Xiaoli Feng

Maternal separation produces lasting changes in cortisol and behavior in rhesus monkeys.

Maternal separation (MS), which can lead to hypothalamic pituitary adrenal axis dysfunction and behavioral abnormalities in rhesus monkeys, is frequently used to model early adversity. Whether this deleterious effect on monkeys is reversible by later experience is unknown. In this study, we assessed the basal hair cortisol in rhesus monkeys after 1.5 and 3 y of normal social life following an early separation. These results showed that peer-reared monkeys had significantly lower basal hair cortisol levels than the mother-reared monkeys at both years examined. The plasma cortisol was assessed in the monkeys after 1.5 y of normal social life, and the results indicated that the peak in the peer-reared cortisol response to acute stressors was substantially delayed. In addition, after 3 y of normal social life, abnormal behavioral patterns were identified in the peer-reared monkeys. They showed decreases in locomotion and initiated sitting together, as well as increases in stereotypical behaviors compared with the mother-reared monkeys. These results demonstrate that the deleterious effects of MS on rhesus monkeys cannot be compensated by a later normal social life, suggesting that the effects of MS are long-lasting and that the maternal-separated rhesus monkeys are a good animal model to study early adversity and to investigate the development of psychiatric disorders induced by exposure to early adversity.

Social rank and cortisol among female rhesus macaques (Macaca mulatta)

In animal societies, some stressful events can lead to higher levels of physiological stress. Such stressors, like social rank, also predict an increased vulnerability to an array of diseases. However, the physiological relationship between social rank and stress varies between different species, as well as within groups of a single species. For example, dominant individuals are more socially stressed at times, while at other times it is the subordinate ones who experience this stress. Together, these variations make it difficult to assess disease vulnerability as connected to social interactions. In order to learn more about how physiological rank relationships vary between groups of a single species, cortisol measurements from hair samples were used to evaluate the effects of dominance rank on long-term stress levels in despotic and less stringent female rhesus macaque hierarchal groups. In despotic groups, cortisol levels were found not to be correlated with social rank, but a negative correlation was found between social rank and cortisol levels in less stringent hierarchies. Low ranking monkeys in less stringent groups secreted elevated levels of cortisol compared to higher ranking animals. These data suggest that variations in the strictness of the dominance hierarchy are determining factors in rank related stress physiology. The further consideration of nonhuman primate social system diversity and the linear degree of their hierarchies may allow for the development of valid rank-related stress models that will help increase our understanding and guide the development of new therapeutics for diseases related to human socioeconomic status.

The first observation of seasonal affective disorder symptoms in Rhesus macaque.

Diurnal animals are a better model for seasonal affective disorder (SAD) than nocturnal ones. Previous work with diurnal rodents demonstrated that short photoperiod conditions brought about depression-like behavior. However, rodents are at a large phylogenetic distance from humans. In contrast, nonhuman primates are closely similar to humans, making them an excellent candidate for SAD model. This study made the first attempt to develop SAD in rhesus macaque (Macaca mulatta) and it was found that short photoperiod conditions could lead monkeys to display depressive-like huddling behavior, less spontaneous locomotion, as well as less reactive locomotion. In addition to these depression-related behavioral changes, the physiological abnormalities that occur in patients with SAD, such as weight loss, anhedonia and hypercortisolism, were also observed in those SAD monkeys. Moreover, antidepressant treatment could reverse all of the depression-related symptoms, including depressive-like huddling behavior, less spontaneous locomotion, less reactive locomotion, weight loss, anhedonia and hypercortisolism. For the first time, this study observed the SAD symptoms in rhesus macaque, which would provide an important platform for the understanding of the etiology of SAD as well as developing novel therapeutic interventions in the future.

