblings, results showed a statistically significant paternal contribution to Orienting/Regulation, Negative Affectivity, and Surgency/Extraversion factor scores. For maternal half-siblings, results showed a statistically significant contribution to Orienting/Regulation factor scores. When parsed by early rearing condition, results showed a paternal contribution Orienting/Regulation, Negative Affectivity, and Surgency/Extraversion scores for paternal half-siblings reared in the neonatal nursery, while there was only a paternal contribution to Surgency/Extraversion for paternal half-siblings reared by their mothers. There was only a maternal contribution to Orienting/Regulation for maternal half-siblings reared by their mothers. These results show that paternal and maternal contributions to temperament vary by environmental context, and that mothers may environmentally buffer their infants from paternal contributions to their temperament., (© 2021 Wiley Periodicals LLC.)

Few studies have longitudinally assessed the relationship between infant stress reactivity and future parenting style. Studies show that stress-induced plasma cortisol concentrations are stable over development and that they can be utilized as a marker for stress reactivity. This study investigates the relationship between stress-induced plasma cortisol concentrations in infancy and later parenting behavior in a translational nonhuman primate model. We hypothesized that higher stress-induced cortisol levels in infancy would predict impairments in maternal behaviors in adulthood. Subjects were rhesus macaque females (N = 122; Macaca mulatta), assessed as infants and again as mothers. At 3-4 months of age, subjects underwent a standardized BioBehavioral Assessment during which blood samples were obtained and they were assessed for behaviorally inhibition. Approximately 7 years later, subjects were observed as they interacted with their own offspring for four 300-s sessions. Typical rhesus monkey mother-offspring behaviors were recorded, including approaches and leaves and maternal cradling. Results showed that subjects' stress-induced cortisol concentrations and whether they exhibited behavioral inhibition as infants predicted later maternal behavior, with high cortisol concentrations and behavioral inhibition predicting high rates of offspring approaches and leaves and low rates of maternal cradling. Results also showed that higher stress-induced cortisol concentrations in infancy predicted higher scores on the Brown Index, an indication that the subjects' offspring, rather than the subject themselves, initiated changes in proximity. Taken together, these results suggest that individuals that exhibit higher stress-induced cortisol concentrations and behavioral inhibition at 3-4 months of age are at risk for engaging in less sensitive parenting behaviors as adults. To the extent that these findings generalize to humans, they suggest an important link between stress-induced cortisol concentrations and behavioral inhibition in infancy and behavior later in life, such that early-life stress reactivity can serve as a marker for later parenting behavior., (© 2021 Wiley Periodicals LLC.)

A variety of studies show that parental absence early in life leads to deleterious effects on the developing CNS. This is thought to be largely because evolutionary-dependent stimuli are necessary for the appropriate postnatal development of the young brain, an effect sometimes termed the "experience-expectant brain," with parents providing the necessary input for normative synaptic connections to develop and appropriate neuronal survival to occur. Principal among CNS systems affected by parental input are the monoamine systems. In the present study, N = 434 rhesus monkeys (233 males, 201 females) were reared in one of two conditions: as mother-reared controls (MR; n = 269) or without adults with 24-h access to same-aged peers (PR; n = 165). When subjects were six-months-old, they underwent a separation paradigm involving 4, sequential, four-day social separations from their mothers or peers, with each separation followed by three-day reunions with their mothers or their peers. Prior to the separation paradigm, baseline cisternal CSF samples were obtained, as well as at the end of each the four social separations, and after final separation, during a recovery period. CSF was assayed for concentrations of monoamine metabolites and a blood sample was genotyped for the serotonin transporter (5-HTT) genotype. Replicating earlier landmark findings, PR subjects with the s allele exhibited lower baseline concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), when compared to PR subjects homozygous for the L allele. MR subjects were undifferentiated by genotype. PR subjects exhibited lower CSF 5-HIAA concentrations during baseline, but higher CSF 5-HIAA during social separations, when compared to MR subjects. There were rearing effects for the dopamine metabolite homovanillic acid (HVA) and for the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), with PR subjects showing higher HVA and lower MHPG when compared to MR subjects. These findings indicate that there are long-term deficits in the response of monoamines following early maternal absence. The results of this study confirm and extend earlier findings that early parental absence has deleterious consequences for the development of the monoamine systems, and that these consequences are modulated by the 5-HTT genotype., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wood, Gabrielle, Hunter, Skowbo, Schwandt, Lindell, Barr, Suomi and Higley.)

Attempts to describe the latent structure of human infant temperament have led some to suggest the existence of three major dimensions. An earlier exploratory factor analysis (EFA) supported a triadic structure of temperament in week-old rhesus monkey infants, paralleling the structure in human infants. This study sought to confirm the latent triadic structure of temperament across the first month of life in a larger sample of rhesus monkey infants (N = 668), reared by their mothers or in a neonatal nursery. A weekly behavioral assessment was obtained during the first month of life using a subset of items from the widely utilized Infant Behavioral Assessment Scale (IBAS), an instrument designed to measure temperament in infant monkeys. Using the latent constructs proposed by the earlier EFA (Orienting/Regulation, Negative Affectivity, Surgency/Extraversion), multi-group, multi-time point confirmatory factor analyses were conducted to confirm the latent temperament structure across rearing groups at each time point (weeks 1-4). Results confirm and extend those of the earlier EFA: latent Orienting/Regulation,  Negative Affectivity, and Surgency/Extraversion constructs were present across the rearing groups at each time point, with the IBAS items consistently loading onto the latent factors to a similar degree across rearing groups at each time point. These findings suggest foundational evolutionary roots for the triadic structure of human infant temperament, but that its behavioral manifestations vary across maturation and rearing condition. Similarities in latent temperament structure in humans and a representative nonhuman primate highlights the potential for utilizing translational nonhuman primate models to increase understanding of human temperament., (© 2020 Wiley Periodicals, Inc.)

