Coaction of stress and serotonin transporter genotype in predicting aggression at the transition to adulthood

Despite consistent evidence that serotonin functioning affects stress reactivity and vulnerability to aggression, research on serotonin gene-stress interactions (G × E) in the development of aggression remains limited. The present study investigated variation in the promoter region of the serotonin transporter gene (5-HTTLPR) as a moderator of the stress-aggression association at the transition to adulthood. Multiple informants and multiple measures were used to assess aggression in a cohort of 381 Australian youth (61% female, 93% Caucasian) interviewed at ages 15 and 20. At age 20, semistructured interviews assessed acute and chronic stressors occurring in the past 12 months. Structural equation modeling analyses revealed a significant main effect of chronic stress, but not 5-HTTLPR or acute stress, on increases in aggression at age 20. Consistent with G × E hypotheses, 5-HTTLPR short allele carriers demonstrated greater increments in aggression following chronic stress relative to long allele homozygotes. The strength of chronic stress G × E did not vary according to sex. Variation at 5-HTTLPR appears to contribute to individual differences in aggressive reactions to chronic stress at the transition to adulthood.     

Association between the recombinant human serotonin transporter linked promoter region polymorphism and behavior in rhesus macaques during a separation paradigm

Human studies have suggested an association between a variable length polymorphism in the serotonin transporter gene promoter region and vulnerability to anxiety and depression. Relative to the long (l) allele, the short (s) allele increases the risk of developing depression in individuals exposed to stressful life events. An orthologue of the human variant is present in rhesus macaques and allows for studies in animals exposed to stress. Here, we used an established model of early life stress exposure, in which rhesus macaques are raised without adults in a group of peers (peer-only reared [PR]), or with their mothers. At 6 months of age, animals were subjected to 4-day long social separations for 4 consecutive weeks, with 3 days of reunion in between. Data were collected during both the acute (Day 1) and chronic phases (Days 2-4) of separation. Behavioral factors were separately extracted for each phase of separation. For acute separation, the behavioral factors generated were despair and behavioral pathology and, for the chronic phase despair, agitation, and behavioral pathology. During both phases of social separation, PR l/s animals were more likely to exhibit pathological behaviors, whereas PR l/l monkeys show higher levels of despair compared to the other three groups. These findings indicate that early stress affects the behavioral response to separation differently as a function of recombinant human serotonin transporter linked polymorphic repeat genotype and suggest that carriers of the s allele are not only more anxious but may also be more vulnerable to developing behavioral pathology in the face of chronic adversity.     

Sex, but not repeated maternal separation during the first postnatal week, influences novel object exploration and amphetamine sensitivity

Sensation seeking and early life stress are both risk factors for developing substance use disorders. Neural adaptations resulting from early life stress may mediate individual differences in novelty responsiveness, and, in turn, contribute to drug abuse vulnerability. Animal models also demonstrate associations between novelty responsiveness or early life stress and increased sensitivity to psychostimulants. We investigated whether repeated maternal separation affects responses to novelty during adolescence and to amphetamine during adulthood, and whether maternal separation alters the relationship between these behavioral variables. Rat pups underwent separation (180 min/day) or control procedures (15 min/day) on postnatal days (PND) 2-8. Novel object exploration and amphetamine response were tested at PND 38 and 60, respectively. Adolescent males were less active in a novel environment and approached novel objects more frequently than females, but adult females showed greater amphetamine-induced locomotion. Maternal separation did not affect novelty responsiveness or amphetamine sensitivity. Locomotor activity in an inescapable, novel environment during adolescence predicted amphetamine-induced locomotor activity during adulthood in maternally separated rats, but not in controls. The results of this study suggest that adolescent responses to novelty may be particularly predictive of future substance abuse among survivors of early life trauma. Furthermore, sex differences in novelty and amphetamine responsiveness may complicate the relationship between these behavioral variables.     