A spontaneous depressive pattern in adult female rhesus macaques

Non-human primates offer unique opportunities to study the development of depression rooted in behavioral and physiological abnormalities. This study observed adult female rhesus macaques within social hierarchies and aimed to characterize the physiological and brain abnormalities accompanying depressive-like behavior. The behaviors of 31 female rhesus macaques from 14 different breeding groups were video recorded, and the footage was analyzed using the focal animal technique. There were 13 monkeys who never displayed huddling behavior (non-huddlers). The remaining 18 monkeys were divided into two groups according the mean time spent in the huddle posture. Four monkeys were designated as high huddlers, whereas the other 14 monkeys were low huddlers. An inverse relationship was discovered between social rank and depression. High huddlers spent more time engaging in physical contact and in close proximity to other monkeys, as well as less time spontaneously and reactively locomoting, than low huddlers and/or non-huddlers. Cortisol levels measured from the hair were elevated significantly in high huddlers compared with low huddlers and non-huddlers, and the measured cortisol levels were specifically higher in high huddlers than subordinate or dominant control monkeys. Regional cerebral blood flow data revealed significant and widespread decreases in high huddlers compared with non-huddlers.

Cortisol responses to chronic stress in adult macaques: moderation by a polymorphism in the serotonin transporter gene.

Accumulating evidence has shown that a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) moderates the association between stress and depressive symptoms. However, the exact etiologies underlying this moderation are not well understood. Here it is reported that among adult female rhesus macaques, an orthologous polymorphism (rh5-HTTLPR) exerted an influence on cortisol responses to chronic stress. It was found that females with two copies of the short allele were associated with increased cortisol responses to chronic stress in comparison to their counterparts who have one or two copies of the long allele. In the absence of stress, no differences related to genotype were observed in these females. This genetic moderation was found without a genetic influence on exposure to stressful situations. Rather it was found to be a genetic modulation of cortisol responses to chronic stress. These findings indicate that the rh5-HTTLPR polymorphism is closely related to hypothalamus-pituitary-adrenal (HPA) axis reactivity, which may increase susceptibility to depression in females with low serotonin transporter efficiency and a history of stress.

Prolonged secretion of cortisol as a possible mechanism underlying stress and depressive behaviour

Stress is associated with the onset of depressive episodes, and cortisol hypersecretion is considered a biological risk factor of depression. However, the possible mechanisms underlying stress, cortisol and depressive behaviours are inconsistent in the literature. This study examined the interrelationships among stress, cortisol and observed depressive behaviours in female rhesus macaques for the first time and explored the possible mechanism underlying stress and depressive behaviour. Female monkeys were video-recorded, and the frequencies of life events and the duration of huddling were analysed to measure stress and depressive behaviour. Hair samples were used to measure chronic cortisol levels, and the interactions between stress and cortisol in the development of depressive behaviour were further evaluated. Significant correlations were found between stress and depressive behaviour measures and between cortisol levels and depressive behaviour. Stress was positively correlated with cortisol levels, and these two factors interacted with each other to predict the monkeys’ depressive behaviours. This finding extends the current understanding of stress/cortisol interactions in depression, especially pertaining to females.

Social correlates of the dominance rank and long-term cortisol levels in adolescent and adult male rhesus macaques (Macaca mulatta)

A common pattern in dominance hierarchies is that some ranks result in higher levels of psychosocial stress than others. Such stress can lead to negative health outcomes, possibly through altered levels of stress hormones. The dominance rank-stress physiology relationship is known to vary between species; sometimes dominants show higher levels of glucocorticoid stress hormones, whereas in other cases subordinates show higher levels. It is less clear how this relationship varies between groups of different ages or cultures. In this study, we used long-term cortisol measurement methods to compare the effect of rank on cortisol levels in adult and adolescent male rhesus macaques. In the adult groups, subordinates had significantly higher cortisol levels. In the adolescents, no significant correlation between cortisol and status was found. Further analysis demonstrated that the adult hierarchy was stricter than that of the adolescents. Adult subordinates received extreme aggression more frequently than dominants, and this class of behavior was positively correlated with cortisol; by contrast, adolescents showed neither trend. Together, these findings provide evidence for a cortisol-rank relationship determined by social factors, namely, despotism of the group, and highlight the importance of group-specific social analysis when comparing or combining results obtained from different groups of animals.