This longitudinal study spans two generations of rhesus monkeys. First, the study investigates the effects of early rearing experiences on the maternal behavior of first-generation mothers (rates of premature infant rejection) and, second, the study investigates the effects of maternal rejection on the behavior of second-generation infants. Rhesus macaque mother-infant dyads (Macaca mulatta-N = 176) were observed twice weekly, with each session lasting 300 s. First-generation mothers were raised in one of three conditions: as mother-reared controls (MR; [n = 95]), in peer groups (PR; raised without adults but with constant access to three same-aged peers [n = 49]), or with an inanimate surrogate (SPR; raised with an inanimate fleece-covered, surrogate mother and limited daily peer-group interactions [n = 32]). Second-generation infants were all raised by their differentially reared mothers and statistically grouped into one of two groups: those that were rejected by their mothers beginning at a more-typical weaning age (controls), starting in the third month of life (n = 108), and those that were prematurely rejected, with mothers showing rejections before the third month of infant life (n = 68). Overall, PR mothers exhibited the highest rates of premature infant rejection, except for month 1 of infant life, when SPR mothers exhibited the highest rates of rejection. Intriguingly, after month 1, SPR mothers showed high rates of infant cradling and seldom rejected their infants. Independent of their mothers' early rearing environment, prematurely rejected infants displayed more aggression and passive vigilance, and were cradled and groomed less by their mothers, and there was evidence that the overall rates of rejection after the first 2 months of life had a cumulative negative effect on the developing infant. Post hoc analyses of plasma cortisol levels showed that the prematurely rejected infants had higher cortisol concentrations, suggesting a high level of stress in the prematurely rejected infants. These results suggest that maternal presence during infancy has long-term effects on a female's future maternal skills which, in turn, have intergenerational consequences for the socioemotional development of second-generation infants., (© 2020 Wiley Periodicals, Inc.)

The second-to-fourth digit (2D:4D) ratio is a sexually-dimorphic biomarker for prenatal sex hormone exposure. We investigated whether titi monkeys (Plecturocebus cupreus) exhibit sexually-dimorphic 2D:4D ratio, and whether variation in 2D:4D ratio correlates with maternal testosterone and estrogen levels during early pregnancy. Subjects were 61 adult titi monkeys (32 males, 29 females). For 26 subjects, maternal urine samples were collected approximately 15-20 weeks before birth and assayed for testosterone and estrone conjugate (E 1 C). Titi monkeys exhibited a human-like pattern of sexual dimorphism in right-hand 2D:4D ratio, with females exhibiting higher 2D:4D ratio than males (β = -0.29, p = 0.023). For left-hand 2D:4D ratio, high levels of maternal E 1 C predicted low offspring 2D:4D ratio (β = -0.48, p = 0.009). For right-hand 2D:4D ratio, high levels of testosterone (β = -0.53, p = 0.005) and testosterone-to-E 1 C ratio (β = -0.41, p = 0.028) predicted low offspring 2D:4D ratio. For 2D:4D ratio asymmetry (right-hand - left-hand), high levels of testosterone (β = -0.43, p = 0.03) and testosterone-to-E 1 C ratio (β = -0.53, p = 0.003) predicted low (right-biased) asymmetry. This is the first report of sexually-dimorphic 2D:4D ratio in New World monkeys, and the results support a growing literature suggesting prenatal sex hormones may modulate offspring 2D:4D ratio., (© 2019 Wiley Periodicals, Inc.)

Teenage alcohol abuse is a major health concern, particularly because the majority of alcohol consumed by teenagers is via binge drinking, a known risk factor for increasing the likelihood for the development of future alcohol use disorders (AUDs). Identifying individuals at risk for excessive alcohol intake in adolescence is a step toward developing effective preventative measures and intervention programs. As adults with AUDs tend to self-medicate their anxiety with alcohol, this longitudinal study assesses the role of infant anxiety-like temperament in the development of adolescent alcohol abuse using a nonhuman primate model. From birth until they were 5 months of age, behaviors of 64 rhesus monkeys (Macaca mulatta) were coded twice a week using an objective mother-infant scoring system that included behaviors traditionally used to assess anxiety and fearfulness in rhesus monkeys. When subjects were four months old, plasma cortisol was obtained. When subjects were adolescents (M age = 44.88 months), another plasma cortisol sample was obtained about one month prior to allowing them unfettered access to an 8.4% (v/v) aspartame-sweetened alcohol solution for one hour a day over five-to-seven weeks. Results showed that behavioral indications of anxiety-like temperament in infancy, including high levels of mother-infant mutual ventral contact, low levels of environmental exploration, and low levels of interactions with peers were predictive of high adolescent alcohol intake (ie, drinking to intoxication). Plasma cortisol levels in infancy were positively correlated with plasma cortisol in adolescence, and both were positively correlated with high adolescent alcohol intake. Our findings indicate that high levels of traditional anxiety-like behaviors measured in the context of mother-infant interactions, coupled with high infant and adolescent plasma cortisol, are associated with binge-like high alcohol intake in adolescence, suggesting that individuals at risk for developing an AUD later in life may be determined, at least in part, by assessing their physiological and behavioral propensity for anxiety early in life., (© 2019 Society for the Study of Addiction.)

Identifying predictors of teenage alcohol use disorder (AUDs) is a major health initiative, with studies suggesting that there are distinct personality-related traits that underlie patterns of alcohol intake. As temperament is biologically based, identifiable early in life, and stable across time, it is considered the foundation of personality. As such, we hypothesized that neonatal temperament traits would predict anxiety-mediated adolescent alcohol consumption. To test this, N = 145 rhesus macaque (Macaca mulatta) infants (14 days of age), reared in a neonatal nursery (n = 82) or in a control condition with their mothers (n = 63) were assessed with a widely used standardized nonhuman primate testing battery, the Infant Behavioral Assessment Scale (IBAS), modeled after the Brazelton Neonatal Assessment Scale, evaluating visual orienting, temperament, motor maturity and, more recently, sensory sensitivity. As adolescents (3-4 years of age), these same subjects were allowed unfettered access to a sweetened-alcohol solution for 1 hr/day, 4 days/week, over 5-7 weeks. Subjects were allowed to self-administer alcohol while housed alone (n = 70) or socially in their home cage (n = 55). Linear regressions showed that alcohol intake was predicted by neonatal orienting ability (β = -.35; p = .01), state control (β = -.19; p = .04), and motor maturity (β = -.24; p = .01). Poor neonatal orienting, state control (ease of consolability), and motor maturity were associated with higher adolescent alcohol intake in rhesus monkeys. These findings suggest that neonatal temperament is predictive of patterns of adolescent alcohol intake. To the extent that these results generalize to humans, they provide evidence that early-life temperament and neurodevelopment may be important risk factors for adolescent AUDs and that the IBAS may be used as an assessment tool for identifying such risk., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

