抑郁症的发病比例在男女之间表现出很大的性别差异，女性患抑郁症的比例大约是男性的两倍。应激总是和抑郁症的发病有很大的相关性，而且可的松的过度分泌也被证明是抑郁症的危险因素。然而，并非全部个体在经历应激事件后都发生抑郁症，一些个体在面对这些应激后仍旧保持健康。因此，可能存在其它的因素来调控社会应激和抑郁症发病之间的关系。其中，研究最多的是遗传因素对抑郁症发病的调控，尤其是5-羟色胺转运体基因多态性(5-HTTLPR)在应激和抑郁症发病过程中所起的调控作用。为了探讨女性在抑郁症发病过程中的特殊性，该研究选用雌性猕猴作为模型，其研究内容分为密切相关的三个部分：第一部分是雌性猕猴社会等级和应激相关性研究；第二部分是雌性猕猴社会应激、可的松和抑郁行为相关性研究；第三部分是雌性猕猴社会等级、5-HTTLPR和抑郁行为相关性研究。

        第一部分：雌性猕猴社会等级和应激相关性研究
在动物社会中，一些应激可能会导致更高水平的生理压力。这样的应激，比如社会等级，也预示着一系列疾病易感性的增加。然而，社会等级和应激的关系在不同物种之间往往千差万别，即使在同一物种的不同种群之间也存在很大的差异。例如，有时高地位的个体受到更多的应激，而在其它时间则是低地位个体经历更高的应激状态，这些差异使得评估社会等级相关的疾病易感性变得极其困难。为了更好地研究同一物种不同种群间社会等级和应激的关系，我们应用毛发中的可的松含量来评估社会等级对雌性猕猴不同社会群体应激水平的影响。研究结果表明，在具有良好线性等级关系的群体中，社会等级和可的松之间没有关系。在没有良好线性等级关系的群体中，社会等级和可的松之间存在着明显的负相关，低地位的猕猴比高地位个体分泌更高浓度的可的松。因此，社会等级制度的线性度制约着雌性猕猴社会等级和应激的关系。鉴于非人灵长类社会群体的多样性，在未来建立社会等级相关的应激模型时应该考虑到社会等级线性度的影响。

    第二部分：雌性猕猴社会应激、可的松和抑郁行为相关性研究
我们在第一部分的研究中发现，低地位猕猴受到更大的社会应激，分泌更多的可的松。社会应激总是预示着抑郁症的发病，而且应激相关激素可的松的过量分泌也被证明是抑郁症的危险因素。然而，社会应激、可的松和抑郁症三者之间的关系却不十分清楚。尤其是在女性中，这三者之间的关系更是模糊。本研究选用雌性猕猴作为模型，探讨了社会应激、可的松和抑郁行为三者之间的关系。研究结果表明，猕猴经历的应激事件数量越多，表现抑郁行为的持续时间越长，两者之间存在着明显的正相关；而且可的松和猕猴表现的抑郁行为之间存在着明显的正相关。进一步的分析表明，社会应激和可的松并不是相互独立的，两者之间存在着明显的正相关。交互作用分析结果显示可的松的过量分泌导致猕猴在受到较多社会应激的时候，表现更长持续时间的抑郁行为。这一结果暗示可的松的过量分泌可能加速了猕猴在面对社会应激时抑郁行为的出现。
     第三部分：雌性猕猴社会等级、5-羟色胺转运体基因多态性(5-HTTLPR)和抑郁行为相关性研究
第一部分和第二部分的研究结果表明，低的社会等级可以带来更多的心理社会应激，从而引发更高的抑郁症发病率。然而，并非全部低地位个体都发生抑郁症，一些个体在面对这些应激后仍旧保持健康。为了探索其中的机制，我们调查了雌性猕猴社会群体的遗传背景，发现携带短5-羟色胺转运体等位基因的猕猴在处于低地位的情况下表现出比长等位基因纯合子更多的抑郁行为。与长等位基因纯合子相比，携带短等位基因的猕猴在受到较多的应激时表现出更多的抑郁行为。在应激不存在的情况下，两者之间抑郁行为的表现没有差异。进一步的分析表明5-羟色胺转运体基因并没有影响猕猴暴露于应激的强度，而是通过调控猕猴的应激反应而影响抑郁行为的产生。总而言之，猕猴表现的抑郁行为受到基因和环境的交互调控，短等位基因携带者只有在处于低地位或经历较多应激的情况下才表现出比长等位基因纯合子更多的抑郁行为。这些发现有助于我们了解人类抑郁症发病过程中基因和环境之间的交互作用，因为抑郁症的发病不仅仅依赖于其基因背景，而是更多地受到基因和环境的交互调控。