Neuroticism-related personality traits are related to symptom severity in patients with premenstrual dysphoric disorder and to the serotonin transporter gene-linked polymorphism 5-HTTPLPR

Neuroticism has been linked to a functional polymorphism in the serotonin transporter gene (5-HTTLPR), with short-allele carriers being overrepresented among high-scorers on neuroticism. Studies evaluating neuroticism-related personality traits in relation to the 5-HTTLPR polymorphism among patients with premenstrual dysphoric disorder (PMDD) and are lacking. The primary aim of this study was to evaluate the relationship between PMDD and neuroticism-related personality traits, and secondly, to relate the personality trait scores of PMDD patients to experienced symptom severity and to the 5-HTTLPR short allele. Thirty PMDD patients and 55 asymptomatic healthy controls were included in the study. The Swedish Universities Scale of Personality was used to evaluate personality traits. Genotype analyses were available in 27 PMDD patients and 18 healthy controls. Women with PMDD displayed higher levels of neuroticism-related personality traits (psychic trait anxiety, somatic trait anxiety, embitterment, stress susceptibility and mistrust) than healthy controls, and these effects were most prominent in women with more severe luteal phase symptoms. Furthermore, PMDD patients with at least one copy of the short allele of the 5-HTTLPR polymorphism scored higher on psychic trait anxiety and lack of assertiveness than PMDD patients who were homozygous for the long allele. PMDD patients who suffer from more severe luteal phase symptoms also display increased scores of neuroticism-related personality traits in comparison with healthy controls. Within the group of PMDD patients, differences in certain personality trait scores are associated with the short allele of the 5-HTTLPR polymorphism.     

Serotonin transporter gene promoter region polymorphism and selective processing of emotional images

Several studies have now documented that the serotonin transporter promoter region (5-HTTLPR) polymorphism predicts neural response to affective images in brain regions involved in the experience of emotion. However, the behavioral consequences of this genetic effect are less well known. The current study used eye-tracking methodology to examine how individuals genotyped for the 5-HTTLPR allocated their attention when simultaneously presented an array of positive and negative emotional scenes. Short 5-HTTLPR allele homozygotes displayed a bias to focus on positive images, particularly in the first half of the 30 s trial. In contrast, long 5-HTTLPR allele homozygotes viewed the stimuli in a more evenhanded fashion. Thus, short 5-HTTLPR allele homozygotes may be attempting to regulate greater reactivity to negative stimuli by purposefully turning their attention towards positive stimuli. Although this sensitivity may have benefits under benign conditions, it may also increase vulnerability to affective disorders when cognitive resources needed to turn attention away from negative stimuli are compromised.     

Serotonin transporter promoter region (5-HTTLPR) polymorphism predicts resting respiratory sinus arrhythmia

Respiratory sinus arrhythmia (RSA) is often conceptualized as an index of physiological flexibility that has been related to emotion regulatory capacity. Although behavioral genetics research indicates that RSA is partly heritable, relatively few molecular genetics studies have been conducted. We examined whether the serotonin transporter promoter region (5-HTTLPR) polymorphism was associated with resting RSA among healthy young adults (N=71). Short 5-HTTLPR allele carriers had significantly lower resting RSA than long 5-HTTLPR homozygotes. Genotype explained 5% of the variance in resting RSA. Although firm conclusions depend on further study, the short allele of the 5-HTTLPR polymorphism may contribute to individual differences in RSA and its behavioral correlates.     

Sensitization of depressive-like behavior during repeated maternal separation is associated with more-rapid increase in core body temperature and reduced plasma cortisol levels

Infant guinea pigs exhibit a 2-stage response to maternal separation: an initial active stage, characterized by vocalizing, and a second passive stage marked by depressive-like behavior (hunched posture, prolonged eye-closure, extensive piloerection) that appears to be mediated by proinflammatory activity. Recently we found that pups showed an enhanced (i.e., sensitized) depressive-like behavioral response during repeated separation. Further, core body temperature was higher during the beginning of a second separation compared to the first, suggesting a more-rapid stress-induced febrile response to separation the second day, though the possibility that temperature was already elevated prior to the second separation could not be ruled out. Therefore, the present study examined temperature prior to, and during, 2 daily separations. We also examined the temperature response to a third separation conducted 3 days after the second, and assessed the effect of repeated separation on plasma cortisol levels. Core temperature did not differ just prior to the separations, but showed a more-rapid increase and then decline during both a second and third separation than during a first. Temperature responses were not associated with changes in motor activity. Depressive-like behavior was greater during the second and third separations. Pups separated a first time showed a larger plasma cortisol response at the conclusion of separation than did animals of the same age separated a third time. In all, the results indicate that the sensitization of depressive-like behavior during repeated separations over several days is accompanied by a more-rapid febrile response that may be related to a reduction of glucocorticoid suppression.     