The second-to-fourth digit ratio (2D:4D ratio) is considered a postnatal proxy measure for the degree of prenatal androgen exposure (PAE), which is the primary factor responsible for masculinizing the brain of a developing fetus. Some studies suggest that the organizational effects of PAE may extend to the hypothalamic-pituitary-adrenal (HPA) axis response to stress. This study investigates the relationship between 2D:4D ratio and HPA axis functioning using a rhesus monkey ( Macaca mulatta ) model. Subjects were N = 268 (180 females, 88 males) rhesus monkey infants (3-4 months of age). Plasma cortisol concentrations were assayed from two blood samples obtained during a 25-h experimental social separation stressor at 2- and 7-h post-separation. Subjects' 2D:4D ratio was measured later in life ( M age = 6.70 years). It was hypothesized that infant rhesus monkeys that exhibited a more masculine-like 2D:4D ratio would show lower levels of circulating cortisol after a social separation and relocation stressor. The results showed that there was a sex difference in the left-hand 2D:4D ratio. The results also showed that there was an overall sex difference in cortisol concentrations and that female, but not male, monkeys that exhibited a more masculine-like right- and left-hand 2D:4D ratio exhibited lower mean stress-induced cortisol concentrations early in life. These findings suggest that higher levels of prenatal androgens in females, as measured by 2D:4D ratio, may be related to an attenuated HPA axis stress-response, as measured by plasma cortisol levels. To the extent that these findings generalize to humans, they suggest that the organizational effects of PAE extend to the infant HPA axis, modulating the HPA axis response, particularly in females., (Copyright © 2020 Wood, Jarman, Cash, Baxter, Capitanio and Higley.)

Environmental and biological factors contribute to sleep development during infancy. Parenting plays a particularly important role in modulating infant sleep, potentially via the serotonin system, which is itself involved in regulating infant sleep. We hypothesized that maternal neglect and serotonin system dysregulation would be associated with daytime sleep in infant rhesus monkeys. Subjects were nursery-reared infant rhesus macaques (n = 287). During the first month of life, daytime sleep-wake states were rated bihourly (0800-2100). Infants were considered neglected (n = 16) if before nursery-rearing, their mother repeatedly failed to retrieve them. Serotonin transporter genotype and concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) were used as markers of central serotonin system functioning. t tests showed that neglected infants were observed sleeping less frequently, weighed less, and had higher 5-HIAA than non-neglected nursery-reared infants. Regression revealed that serotonin transporter genotype moderated the relationship between 5-HIAA and daytime sleep: in subjects possessing the Ls genotype, there was a positive correlation between 5-HIAA and daytime sleep, whereas in subjects possessing the LL genotype there was no association. These results highlight the pivotal roles that parents and the serotonin system play in sleep development. Daytime sleep alterations observed in neglected infants may partially derive from serotonin system dysregulation.

Prenatal androgen exposure (PAE) plays a pivotal role in masculinizing the developing body and brain, and extreme exposure may contribute to autism, anxiety disorder and schizophrenia. One commonly used biomarker for PAE is the pointer-to-ring-finger digit length (2D:4D) ratio. Although this biomarker is widely used in human studies, relatively few studies have investigated 2D:4D ratio in nonhuman primates, particularly rhesus macaques ( Macaca mulatta ), one of the most commonly used animals in biomedical research. Thus far, data suggest that sexual dimorphism in 2D:4D ratio may be in the opposite direction in some monkey species, when compared to the pattern exhibited by humans and great apes. Using a large sample size, we investigated whether rhesus monkeys' 2D:4D ratio shows the same sex-differentiated pattern present in other Old World monkey species. We also investigated whether individual differences in 2D:4D ratio are associated with the social dominance rank of subjects' mothers during pregnancy, and the social dominance rank the subjects attained as adults. Subjects were 335 rhesus monkeys between 3 years and 24 years of age ( M = 6.6). Maternal dominance rank during pregnancy and subjects' adult dominance rank were categorized into tertiles (high, middle and low). Results showed that, across both hands, male rhesus monkeys exhibited higher 2D:4D ratio than females, a pattern consistent with other monkey species and a reversal from the pattern typically observed in humans and apes. This sex difference was modulated by maternal dominance rank, with female offspring of high-ranking and middle-ranking mothers exhibiting masculinized 2D:4D ratio, indicating that maternal dominance rank during pregnancy may influence levels of PAE. There was no association between subjects' 2D:4D ratio and the social dominance rank they attained as adults. These findings show a consistent sex difference in Old World monkeys' 2D:4D ratio that diverges from the pattern observed in apes and humans, and suggest maternal social dominance rank modulates PAE in rhesus monkeys.

Background: Type 2 alcoholism is characterized by low serotonin system functioning and has a high degree of heritability, with offspring of alcoholics often showing a reduced response to the intoxicating effects of ethanol (EtOH), which is thought to be marker for future alcohol use disorders (AUDs). As such, an important aim of studies investigating the origins of AUDs is to understand the relationship between serotonin system functioning and level of intoxication. A nonhuman primate model was used to evaluate observational ratings of sensitivity to EtOH and to further investigate the relationship between central serotonin activity and behavioral response to EtOH., Methods: Cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) were obtained from 4 cohorts of alcohol-naïve, adolescent rhesus macaques (N = 82, 45 females, 37 males). One to 3 months after the CSF sample, subjects were administered a standardized intravenous EtOH bolus (males: 2.1 g/kg body weight, females: 2.0 g/kg body weight), placed into an open-top, clear plexiglass chamber suspended from the ceiling, and their latency to escape was recorded as a measure of the degree of intoxication. Thereafter, subjects were rated using a Likert scale for the degree of intoxication during a 30-minute observation period., Results: Our results indicate that latency to escape from the chamber was associated with intoxication ratings (p = 0.0009) following the standardized intravenous administration of EtOH. Low CSF 5-HIAA concentrations predicted short escape latency (p = 0.007) and were associated with low intoxication ratings (p = 0.02), indicating that low central nervous system (CNS) serotonin functioning is related to relative insensitivity to the intoxicating effects of alcohol., Conclusions: Our study shows that, in monkeys exposed to alcohol for the first time, objective measures of intoxication are associated with subjective ratings for intoxication, and both were associated with CSF 5-HIAA concentrations. Our data confirm and extend the finding that low CNS serotonin functioning is predictive of intrinsic low sensitivity to the intoxicating effects of EtOH., (Copyright © 2017 by the Research Society on Alcoholism.)

