Effects of Early Stress on Central Serotonin System Functioning Traumatic experiences in childhood are associated with increased risk for developing mood and anxiety disorders. Low serotonin(1A) receptor (5-HT(1A)R) density during development has been proposed as a trait-like characteristic leading to increased vulnerability to neuropsychiatric disorders. To assess the relationship between early adversity and alterations in the serotonin system, we used PET to measure in vivo 5-HT(1A)R density and dissociation constant (K(D)(app)) in the brains of juvenile rhesus monkeys with and without histories of stress in the form of peer rearing (PR vs. mother-reared, MR). We found that 5-HT(1A)R density and K(D)(app) were decreased in PR animals. We also observed an increase in receptor density in the dorsomedial prefrontal cortex of PR females. These findings demonstrate that early adversity is associated with long-term alterations in the serotonin system and support human studies suggesting that reduced 5-HT(1A)R density during development might increase vulnerability to stress-related neuropsychiatric disorders. As alterations in the serotonin system were both gender- and region-specific, this may suggest a biological basis for the higher prevalence of affective disorders in women. Early Life Stress and GxE Interactions in Nonhuman Primates Genetic factors interact with environmental stressors to moderate risk for human psychopathology. The first genetic variants to have been shown to interact with early experience in humans were repeat variants present in regulatory regions for the Monoamine Oxidase A and Serotonin Transporter genes (MAOA-VNTR and HTT-LPR, respectively). These variants occur across the catarrhine primates, providing an opportunity to examine effects of MAOA-VNTR or HTT-LPR genotype in laboratory and free-ranging primates and to determine whether these variants predict differences in behavior as a function of stress. MAOA-VNTR In humans, the promoter of the MAOA gene is sensitive to both glucocorticoids and androgens, and interactions between MAOA genotype and both early stress and testosterone levels increase levels of aggression. We have found that the orthologue of the human MAOA-VNTR low activity allele predicts highly aggressive responses to unfamiliar conspecfics, particularly in adolescent/adult males. The interaction between genotype and age might suggest that testosterone levels influence aggressive responding as a function of MAOA-VNTR variation and, consistent with this, we find that free-ranging macaque males with low activity allele that have high age-adjusted levels of testosterone are more likely to emigrate at a young age from the natal troop. In macaques, highly aggressive males are often peripheralized from the natal troop, forcing early emigration. This can result in early mortality, but is thought to be balanced by the potential increase in reproductive output for these individuals. As stated above, the low activity MAOA-VNTR allele predicts antisocial behavior in humans exposed to early adversity. We wanted to investigate the effects of the orthologous rhesus variant on high-risk aggression and alcohol consumption in rhesus macaques that were either MR or PR. We found that, when controlling for age, MAOA-VNTR genotype interacts with early stress to predict high risk aggression towards an unfamiliar conspecific and, further, that under conditions that involve availability of alcohol, PR monkeys that are carriers of the low activity MAOA-VNTR allele exhibit higher levels of alcohol consumption. Our results demonstrate that macaques carrying the low-activity MAOA-VNTR allele and who are exposed to early life stress are more prone to high risk behaviors, such as aggression and alcohol consumption, and provide further evidence that MAOA-VNTR may be a risk allele for early onset alcohol dependence in human subjects. HTT-LPR The short (s) HTT-LPR allele has been shown to moderate 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. We have previously demonstrated that the effects early stress in the form of peer rearing is moderated by HTT-LPR genotype, and these findings have been shown to translate to the human condition. However, whether genotype predicts responses to stress in normally-reared primates and across step-wise increases in cumulative stress exposures has not yet been examined. Such an approach could be important because of its potential to be highly sensitive for detecting moderating effects of genotype on depression-related behavior. It could also inform us of how genotype predicts tendencies toward habituation and/or sensitization to stress, which could potentially be more easily translated to the human condition. We wanted to explore whether behavioral responses to repeated maternal separation stress would be influenced by HTT-LPR genotype in infant rhesus macaques and whether these responses differed as a function of duration and repetition (number of exposures) of the stressor. We found that, across successive exposures to stress and as a function of increased duration of the stressor, infants carrying the HTT-LPR s allele were more likely to develop signs of distress and behavioral pathology. Our data in nonhuman primates suggest that in children, the s allele may increase sensitivity to repeated, chronic stressors, leaving them more vulnerable to affective psychopathology. This may make such individuals more reactive during early development, may influence the trajectory of responses over periods of adjustment or stress, and may predict vulnerability to psychopathology later in life. Effects of Early Adversity on Alcohol Consumption Patterns in Humans Over the years, we have been examining persistent effects of early adversity on endocrine and behavioral responses to stress and alcohol consumption using a rhesus macaque model. The advantage of this model is that it is tightly controlled and that potential confounds are reduced or eliminated. The ultimate goal of these studies has been to identify effects of stress in macaques that may increase risk for human psychopathology. We recently performed analyses on a clinical sample to determine whether our primate findings would translate to the human condition. We wanted to determine the prevalence of early life trauma and stress in a sample of detoxified alcoholics to determine whether early stress increased risk for alcohol problems in our sample. We then wanted to evaluate the relationship between childhood adversity and alcohol-related outcome measures, including co-morbid psychiatric diagnoses. We found that adverse childhood experiences were highly prevalent in our sample of recently detoxified alcoholics. While patients who experienced early life stress or trauma did not differ from patients lacking these experiences in their recent drinking history, they did exhibit earlier onset of alcohol use as well as a higher level of alcohol dependence severity. In addition, early adversity was associated with a higher risk of co-morbid anxiety, mood, and substance use disorders. Our findings are consistent with data derived from nonhuman primate studies and with previous research demonstrating the impact of adverse childhood experiences on adult alcohol-related and behavioral health outcomes. Future investigations will examine the moderating role of sex and of genetic factors on the effects of early life stress exposure in this population.