Early adversity contributes to chronic stress induced depression-like behavior in adolescent male rhesus monkeys

Chronic stress is an important cause for depression. However, not everyone who is exposed to chronic stress will develop depression. Our previous studies demonstrated that early adversity can cause lasting changes in adolescent rhesus monkeys, but depressive symptoms have not been observed. Compared to adults, it is still unknown that whether adolescent rhesus monkeys experiencing early adversity are more likely to develop depressive symptoms. In this study, we investigated the long term relationship between early adversity, chronic stress and adolescent depression for the first time. Eight male rhesus monkeys were reared in maternal separation (MS) or mother-reared (MR) conditions. All of them went through unpredictable chronic stress for two months at their age four. The stressors included space restriction, intimidation, long illumination and fasting. Behavioral and physiological data were collected during the experiment. The results showed that, compared with the MR group, the locomotor activity of MS group was significantly decreased after one month of chronic stress while huddling up and stereotypical behaviors were significantly increased. Moreover, this trend continued and even worsened at the second month. Significantly higher hair cortisol levels and lower body weight were observed in MS group after two months of stress. These results indicate that early adversity is one of the environmental factors which can increase the susceptibility of depression when experiencing chronic stress in the later life. This will further clarify the important roles of early environmental factors in the development of adolescent depression and children rearing conditions should receive more attention.

A Reliable Procedure for Measuring Cortisol Levels in Rhesus Macaque Hair Samples: A Reliable Procedure for Measuring Cortisol Levels in Rhesus Macaque Hair Samples

Hair provides a suitable sample inassessing long-term changes in hypothalamic-pituitary-adrenocortical axis (HPA) system activity. The procedure used for hair analysis is therefore very important. To ensure that our procedure is reliable, liquid nitrogen was used to deepfreeze the samples before powdering them. Experimental trials used three treatment types: blank group (phosphate buffered saline (PBS)) (n=3), old tube group (n=10) and new tube group (n=10). The potential effects of PBS and tubes was then investigated. Additionally, both the relationship between the results of two samples of the same individuals (n=16) yielded by the same procedures but at different times, and the relationship between hair cortisol concentrations and the number of received intense aggressions (n=16) were also investigated. The results showed that the cortisol concentration of the blank group was 0 pg/mg; new tubes did not differ from old tubes(F (1,19)=0.041, P=0.843,one-way ANOVA); and there was a high association between the results of two samples of the same individuals, yielded by same procedures operated at different times (r=0.893,P=0.000). Moreover, hair cortisol concentrations were moderately correlated with the number of received intense aggressions (r=0.591,P=0.008). Therefore, PBS and tubes did not affect the results significantly, therefore, our procedure was deemed reliable.

Alterations of Gray Matter Volume and White Matter Integrity in Maternal Deprivation Monkeys

Maternal deprivation (MD) in rhesus monkeys has been demonstrated to be an effective model to mimic early adversity in humans because of the close phylogenetic similarity affinity. Although behavioral and hormonal abnormalities have been observed in MD monkeys, the neurobiological underpinning of the long-term deleterious effect of MD on monkeys is still unclear. In this study, we assessed emotional changes and socio-behavioral abnormalities induced by long-term MD and assessed structural alterations of gray matter volume (GMV) and white matter integrity (WMI) in 15 MD rhesus monkeys and in 15 age-, gender-matched normal controls (NC) using voxel-based morphology and voxel-based analysis methods. We found increased stereotypical behavioral durations and decreased social grooming durations in MD monkeys. Reduced GMV in the primary visual cortex (V1) and increased fractional anisotropy (FA) in the left posterior superior temporal sulcus (pSTS) was also found in MD monkeys. Moreover, the mean FA values in pSTS showed positive correlation with the stereotypical behavioral durations in MD monkeys and negative correlation with social grooming durations in NC monkeys. Our findings indicated that the deleterious effects of MD on rhesus monkeys resulted in structural abnormalities in the visual cortex and premature myelination in the pSTS. These findings provide new insights into understanding the impact of maternal deprivation on the neurological basis of brain development.