We measured skin conductance response (SCR) to escalating levels of a direct social threat from a novel, ecologically-relevant experimental paradigm, the Intruder Threat Task. We simultaneously evaluated the contribution of social symptom severity and behavioral movement. Children with AS group showed less psychophysiological reactivity to social threat than controls across all three phases of the experiment. In the AS group, greater social impairment was significantly associated with reduced SCR. However, movement activity predicted SCR while diagnosis did not. Research and treatment need to account for the complex interplay of emotional reactivity and social behavior in AS. Psychophysiology studies of AS should consider the impact of possible confounds such as movement.

Although the notion that alcohol promotes violence is widespread, not all individuals are aggressive while intoxicated. Genetic variation could be a contributing factor to individual differences in alcohol-heightened aggression. The present study examines the effects of OPRM1C77G genotype on responses to threat in rhesus macaques under normal conditions and following alcohol administration. Prior studies have shown that a low CSF level of 5-HIAA is a trait marker for individuals prone to escalated aggression. We wanted to examine whether the predictive value for this marker on aggression was moderated by OPRM1 genotype. Animals were administered alcohol (BAC 100-200 mg%), were provoked by a human intruder, and aggressive responses were recorded. Factor analysis was performed to generate aggressive response factors, which were then used as dependent variables for ANOVA, with OPRM1 genotype and CSF 5-HIAA as independent variables. Factor analysis generated three factors ('Threatening', 'Distance Decreasing' and 'High Intensity'). We found that High Intensity aggression was increased among carriers of the OPRM1 G allele, especially among individuals with low CSF levels of 5-HIAA. Aggression in the non-intoxicated state was predicted by 5-HIAA, but not by genotype. This study demonstrates that OPRM1 genotype predicts alcohol-heightened aggression in rhesus macaques with low CSF levels of 5-HIAA. Because OPRM1 variation predicts similar effects on alcohol response and behavior in humans and macaques, this study could suggest a role for OPRM1 genotype in alcohol-heightened aggression in humans. If so, it may be that compounds that block this receptor could reduce alcohol-associated violence in selected patient populations., (© Published 2016. This article is a U.S. Government work and is in the public domain in the USA.)

Adaptations to stress can occur through epigenetic processes and may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing for H3K4me3 to examine effects of early maternal deprivation (peer-rearing, PR) in archived rhesus macaque hippocampal samples (male, n = 13). Focusing on genes with roles in stress response and behavior, we assessed the effects of rearing on H3K4me3 binding by ANOVA. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene OXTR , for which we observed a corresponding decrease in RNA expression. Based on this finding, we performed behavioral analyses to determine whether a gain-of-function nonsynonymous OXTR SNP interacted with early stress to influence relevant behavioral stress reactivity phenotypes ( n = 194), revealing that this SNP partially rescued the PR phenotype. PR infants exhibited higher levels of separation anxiety and arousal in response to social separation, but infants carrying the alternative OXTR allele did not exhibit as great a separation response. These data indicate that the oxytocin system is involved in social-separation response and suggest that epigenetic down-modulation of OXTR could contribute to behavioral differences observed in PR animals. Epigenetic changes at OXTR may represent predictive adaptive responses that could impart readiness to respond to environmental challenge or maintain proximity to a caregiver but also contribute to behavioral pathology. Our data also demonstrate that OXTR polymorphism can permit animals to partially overcome the detrimental effects of early maternal deprivation, which could have translational implications for human psychiatric disorders., Competing Interests: The authors declare no conflict of interest., (Copyright © 2017 the Author(s). Published by PNAS.)

Rationale: Although widely prescribed, little is known about the effects of selective serotonin reuptake inhibitors (SSRIs) on social behavior and cerebrospinal fluid (CSF) monoamines in female primates., Objective: The objective of this study was to determine the effects of sertraline on agonistic and affiliative behavior., Methods: Twenty-one adult female cynomolgus monkeys were housed in small, stable social groups, trained to participate in oral dosing, and began a 5-week cumulative dose-response study. Serial doses of 0, 5, 10, 15, and 20 mg/kg of sertraline were administered orally for 1 week each. Behavior was recorded daily during 10-min observations before and 4 h after dosing. On the seventh day of dosing, circulating sertraline/desmethylsertraline and CSF monoamines/metabolites were determined 4 h after the last dose., Results: At 20 mg/kg, circulating sertraline/desmethylsertraline was in the therapeutic range. CSF 5-hydroxyindole acetic acid decreased by 33 % (p < 0.05). Overall aggression, submission, locomotion, and time alone decreased, whereas affiliative behaviors (body contact, grooming) increased (all p values <0.05). Effects of sertraline on aggression and submission were social status-dependent, reducing aggression in dominants and submission in subordinates., Conclusions: A clinically relevant oral dose of sertraline resulted in CSF metabolite changes similar to those observed in patients and altered the socioemotional behavior of female monkeys. Changes in CSF 5-HT and dopamine are novel observations that may be sex-specific. The robust effects of sertraline on aggression and affiliation may explain the efficacy of SSRIs on a range of human behavioral pathologies that share the characteristics of increased aggression and decreased sociality.

Primate behavior is influenced by both heritable factors and environmental experience during development. Previous studies of rhesus macaques ( Macaca mulatta ) examined the effects of genetic variation on expressed behavior and related neurobiological traits (heritability and/or genetic association) using a variety of study designs. Most of these prior studies examined genetic effects on the behavior of adults or adolescent rhesus macaques, not in young macaques early in development. To assess environmental and additive genetic variation in behavioral reactivity and response to novelty among infants, we investigated a range of behavioral traits in a large number ( N = 428) of pedigreed infants born and housed in large outdoor corrals at the Oregon National Primate Research Center (ONPRC). We recorded the behavior of each subject during a series of brief tests, involving exposure of each infant to a novel environment, to a social threat without the mother present, and to a novel environment with its mother present but sedated. We found significant heritability ( h 2 ) for willingness to move away from the mother and explore a novel environment ( h 2 = 0.25 ± 0.13; P = 0.003). The infants also exhibited a range of heritable behavioral reactions to separation stress or to threat when the mother was not present ( h 2 = 0.23 ± 0.13-0.24 ± 0.15, P < 0.01). We observed no evidence of maternal environmental effects on these traits. Our results extend knowledge of genetic influences on temperament and reactivity in nonhuman primates by demonstrating that several measures of behavioral reactivity among infant rhesus macaques are heritable.