       Relationship between social stress, serotonin transporter gene-linked polymorphic region (5-HTTLPR) and depressive behavior among female rhesus macaques (Macaca mulatta)
The prevalence of depression in women is twice as high as in men. Social stress has been associated with the onset of depressive episodes and cortisol hypersecretion has been considered a biological risk factor of depression. However, most people confronted with social stress remain psychologically healthy. Although, the basis of the variable responses to the stress is not known, the serotonin transporter gene-linked polymorphic region (5-HTTLPR) is a putative factor linked to depression susceptibility. In order to explore the particularity of females in the development of depression, this study used the female rhesus monkeys as the animal model. It was divided into three closely related parts: the first part introduced the relationship between social rank and stress among female rhesus macaques, the second part examined the relationship between social stress, cortisol and observed depressive behaviors in female rhesus macaques, and the third part was about the moderation of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) in the development of depression.

   Part 1: Social rank and stress 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.

     Part 2: Relationship between social stress, cortisol and depressive behavior in adult female rhesus macaques (Macaca mulatta)
It was found in the first part that low ranking monkeys experienced more stress and secreted elevated levels of cortisol than higher ranking animals. Social stress has been associated with the onset of depressive episodes and cortisol hypersecretion has been considered a biological risk factor of depression. However, the interacting relationships among these three variables are inconsistent in literature, especially how they pertain to women. This study examined the relationship between social stress, cortisol and observed depressive behaviors in female rhesus macaques. Significant relationships were evident between social stress and depressive behavior measures as well as between cortisol levels and depressive behavior. Social stress was positively correlated with cortisol levels. An interactive relationship was also apparent between social stress and cortisol levels, which suggested that cortisol hypersecretion led to the monkeys’ depressive behaviors in the presence of social stress.
      Part 3: Influence of social rank on depressive behavior in female macaques: moderation by a polymorphism in the serotonin transporter gene The results from the first part and the second part showed that the psychosocial stress of low rank may be a causal factor in depression. However, most people confronted with this stress remain psychologically healthy. Although, the basis of the variable responses to rank-related stress is not known, the serotonin transporter gene-linked polymorphic region (5-HTTLPR) is a putative factor linked to depression susceptibility. In order to explore the regulatory mechanism of 5-HTTLPR in the development of depression, we investigated the genetic background of female rhesus monkeys. It was found that monkeys with one or two copies of the short allele (S) of the 5-HTTLPR exhibited more depressive behavior in relation to subordination stress than monkeys homozygous for the long allele. Compared to the monkeys homozygous for the long allele , the S carriers exhibited more depressive behavior only if they received high frequencies of aggression and displayed a high frequency of submissive behaviors. High basal cortisol levels were also found to manifest in behavioral depression among short allele carriers. Further analysis showed that this gene did not influence social stress exposure, suggesting that the gene polymorphism moderated the depressogenic effect of social stress. In summary, depressive behaviors in monkeys were found to be dependent on a gene-environment interaction, in which a monkey’s response to social subordination stress was moderated by its polymorphism in the serotonin transporter gene. These findings are important to the etiological understanding of major depression in humans, as they suggest that depression onset is not dependent solely on genetic variables, but rather on vulnerabilities to biological defense mechanisms against stressful situations.