Maternal pituitary-adrenal responsiveness as a function of differential treatment of rat pups

The effects of litter separation and pup treatment on the maternal pituitary-adrenal system were investigated in 3 experiments. Lactating females did not show a pituitary-adrenal response to separation from their pups. However, the lactating females showed an increase in plasma corticosterone when their pups had been briefly removed and then returned. If, in addition, the pups were subjected to a noxious stimulus (electric shock) during the 2-min separation, mothers showed a further increase in corticosterone. When pups were returned after 3 hr of separation, mothers again showed a differential pattern of corticoid responsiveness. The magnitude of the mother's pituitary adrenocortical response depended upon the intensity of treatment given to the pups. These data lend physiological support to behavioral studies which have shown that maternal behavior is differentially influenced by pup-produced stimuli.     

Maternal smoking during pregnancy and child emotional problems: the relevance of maternal and child 5-HTTLPR genotype

Serotonin is involved in the development of neural circuits modulating emotional behavior. The short allele (s) of a polymorphism (5-HTTLPR) of the serotonin transporter gene is a risk factor for psychopathology in the presence of environmental stressors. Maternal smoking is associated with growth restriction of the human fetal brain and adverse effects of nicotine on the developing serotonin system have been documented. We hypothesized that maternal smoking interacts with both child and mother 5-HTTLPR genotype as a risk factor for later child emotional problems. In a sample of n?=?1,529 mother-child dyads, smoking habits were assessed by questionnaires during pregnancy. Child emotional problems were measured by the Child Behavior Checklist at the child's age of 3 years. Maternal smoking during pregnancy significantly increased the risk for emotional problems in children carrying the s-allele; β?=?0.24, P?=?0.03 (mother-report), and β?=?0.46, P?=?0.001 (father-report). In children heterozygous at 5-HTTLPR and exposed to maternal prenatal smoking (n?=?79) risk of emotional problems increased with each additional s-allele the mother carried. The associations between 5-HTTLPR and child emotional problems were not moderated by paternal prenatal smoking. These findings imply that the vulnerability for emotional problems in s-allele carriers may already originate in fetal life.     

Serotonin transporter gene (5-HTTLPR) polymorphisms are associated with emotional modulation of pain but not emotional modulation of spinal nociception

The short allele of the serotonin transporter gene (5-HTTLPR) is associated with greater negative emotionality. Given that emotion modulates pain, short allele carriers (s-carriers) may also demonstrate altered pain modulation. The present study used a well-validated emotional picture-viewing paradigm to modulate pain and the nociceptive flexion reflex (NFR, a measure of spinal nociception) in 144 healthy genotyped participants. As expected, pain/NFR responses were largest during unpleasant pictures and smallest during pleasant pictures. However, relative to l/l-carriers, s-carriers demonstrated greater pain inhibition during pleasant pictures and greater pain facilitation during unpleasant pictures. Neither emotional modulation of NFR nor NFR threshold was associated with 5-HTTLPR polymorphisms. Results also indicated that men who were s-carriers had a higher pain threshold and tolerance than other participants. Taken together, our results indicate 5-HTTLPR polymorphisms may influence pain modulation at the supraspinal (not spinal) level; however, the influence on pain sensitivity may be sex-specific.     

Temperamental fearfulness in childhood and the serotonin transporter promoter region polymorphism: a multimethod association study

OBJECTIVES: Early-emerging, temperamental differences in fear-related traits may be a heritable vulnerability factor for anxiety disorders. Previous research indicates that the serotonin transporter promoter region polymorphism is a candidate gene for such traits. METHODS: Associations between 5-HTTLPR genotype and indices of fearful child temperament, derived from maternal report and standardized laboratory observations, were examined in a community sample of 95 preschool-aged children. RESULTS: Children with one or more long alleles of the 5-HTTLPR gene were rated as significantly more nervous during standardized laboratory tasks than children who were homozygous for the short alleles. Children homozygous for the short alleles were also rated as significantly shyer, by maternal report, than those with at least one copy of the long allele of the 5-HTTLPR gene. CONCLUSIONS: This study extends the literature linking the short alleles of the serotonin transporter promoter region polymorphism to fear and anxiety-related traits in early childhood and adulthood, and is one of very few studies to examine the molecular genetics of preschoolers' temperament using multiple measures of traits in a normative sample.     

5-HTTLPR genotype and gender, but not chronic fluoxetine administration, are associated with cortical TREK1 protein expression in rhesus macaques

TREK1 is a widely expressed background potassium channel. Similar to mice treated with selective serotonin reuptake inhibitors (SSRIs), TREK1 knockout mice are resistant to depression-like behavior and have elevated serotonin levels leading to speculation that TREK1 inhibition may contribute to the therapeutic effects of SSRIs. This study examined how chronic fluoxetine administration and a common functional polymorphism in the serotonin-transporter-linked promoter region (5-HTTLPR) influence cortical TREK1 expression in 24 rhesus monkeys. The short rh5-HTTLPR allele as well as female gender were associated with reduced cortical TREK1 protein expression but chronic SSRI administration had no effect. These results suggest that serotonin may influence TREK1, but that chronic SSRI treatment does not result in long lasting changes in cortical TREK1 protein expression. TREK1 gender differences may be related to gender differences in serotonin and require further research.     