Background: Studies show that the hypothalamic-pituitary-adrenal (HPA) axis is dysregulated in depression. Some studies suggest that variation in the serotonin transporter genotype (hereafter 5HTT ) modulates both risk for depression and psychopathological HPA axis responsiveness. Rhesus monkeys are well suited to model such relationships. Rhesus macaque models of human psychopathology have assessed the effect of the serotonin transporter ( rh5HTT ) on levels of cortisol in stressed subjects. These studies show that that under conditions of stress, heterozygous females (Ls) reared under adversity exhibit high levels of cortisol. Studies have not to our knowledge, however, assessed the potential additive effect on the cortisol response in a number of macaque subjects homozygous for the serotonin transporter short allele (ss). Moreover, little is known about the level of the central or peripheral nervous system at which the 5HTT genotype acts to modulate the cortisol response., Methods: This study assesses a relatively large number of subjects homozygous and heterozygous for the rh5HTT short and long alleles (a) during stress; (b) following a dexamethasone suppression test; and (c) following an adrenocorticotropic hormone (ACTH) challenge. Subjects included 190 infant rhesus macaques ( Macaca mulatta - 84 males and 106 females; 118 LL, 60 Ls, and 12 ss subjects), obtaining two blood plasma samples during the stress of separation from their mothers. Then on the following day, we obtained a blood sample following a dexamethasone test, and later that day we obtained a blood sample after an ACTH challenge test. Subjects ranged in age between 90 and 128 days, with a mean age of 107 days., Results: Subjects homozygous for the short allele had significantly higher levels of cortisol across all test conditions, when compared to those homozygous for the long allele, or those heterozygous with Ls alleles. Subsequent analyses showed a high correlation between individual cortisol levels across the three different tests., Conclusions: These data suggest that subjects homozygous for the short allele are more likely to show dysregulated cortisol levels in response to stress. Given the correlation in individual responses of the HPA axis across the different tests, our data suggest that the effect of the 5HTT genotype shows some commonality in its regulation of stress, feedback, and ACTH-stimulated cortisol output. Our data suggest that under conditions of stress, the serotonin transporter may modulate HPA axis psychopathology.

In humans, it has been demonstrated that the serotonin transporter linked polymorphic region (5-HTTLPR) genotype moderates risk in the face of adversity. One mechanism by which stress could interact with genotype is via epigenetic modifications. We wanted to examine whether stress interacted with genotype to predict binding of a histone 3 protein trimethylated at lysine 3 (H3K4me3) that marks active promoters. The brains (N = 61) of male rhesus macaques that had been reared in the presence or absence of stress were archived and the hippocampusi dissected. Chromatin immunoprecipitation was performed with an antibody against H3K4me3 followed by sequencing on a SolexaG2A. The effects of age, genotype (5-HTTLPR long/long vs. short), and stress exposure (peer-reared vs. mother-reared) on levels of H3K4me3 binding were determined. We found effects of age and stress exposure. There was a decline in H3K4me3 from preadolescence to postadolescence and lower levels in peer-reared monkeys and no effects of genotype. When we controlled for age, however, we found that there were effects of 5-HTTLPR genotype and rearing condition on H3K4me3 binding. In a larger sample, we observed that cerebrospinal fluid 5-hydroxyindoleacetic acid levels were subject to interactive effects among age, rearing history, and genotype. Genes containing both genetic selection and epigenetic regulation may be particularly important in stress adaptation and development. We find evidence for selection at the solute carrier family C6 member 4 gene and observe epigenetic reorganization according to genotype, stress, and age. These data suggest that developmental stage may moderate effects of stress and serotonin transporter genotype in the emergence of alternative adaptation strategies and in the vulnerability to developmental or psychiatric disorders.

Background: As a model organism in biomedicine, the rhesus macaque (Macaca mulatta) is the most widely used nonhuman primate. Although a draft genome sequence was completed in 2007, there has been no systematic genome-wide comparison of genetic variation of this species to humans. Comparative analysis of functional and nonfunctional diversity in this highly abundant and adaptable non-human primate could inform its use as a model for human biology, and could reveal how variation in population history and size alters patterns and levels of sequence variation in primates., Results: We sequenced the mRNA transcriptome and H3K4me3-marked DNA regions in hippocampus from 14 humans and 14 rhesus macaques. Using equivalent methodology and sampling spaces, we identified 462,802 macaque SNPs, most of which were novel and disproportionately located in the functionally important genomic regions we had targeted in the sequencing. At least one SNP was identified in each of 16,797 annotated macaque genes. Accuracy of macaque SNP identification was conservatively estimated to be >90%. Comparative analyses using SNPs equivalently identified in the two species revealed that rhesus macaque has approximately three times higher SNP density and average nucleotide diversity as compared to the human. Based on this level of diversity, the effective population size of the rhesus macaque is approximately 80,000 which contrasts with an effective population size of less than 10,000 for humans. Across five categories of genomic regions, intergenic regions had the highest SNP density and average nucleotide diversity and CDS (coding sequences) the lowest, in both humans and macaques. Although there are more coding SNPs (cSNPs) per individual in macaques than in humans, the ratio of dN/dS is significantly lower in the macaque. Furthermore, the number of damaging nonsynonymous cSNPs (have damaging effects on protein functions from PolyPhen-2 prediction) in the macaque is more closely equivalent to that of the human., Conclusions: This large panel of newly identified macaque SNPs enriched for functionally significant regions considerably expands our knowledge of genetic variation in the rhesus macaque. Comparative analysis reveals that this widespread, highly adaptable species is approximately three times as diverse as the human but more closely equivalent in damaging variation.

