Genotypic variation in the promoter region of the CRH-248 gene interacts with early rearing experiences to disrupt the development of the HPA axis in infant rhesus macaques (Macaca mulatta).

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.

Variation in the Mu-Opioid Receptor (OPRM1) and Offspring Sex Are Associated With Maternal Behavior in Rhesus Macaques (Macaca mulatta).

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.

Central nervous system monoamine metabolite response to alcohol exposure is associated with future alcohol intake in a nonhuman primate model (Macaca mulatta).

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.

Mismatches in resident and stranger serotonin transporter genotypes lead to escalated aggression, and the target for aggression is mediated by sex differences in male and female rhesus monkeys (Macaca mulatta).

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.

A nonhuman primate model of human non-suicidal self-injury: serotonin-transporter genotype-mediated typologies.

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.

Photochemical transformation of a cellulose biosynthesis inhibitor into phytoene desaturase inhibitors.

Mode of action studies showed that 5-methyl-N,N-bis[6-(trifluoromethyl)pyridin-3-yl]pyridin-2-amine (4), a representative from a new class of herbicidal tris-pyridyl amines, is an inhibitor of cellulose biosynthesis (CB). The compound undergoes an oxidative photocyclization, when exposed to UV-B light (300-340 nm) in the presence of oxygen, to give a new class of herbicidal pyrrolodipyridines. These compounds are potent inhibitors of the herbicide target enzyme phytoene desaturase and no longer inhibit CB.

Mechanism and structure based design of inhibitors of AMP and adenosine deaminase.

Inhibitors of the enzyme adenosine monophosphate deaminase (AMPD) show interesting levels of herbicidal activity. An enzyme mechanism-based approach has been used to design new inhibitors of AMPD starting from nebularine (6) and resulting in the synthesis of 2-deoxy isonebularine (16). This compound is a potent inhibitor of the related enzyme adenosine deaminase (ADA; IC50 16 nM), binding over 5000 times more strongly than nebularine. It is proposed that the herbicidal activity of compound 16 is due to 5́-phosphorylation in planta to give an inhibitor of AMPD. Subsequently, an enzyme structure-based approach was used to design new non-ribosyl AMPD inhibitors. The initial lead structure was discovered by in silico screening of a virtual library against plant AMPD. In a second step, binding to AMPD was further optimised via more detailed molecular modeling leading to 2-(benzyloxy)-5-(imidazo[2,1-f][1,2,4]triazin-7-yl)benzoic acid (36) (IC50 300 nM). This compound does not inhibit ADA and shows excellent selectivity for plant over human AMPD.

The Effects of At-Birth Adoption on Atypical Behavior and Anxiety: A Nonhuman Primate Model.

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.

Early Rearing Conditions Affect Monoamine Metabolite Levels During Baseline and Periods of Social Separation Stress: A Non-human Primate Model (Macaca mulatta).

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.

Parental genetic contributions to neonatal temperament in a nonhuman primate (Macaca mulatta) model.

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.

Intergenerational effects of mother's early rearing experience on offspring treatment and socioemotional development.

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.

Neonatal temperament and neuromotor differences are predictive of adolescent alcohol intake in rhesus monkeys (Macaca mulatta).

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 (ß = -.35; p = .01), state control (ß = -.19; p = .04), and motor maturity (ß = -.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.

Early life temperamental anxiety is associated with excessive alcohol intake in adolescence: A rhesus monkey (Macaca mulatta) model.

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 (Mage = 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.

The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity.

Resistance to 157 different herbicides and 88% of known sites of action has been observed, with many weeds resistant to two or more modes. Coupled with tighter environmental regulation, this demonstrates the need to identify new modes of action and novel herbicides. The plant sphingolipid biosynthetic enzyme, inositol phosphorylceramide synthase (IPCS), has been identified as a novel, putative herbicide target. The non-mammalian nature of this enzyme offers the potential of discovering plant specific inhibitory compounds with minimal impact on animals and humans, perhaps leading to the development of new non-toxic herbicides. The best characterised and most highly expressed isoform of the enzyme in the model-dicot Arabidopsis, AtIPCS2, was formatted into a yeast-based assay which was then utilized to screen a proprietary library of over 11,000 compounds provided by Bayer AG. Hits from this screen were validated in a secondary in vitro enzyme assay. These studies led to the identification of a potent inhibitor that showed selectivity for AtIPCS2 over the yeast orthologue, and activity against Arabidopsis seedlings. This work highlighted the use of a yeast-based screening assay to discover herbicidal compounds and the status of the plant IPCS as a novel herbicidal target.

Synthesis of α-Chlorolactams by Cyanoborohydride-Mediated Radical Cyclization of Trichloroacetamides.

A cyanoborohydride-promoted radical cyclization methodology has been developed to access α-chlorolactams in a simple and efficient way using NaBH3 CN and trichloroacetamides easily available from allylic and homoallylic secondary amines. This methodology allowed the synthesis of a library of α-chlorolactams (mono- and bicyclic), which were tested for herbicidal activity, trans-3-chloro-4-methyl-1-(3-trifluoromethyl)phenyl-2-pyrrolidinone being the most active.

Trifluoromethyl Vinyl Sulfide: A Building Block for the Synthesis of CF3S-Containing Isoxazolidines.

Trifluoromethyl vinyl sulfide, a potential building block for pharmaceutically and agrochemically relevant products, is prepared and used for the first time in high-pressure-mediated 1,3-dipolar cycloaddition reactions with nitrones to synthesize (trifluoromethyl)sulfanyl isoxazolidines.

Low Inherent Sensitivity to the Intoxicating Effects of Ethanol in Rhesus Monkeys with Low CSF Concentrations of the Serotonin Metabolite 5-Hydroxyindoleacetic Acid.

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.

Early rearing history influences oxytocin receptor epigenetic regulation in rhesus macaques.

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.

OPRM1 genotype interacts with serotonin system dysfunction to predict alcohol-heightened aggression in primates.

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.

Dopamine D4 receptor genotype variation in free-ranging rhesus macaques and its association with juvenile behavior.

A polymorphism in the dopamine receptor D4 (DRD4) gene has been associated with significant variation in behavioral impulsivity, novelty-seeking, and risk-taking in humans and other animals. Rhesus macaques are an excellent animal model for research on the genetic basis of behavior using the candidate gene approach. Little is known, however, about allelic variation in DRD4 in large free-ranging populations of rhesus macaques and how this allelic variation relates to emotion regulation and behavior. In this study, we genotyped for the DRD4 polymorphism 178 individuals of different age and sex categories in the free-ranging rhesus macaque population on the island of Cayo Santiago, PR. Moreover, we examined the possible association between DRD4 allelic variation and three measures of juvenile behavior (time spent in proximity to the mother, avoidance of other individuals, and behavioral restlessness). Five different DRD4 alleles (5R, 5.5R, 6R, 6.5R, and 7R) were identified in the subject population. The most common allele was the 5R allele (78.5%), followed by the 7R allele (16.1%). Juveniles carrying the long form of the DRD4 allele (7R) spent less time in proximity to their mothers, avoided other individuals more often, and scored higher on behavioral restlessness than juveniles carrying the shorter alleles. Behavioral restlessness was also influenced by maternal DRD4 genotype. These results highlight both similarities and differences in the relative occurrence of DRD4 alleles and their association with behavior in this rhesus macaque population, other nonhuman primate species or populations, and humans.