5-羟色胺转运蛋白基因多态性与脑卒中后抑郁的关联

目的:探讨5-羟色胺转运体连锁启动区(5-hydroxytryptamine transporter linked promoter region,5-HTTLPR)基因多态性与脑卒中后抑郁发病、自杀行为是否相关。方法:应用聚合酶链反应(PCR)扩增技术测定中国汉族脑卒中抑郁(poststroke depression,PSD)患者90例(PSD组)和无抑郁脑卒中患者90例(非PSD组)的5-HTTLPR基因型及等位基因,分别验证各种基因型与脑卒中抑郁症发病及自杀行为的相关性。结果:PSD组SS基因型及S等位基因频率(64.4%,75.6%)明显高于非PSD组(38.9%,58.3%),S等位基因携带者PSD患病率为LL型纯合子的1.29倍(OR=1.29,P<0.001,95%CI:1.11～1.50);对PSD组自杀行为分层比较,有自杀行为组SS基因型及S等位基因频率(76.8%,75.6%)明显高于无自杀行为组(44.1%,58.3%),PSD患者中,S等位基因携带者自杀行为发生概率为LL纯合子的1.3倍(OR=1.3,P<0.01,95%CI:1.08～1.6)。结论:5-HTTLPR基因可能是PSD的易感基因,S等位基因可能与PSD及自杀行为相关。     

Early impact of 5-HTTLPR polymorphism on the neural correlates of sadness

Healthy adults carrying the short (S) allele of the human serotonin transporter gene linked polymorphism (5-HTTLPR) show increased amygdala activation during visual processing of emotionally negative stimuli compared to healthy adults homozygous for the long (L) allele. To determine whether abnormal brain responses during negative emotion appear early in life in S allele carriers, functional magnetic resonance imaging (fMRI) was used to measure brain activity during a transient state of sadness in children carrying the S allele (S group) or homozygous for the L allele (L group). Blood-oxygen-level dependent (BOLD) signal changes were measured while subjects viewed blocks of neutral film excerpts and sad film excerpts. During the sad condition (relative to the neutral condition), there was significantly greater activation in the S group compared to the L group in brain regions known to be involved in normal sadness and major depression. Given that the 5-HTTLPR polymorphism has been associated with mood disorders, it is plausible that the abnormal pattern of regional brain activity detected here, in children carrying the S allele, increases susceptibility to emotional dysregulation and depressive symptoms.     

Sexual behavior of maternally separated gibbons (Hylobates)

The effect of early maternal separation on the sexual behavior of captive gibbons was investigated because (a) maternal separation compromises sexual behavior of some nonhuman primates and (b) adequate sexual behavior is essential to species propagation. Most of the maternally separated gibbons (24/31) were sexually proficient. Sexual behavior overall did not differ significantly in relation to species, sex, origin (wild- vs. captive-born), or type of rearing facility (home vs. zoo). Sexual proficiency was not related to the age at separation from the mother, but it was associated with introduction within 19 months of age to a conspecific of less than 3 years of age and an absolute age difference of less than 2 years. Sexual proficiency was associated with rearing and adult housing in relatively large enclosures. Gibbons that were isolated from conspecifics between 6 months and 2 years of age were strongly attached to humans, but this did not prevent sexual proficiency. A greater proportion of males than females were adversely affected sexually by prolonged early social isolation. Inadequate sexual behavior was associated with fearfulness of conspecifics, which probably interfered with compatible social relationships, including duetting. Inadequate sexual behavior was but one aspect of a more general behavioral deficiency resulting from inadequate early socialization. Early maternal separation in gibbons is compatible with species-typical sexual behavior under the conditions described above. It is not necessary for gibbons to learn sexual and parental behavior by observing experienced adult conspecifics. ©1997 John Wiley & Sons, Inc. Dev Psychobiol 31: 149–161, 1997     