The short allele of the serotonin transporter linked polymorphic region (5-HTTLPR) moderates the effects of stress on vulnerability to mood and anxiety disorders. The mechanism by which this occurs may relate to differential sensitivity to stressful life events. Here we explored whether 5-HTTLPR and sex affected behavioral responses to repeated maternal separation in infant rhesus macaques. Behaviors were collected during the acute (Day 1) and the chronic (Days 2-4) phases of the separation, and the effects of duration of separation (acute vs. chronic), genotype (long/long vs. short allele), and sex (male vs. female) on behavioral responses were analyzed across four successive separations. Males increased their levels of locomotion with repeated maternal separation, whereas females exhibited an increase in frequency of self-directed behavior, a measure of "depression-like" behavior. The short-allele predicted increased environmental exploration, particularly during the chronic phase of social separation, indicative of higher arousal. In addition, the short-allele carriers were more likely to increase their levels of self-directed behavior during the chronic phase of separation, as a function of repeated exposures. These findings suggest that the short allele may increase reactivity to repeated, chronic stressors, leaving them more vulnerable to affective psychopathology, with females particularly vulnerable.

The endogenous opioid system is involved in modulating a number of behavioral and physiological systems, including the hypothalamic-pituitary-adrenal (HPA) axis. In humans, a functional variant in the OPRM1 gene (OPRM1 A118G) is associated with a number of outcomes, including attenuated HPA axis responses to stress. A nonsynonymous variant (OPRM1 C77G) in the rhesus macaque has been shown to have similar effects in vivo to the human variant. The current study investigated whether OPRM1 C77G influences HPA axis response to stress in rhesus macaques. We analyzed plasma adrenocorticotropic hormone (ACTH) and cortisol levels measured in response to three different stressors: (1) maternal separation in infant subjects at 6 months of age, (2) acute ethanol administration in adolescent subjects at 4 years of age, and (3) postpartum HPA axis function in adult rhesus macaque females. For the maternal separation paradigm, ACTH and cortisol levels were determined at baseline as well as peak levels during each of 4 consecutive separation episodes. For the acute ethanol administration paradigm, hormone levels were determined at baseline and again at 5 min, 10 min, and 60 min following the ethanol infusion. For postpartum sampling, hormone levels were determined at postpartum days 7, 14, 21, 30, 60, 90, 120, and 150. Infants carrying the 77G allele exhibited lower levels of cortisol across all 4 separation episodes. Furthermore, adolescents carrying the 77G allele exhibited lower cortisol levels at 5 and 10 min following acute ethanol administration. Adult females with prior reproductive experience and who carry the 77G allele exhibited lower cortisol levels across the postpartum period. No significant genotype effects were found for ACTH, although there were some trends for lower ACTH levels in 77G allele carriers. These data are consistent with human studies that have demonstrated attenuated cortisol responses to stress among carriers of the OPRM1 118G allele, lending further support to the argument that the rhesus and human allelic variants are functionally similar. Our results also suggest that OPRM1 variation may influence coping style, as well as alcohol-induced and postpartum levels of HPA axis activity and, as such, may modify vulnerability to alcohol use disorders and postpartum depression., (Published by Elsevier Ltd.)

Background: Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. MATERIALS/METHODOLOGY: Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels., Results: Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation., Conclusion: We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants.

Background: Traumatic experiences in early childhood are associated with increased risk for developing mood and anxiety disorders later in life. Low serotonin(1A) receptor (5-HT(1A)R) density during development has been proposed as a trait-like characteristic leading to increased vulnerability of stress-related neuropsychiatric disorders., Methods: To assess the relationship between early-life stress and alterations in the serotonin system during development, we used positron emission tomography to measure in vivo 5-HT(1A)R density and apparent dissociation constant (K(D)(app)) in the brain of juvenile Rhesus monkeys exposed to the early-life stress of peer-rearing., Results: In general, 5-HT(1A)R density and K(D)(app) were decreased in peer-reared compared with control mother-reared animals. However, increase in receptor density was found in the dorsomedial prefrontal cortex of peer-reared females., Conclusions: These findings suggest that exposure to an adverse early-life environment during infancy is associated with long-term alterations in the serotonin system and support previous studies suggesting that reduced 5-HT(1A)R density during development might be a factor increasing vulnerability to stress-related neuropsychiatric disorders. Furthermore, alterations in the serotonin system seemed to be gender- and region-specific, providing a biological basis for the higher prevalence of affective disorders in women.

A powerful convergence of genetics, neuroimaging and epidemiological research has identified the biological pathways mediating individual differences in complex behavioral processes and the related risk for disease. Orthologous genetic variation in non-human primates (NHPs) represents a unique opportunity to characterize the detailed molecular and cellular mechanisms that bias behaviorally and clinically relevant brain function. We report that a rhesus macaque orthologue of a common polymorphism of the serotonin transporter gene (rh5-HTTLPR) has strikingly similar effects on behavior and brain morphology to those in humans. Specifically, the rh5-HTTLPR (S)hort allele broadly affects cognitive choice behavior and brain morphology without observably affecting the 5-hydroxytryptamine (5-HT) transporter or 5-HT(1A) concentrations in vivo. Collectively, our findings indicate that 5-HTTLPR-associated behavioral effects reflect genotype-dependent biases in cortical development rather than static differences in serotonergic signaling mechanisms. Moreover, these data highlight the vast potential of NHP models in advancing our understanding of human genetic variation affecting behavior and neuropsychiatric disease liability.

Context: Neuropeptide Y (NPY) counters stress and is involved in neuroadaptations that drive escalated alcohol drinking in rodents. In humans, low NPY expression predicts amygdala response and emotional reactivity. Genetic variation that affects the NPY system could moderate stress resilience and susceptibility to alcohol dependence., Objective: To determine whether functional NPY variation influences behavioral adaptation to stress and alcohol consumption in a nonhuman primate model of early adversity (peer rearing)., Design: We sequenced the rhesus macaque NPY locus (rhNPY) and performed in silico analysis to identify functional variants. We performed gel shift assays using nuclear extract from testes, brain, and hypothalamus. Levels of NPY in cerebrospinal fluid were measured by radioimmunoassay, and messenger RNA levels were assessed in the amygdala using real-time polymerase chain reaction. Animals were exposed to repeated social separation stress and tested for individual differences in alcohol consumption. Animals were genotyped for -1002 T > G, and the data were analyzed using analysis of variance., Setting: National Institutes of Health Animal Center. Subjects Ninety-six rhesus macaques. Main Outcome Measure Behavior arousal during social separation stress and ethanol consumption., Results: The G allele altered binding of regulatory proteins in all nuclear extracts tested, and -1002 T > G resulted in lower levels of NPY expression in the amygdala. Macaques exposed to adversity had lower cerebrospinal fluid NPY levels and exhibited higher levels of arousal during stress, but only as a function of the G allele. We also found that stress-exposed G allele carriers consumed more alcohol and exhibited an escalation in intake over cycles of alcohol availability and deprivation., Conclusions: Our results suggest a role for NPY promoter variation in the susceptibility to alcohol use disorders and point to NPY as a candidate for examining gene x environment interactions in humans.

