Cellular and Molecular Basis of Hippocampal Atrophy in Depressed Female Monkeys

描述(由申请人提供)：临床和实验研究表明，抑郁症患者的海马体体积可能较小，尽管这种关系背后的细胞机制尚不清楚。应激性生活事件与抑郁风险的增加有关，而暴露在慢性应激下的动物模型以前曾被用来研究抑郁症患者的海马体萎缩。尽管来自临床前应激模型的数据令人信服，但动物模型中的应激反应与人类抑郁症的相关性程度仍然存在争议，特别是考虑到女性患抑郁症的风险是男性的两倍，而且动物模型大多是雄性啮齿动物。在一个更接近人类抑郁症的实验模型中评估海马体体积减少的原因将是有价值的。我们在成年雌性食蟹猴身上建立了一种与人类抑郁症非常相似的灵长类抑郁模型，最近观察到抑郁的猴子的前海马区相对较小。这项建议的总体目标是评估抑郁和非抑郁雌性猴子的海马区的形态、细胞和分子特征，以确定抑郁雌性猴子的较小海马区是否伴随着神经纤维和突触、棘突和树突完整性的减少。我们有一个独特的，有价值的固定的，冷冻的海马体，来自成年雌性猴子的种群，其中抑郁症的行为和生理特征在死前进行了4年的研究。用8只抑郁和8只非抑郁猕猴的组织，我们将测定行为抑郁和非抑郁猕猴大脑前、后角(CA)CA1、CA2、CA3和DG的星形胶质细胞、锥体和颗粒神经元的大小和数量，以及突触、棘突和树突完整性标志物的蛋白质和mRNA水平。这项研究的结果将在未来研究抑郁症的机制和干预抑郁症的有效性方面建立该模型的使用。这项研究尤其对题为“推进妇女健康研究中的新奇科学”(PAS-07-381)的FOA做出了回应。建议的研究结果将用于支持国家卫生研究院的竞争性申请。公共卫生相关性：在美国，抑郁症是一个严重的健康问题，特别是在女性中，因为20%的育龄妇女经历了临床上严重的抑郁症。不幸的是，在抑郁症的雌性动物模型上进行的研究很少。首次提出的雌性成年抑郁症灵长类动物模型与人类神经生物学和抑郁症的相似性高于啮齿动物模型，这将促进我们对抑郁症，特别是女性抑郁症的神经生物学的理解。

DESCRIPTION (provided by applicant): Clinical and experimental studies suggest that hippocampal volumes may be smaller in individuals with depression, although the cellular mechanisms underlying this relationship are unclear. Stressful life events are associated with an increased risk of depression, and animal models, exposed to chronic stress have been used previously to investigate hippocampal shrinkage in depression. Although the data from preclinical stress models are compelling, the degree to which stress responses in animal models are relevant to human depression remains controversial, particularly since women are at two-fold greater risk of depression and the animal models are mostly male rodents. Evaluation of the causes of reduced hippocampal volume in an experimental model that more closely resembles human depression would be valuable. We have developed a primate model of depression in adult female cynomolgus monkeys which closely resembles human depression, and recently observed that depressed monkeys have relatively small anterior hippocampi. The overall goal of this proposal is to evaluate hippocampal morphologic, cellular, and molecular characteristics in depressed and nondepressed female monkeys to determine whether the smaller hippocampi of depressed female monkeys are accompanied by reductions in neuropil and synaptic, spinous, and dendritic integrity. We have a unique and valuable collection of fixed, frozen hippocampi derived from the population of adult female monkeys in which the behavioral and physiological characteristics of depression were studied premortem for 4 years. Using the tissue from 8 depressed and 8 nondepressed monkeys we will determine astrocyte, pyramidal, and granule neuron size and number, and protein and mRNA levels of markers of synaptic, spinous, and dendritic integrity in the cornu ammonis (CA) CA1, CA2, CA3, and DG of the anterior and posterior HC of behaviorally depressed and nondepressed monkeys. The results of this study will establish the use of the model in future investigations of the mechanisms of depression and the efficacy of interventions for depression. The research is particularly responsive to the FOA entitled "Advancing Novel Science in Women's Health Research" (PAS-07-381). The results of the proposed study will be used in support of a competitive NIH application. PUBLIC HEALTH RELEVANCE: Depression is a significant health problem in the US, particularly in women, as 20% of reproductive-aged women experience clinically significant depression. Unfortunately very little research has been conducted in female animal models of depression. The use of the first primate model of adult depression in females proposed here, which has greater similarity to human neurobiology and depression than rodent models, will advance our understanding of the neurobiology of depression especially in women.