Effect of maternal separation on feeding behavior of rats in later life

Effects of maternal separation on feeding behavior, particularly on rebound hyperphagia, in adult rats were examined. Time-restricted scheduled feeding (2 h per day for 6 days), was given at the age of 3, 6, 9 or 12 weeks in rats that were maternal separated from postnatal days (PD) 1–21 and control rats. Following the time-restricted scheduled feeding, rats were fed freely for 24 h (rebound hyperphagia). Body weight, daily normal food consumption and food consumption during time-restricted scheduled feeding and rebound hyperphagia were measured. Body weight of 3-week-old maternally separated rats were less than those of control rats. There was no significant difference in normal daily food consumption. Food consumption during rebound hyperphagia was significantly increased in 6- to 9-week-old female maternally separated rats, but there was no difference observed in males. Postnatal maternal separation enhanced rebound hyperphagia of female rats in later life. These results indicate that postnatal maternal separation made rats more vulnerable to the development of abnormal feeding behavior in response to food restriction in later life.     

Effects of maternal separation on hypothalamic-pituitary-adrenal responses, cognition and vulnerability to stress in adult female rats

We studied the long term effects of neonatal stress in female rats and subsequent responses to stress when adults. Female rats that experienced maternal separation (MS) showed in adulthood depressive-like behavior in the forced swimming test and cognitive impairments in the novel object recognition test, which were reverted by the glucocorticoid receptor antagonist mifepristone or the beta-adrenoceptor antagonist propranolol. Markers of HPA axis (corticosterone levels, CRF mRNA levels in the paraventricular nucleus and glucocorticoid receptor density in the hippocampus) were altered by MS, suggesting that an altered HPA axis function may be associated to behavioral and cognitive deficits in MS female rats. In addition, MS rats were found to be more vulnerable to chronic stress than controls as shown by decreases in open field activity, increases in immobility time in the forced swim test, and changes in markers of HPA axis (decreases in the density of glucocorticoid receptors). These present findings are discussed in terms of gender differences in adulthood.     

Female pups receive more maltreatment from stressed dams

The effects of exposure to developmental stress often diverge for males and females. Using the scarcity-adversity model of low nesting resources outside the home cage, our lab has discovered sex differences in both behavioral and epigenetic consequences of repeated exposure to caregiver maltreatment. For the measures we have performed to date, we have found more consequences for females. The reasons underlying this sex disparity are unknown. In the current experiment, we aimed to discern the quality of maternal care received by male and female pups in our model. As we have previously found more behavioral and epigenetic consequences in females, we hypothesized that females receive more adverse care compared to their male littermates. Our hypothesis was supported; in our maltreatment condition, we found that female pups received more adverse care than males. This sex difference in adverse care was not present in our two control conditions (cross-foster and normal maternal care). These data lend support to the notion that one reason females in our model incur more behavioral and epigenetic consequences is a result of greater mistreatment by the dam.     

Persistent sensitization of depressive-like behavior and thermogenic response during maternal separation in pre- and post-weaning guinea pigs

Early attachment disruption is thought to promote later onset of depressive illness through a process involving sensitization. Maternal separation in guinea pig pups produces depressive-like behavior and core body temperature fluctuations that appear to be mediated by proinflammatory activity. In pups near the age of weaning (~20 days of age), these responses are increased during repeated separations occurring over several days. Here, enhanced depressive-like behavior and core body temperature responses were observed during repeated separations in guinea pigs from ~10 to 30 days of age. The sensitization lasted for more than a week, with the greatest temperature response occurring during the final separation. These results demonstrate persisting sensitization of behavioral and thermogenic responses to maternal separation over the age range in which these responses are known to occur. The findings are consistent with the hypothesis that proinflammatory activity contributes to the sensitization response and provide further suggestion that the impact of early attachment disruption on susceptibility to depression may involve proinflammatory processes.     

Influence of maternal proximity on behavioral and physiological responses to separation in infant rhesus monkeys (Macaca mulatta).

The effects of maternal proximity on the behavioral and physiological responses of infant rhesus macaques during 4 days of total or adjacent separations from the mother were studied. The 6 infants tested showed behavioral responses that differentiated the two separation conditions. Major differences were found in the quantity and quality of vocalizations, the occurrence of cage-biting and cage-shaking behavior, object exploration, and hunched and freezing postures. In particular, the structure of coo vocalizations clearly discriminated between the presence or the absence of the mother during separation. Cerebrospinal fluid (CSF) concentrations of dopamine and serotonin metabolites did not discriminate between the two separation conditions but showed a transient elevation at 24 hr after separation and were not different from baseline by 96 hr after separation. In contrast, both the plasma cortisol and the CSF norepinephrine metabolite responses tended to be greater and to persist for a longer period of time when infants were totally isolated. The results are discussed within the context of attachment and coping theories.