Background: Genetic factors interact with environmental stressors to moderate risk for human psychopathology, but sex may also be an important mediating factor. Different strategies for coping with environmental stressors have evolved in males and females, and these differences may underlie the differential prevalence of certain types of psychopathology in the two sexes. In this study, we investigated the possibility of sex-specific gene-environment interactions in a nonhuman primate model of response to social threat., Methods: Rhesus macaques (77 males and 106 females) were exposed to an unfamiliar conspecific. Using factor analysis, we identified three behavioral factors characterizing the response to social threat. Monkeys were genotyped for the serotonin transporter-linked polymorphism (5-HTTLPR), and the effects of genotype, early life stress, and sex on behavioral responses were evaluated., Results: Factor analysis produced five factors: High-Risk Aggression, Impulsivity/Novelty-Seeking, Gregariousness/Boldness, Harm Avoidance, and Redirected Aggression. Overall, males displayed higher levels of High-Risk Aggression and Gregariousness/Boldness than females. Levels of High-Risk Aggression in males carrying the s allele were significantly higher if they were also exposed to early adversity in the form of peer rearing., Conclusions: Our findings support those from studies in humans suggesting that males are more vulnerable to externalizing or aggression-related disorders. The results highlight the importance of interactions that exist among behavior, genes, and the environment and suggest that sex differences in vulnerability to psychopathology may be grounded in our evolutionary history., (2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Platelet monoamine oxidase B (MAO-B) has been proposed to be a biological marker for the properties of monoamine systems, with low activity being associated with vulnerability for high scores on personality traits such as sensation seeking, monotony avoidance, and impulsiveness, as well as for vulnerability for alcoholism. In the present study, platelet MAO-B activity was analysed in 78 rhesus macaques, and its relation to voluntary alcohol intake and behaviours after intravenous alcohol administration was observed. Monkeys with low platelet MAO-B activity had low levels of 5-hydroxyindole acetic acid in cerebrospinal fluid and showed excessive aggression after alcohol administration. A novel finding was that animals with low platelet MAO-B activity showed less intoxication following alcohol administration. As we have shown previously, they also voluntarily consumed more alcohol. We here replicate results from studies on both humans and non-human primates, showing the utility of platelet MAO as a marker for risk behaviours and alcohol abuse. Furthermore, we link platelet MAO activity to alcohol sensitivity.

The triadic model of human infant temperament, involving Negative Affectivity, Orienting/Regulation, and Surgency/Extraversion factors, was applied to the rhesus neonate using exploratory factor analysis (EFA). Replicating and expanding earlier work in rhesus monkeys, the three-factor solution produced latent constructs comparable to human neonatal temperament., (Published by Elsevier Inc.)

The use of alcohol by adolescents is a growing problem and has become an important research topic in the etiology of the alcohol use disorders. A key component of this research has been the development of animal models of adolescent alcohol consumption and alcohol response. Because of their extended period of adolescence, rhesus macaques are especially well suited for modeling alcohol-related phenotypes that contribute to the adolescent propensity for alcohol consumption. In this review, we discuss studies from our laboratory that have investigated both the initial response to acute alcohol administration and the consumption of alcohol in voluntary self-administration paradigms in adolescent rhesus macaques. These studies confirm that adolescence is a time of dynamic change both behaviorally and physiologically, and that alcohol response and alcohol consumption are influenced by life history variables, such as age, sex, and adverse early experience in the form of peer-rearing. Furthermore, genetic variants that alter functioning of the serotonin, endogenous opioid, and corticotropin-releasing hormone systems are shown to influence both physiological and behavioral outcomes, in some cases interacting with early experience to indicate gene by environment interactions. These findings highlight several of the pathways involved in alcohol response and consumption, namely reward, behavioral dyscontrol, and vulnerability to stress, and demonstrate a role for these pathways during the early stages of alcohol exposure in adolescence., (2010 Elsevier Inc. All rights reserved.)

Corticotropin-releasing factor (CRF), encoded by the CRH gene, is a key integrator of stress responses, and, as such, CRH gene variation may contribute to individual differences in susceptibility to stress-related pathology. In rhesus macaques, a single nucleotide polymorphism (SNP) is found within the CRH promoter (-248C--> T). Here, we assessed whether this variant influenced stress responding and, because increased CRF system activity drives alcohol drinking in rodents, we examined whether it predicted voluntary alcohol consumption as a function of prior stress exposure. Using a hypothalamic nuclear extract, we showed that the -248 T allele resulted in increased DNA protein interactions relative to the C allele. In vitro, the T allele resulted in CRH promoter activity that was higher following both stimulation with forskolin and treatment with dexamethasone. Endocrine and behavioral responses to social separation stress (release of ACTH and cortisol, and suppression of environmental exploration, respectively) were higher among carriers of the T allele, particularly among those exposed to early adversity in the form of peer rearing. We also found that T allele carriers with a history of early life adversity consumed more alcohol in a limited-access paradigm. Our data suggest that CRH promoter variation that confers increased stress reactivity increases the risk for alcohol use disorders in stress-exposed individuals.

The mesolimbic dopamine system plays an important role in mediating a variety of behaviors and is involved in mediating the reinforcing effects of ethanol. Genes encoding dopamine receptor subtypes are thus good candidate loci for understanding the genetic etiologies of susceptibility to alcohol dependence and its antecedent behavioral phenotypes. We tested whether variation in DRD1 influences alcohol consumption in rhesus macaques and whether its influence is mediated by sex and early rearing experience. We genotyped a single nucleotide polymorphism (-111 G/T) in the 5'UTR of DRD1 in 96 subjects raised with their mothers until 6 months of age (n = 43) or in peer-only groups (n = 53). As young adults they underwent a 7-week voluntary ethanol consumption experiment. anova revealed a significant main effect of sex (F(1,95) = 6.3, P = 0.014) and an interaction between genotype, sex and rearing on ethanol consumption (F(7,95) = 4.63, P = 0.0002). Maternally deprived males heterozygous for the T allele consumed significantly more ethanol (P > t

Context: Traumatic experiences in early childhood are associated with increased risk of developing stress-related disorders, which are linked to structural brain abnormalities. However, it is unclear whether these volumetric brain changes are present before disease onset or reflect the consequences of disease progression., Objective: To identify structural abnormalities in the nonhuman primate brain that may predict increased risk of stress-related neuropsychiatric disorders in human beings., Design: Rhesus monkeys were divided into 2 groups at birth: a group raised with their mothers and other juvenile and adult animals (mother reared) and a group raised with 3 age-matched monkeys only (peer reared) for the first 6 months of life. Anatomical brain images were acquired in juvenile male and female rhesus monkeys using magnetic resonance imaging., Setting: National Institutes of Health Animal Center in Poolesville, Maryland. Subjects Twenty-eight rhesus monkeys (Macaca mulatta) aged 24 to 30 months were used for the study., Main Outcome Measures: Volumetric measures of the anterior cingulate cortex, medial prefrontal cortex, hippocampus, corpus callosum, and cerebellar vermis were compared between mother-reared (n = 15) and peer-reared animals (n = 13)., Results: Compared with mother-reared monkeys, we found an enlarged vermis, dorsomedial prefrontal cortex, and dorsal anterior cingulate cortex in peer-reared monkeys without any apparent differences in the corpus callosum and hippocampus., Conclusions: Peer-rearing during infancy induces enlargement in stress-sensitive brain regions. These changes may be a structural phenotype for increased risk of stress-related neuropsychiatric disorders in human beings.

A functional polymorphism in the promoter region of the serotonin transporter (5-HTTLPR) gene has been associated with variation in anxiety and hypothalamus-pituitary-adrenal (HPA) axis function in humans and rhesus macaques. Individuals carrying the short allele are at a higher risk for developmental psychopathology, and this risk is magnified in short allele carriers who have experienced early life stress. This study investigated the relationship between 5-HTTLPR allelic variation, infant abuse, and behavioral and hormonal responses to stress in rhesus macaques. Subjects were 10 abusive mothers and their infants, and 10 nonabusive mother-infant pairs. Mothers and infants were genotyped for the rh5-HTTLPR, and studied in the first 6 months of infant life. For mothers and infants, we measured social group behavior, behavioral responses to handling procedures, and plasma concentrations of ACTH and cortisol under basal conditions and in response to stress tests. The proportion of individuals carrying the short rh5-HTTLPR allele was significantly higher among abusive mothers than controls. Among mothers and infants, the short allele was associated with higher basal cortisol levels and greater hormonal stress responses in the infants. In addition, infants who carried the short rh5-HTTLPR allele had higher anxiety scores than infants homozygous for the long allele. The rh5-HTTLPR genotype also interacted with early adverse experience to impact HPA axis function in the infants. These results are consistent with those of previous studies which demonstrate associations between serotonergic activity and anxiety and stress reactivity, and add additional evidence suggesting that genetic variation in serotonergic function may contribute to the occurrence of abusive parenting in rhesus macaques and modulate emotional behavior and HPA axis function.

Studies of mother-infant relationships in nonhuman primates have increasingly attempted to understand the neuroendocrine bases of interindividual variation in mothering styles and the mechanisms through which early exposure to variable mothering styles affects infant behavioral development. In this study of free-ranging rhesus macaques on Cayo Santiago, Puerto Rico, we aimed to: 1) compare lactating and nonlactating females to investigate whether lactation is associated with changes in plasma cortisol, prolactin and oxytocin, as well as changes in CSF levels of serotonin and dopamine metabolites (5-HIAA and HVA); 2) examine the extent to which interindividual variation in maternal physiology is associated with variation in maternal behavior; 3) examine the extent to which interindividual variation in infant physiology and behavior is accounted for by variation in maternal physiology and behavior. Lactating females had higher plasma concentrations of cortisol, prolactin, and oxytocin but lower CSF concentrations of HVA than nonlactating females. Variation in maternal rejection behavior was positively correlated with variation in maternal plasma cortisol levels and in CSF 5-HIAA levels while variation in the time spent nursing and grooming was associated with maternal plasma oxytocin levels. Infants who were protected more by their mothers had higher cortisol levels than those who were protected less, while infants who were rejected more had lower CSF 5-HIAA than infants who were rejected less. Since exposure to high levels of maternal protectiveness and rejection is known to affect the offspring's behavior and responsiveness to the environment later in life, our results are consistent with the hypothesis that these effects are mediated by long-term changes in the activity of the offspring's HPA axis and brain serotonergic system.

Background: Acute and chronic tolerance, as well as locomotor sensitization, have been linked to ethanol intake. This study examined the change in response between 2 acutely administered doses of ethanol in adolescent rhesus macaques, with the objective of investigating rapid tolerance and locomotor sensitization to the behavioral effects of ethanol, and whether these phenomena are related to voluntary ethanol consumption in nonhuman primates., Methods: Rhesus macaques (n = 109, 42 males, 67 females) were administered 2 sequential intravenous doses of ethanol (2.2 g/kg for males, 2.0 g/kg for females) separated by a period of 5 to 30 days. Following each injection, subjects underwent a 30-minute behavior assessment. Behavioral data were summarized using factor analysis, and compared between the 2 doses using repeated measures ANOVA. The relationship between behavioral response measures and the number of days between doses was analyzed using regression analyses. Following the second ethanol dose, subjects were given free access to an aspartame-sweetened 8.4% ethanol solution for 1 hour a day for 4 weeks. Percent change in behavioral response measures from dose 1 to dose 2 was analyzed for associations with ethanol consumption using multiple regression analyses., Results: Factor analysis yielded 3 factors: ataxia, stimulation, and jumping. From dose 1 to dose 2 there was a significant decrease in ataxia and a significant increase in stimulation. Peak blood ethanol concentration did not differ between doses. There were no significant associations between the number of days between doses and the magnitude of change in response for any of the behavioral measures. Percent change in stimulation from dose 1 to dose 2 was positively associated with subsequent oral ethanol consumption only in females tested in a social setting., Conclusions: Adolescent rhesus macaques develop rapid tolerance to the motor-impairing effects of alcohol, while at the same time developing locomotor sensitization. These changes in response are not necessarily short lived, and may persist for some time following the first ethanol dose. Clear and consistent associations between rapid tolerance and locomotor sensitization and ethanol intake levels have yet to be demonstrated, however.