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症的风险增加有关，暴露于慢性应激的动物模型先前已被用于研究抑郁症中的海马萎缩。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程度仍然存在争议，特别是因为女性患抑郁症的风险高出两倍，而动物模型大多是雄性啮齿动物。在更接近人类抑郁症的实验模型中评估海马体积减少的原因将是有价值的。我们已经在成年雌性食蟹猴中开发了一种与人类抑郁症非常相似的灵长类抑郁症模型，最近观察到抑郁症猴的前额叶相对较小。这项建议的总体目标是评估海马的形态，细胞和分子特征，在抑郁症和非抑郁症的雌性猴子，以确定是否较小的抑郁症的雌性猴子的海马伴随着减少神经元和突触，棘，树突的完整性。我们有一个独特的和有价值的收集固定的，冷冻campi来自人口的成年雌性猴子，其中抑郁症的行为和生理特征进行了研究死前4年。使用组织从8抑郁症和8 nondepressed猴子，我们将确定星形胶质细胞，锥体，颗粒神经元的大小和数量，蛋白质和mRNA水平的标记物的突触，棘，树突的完整性在角amnus（CA）CA 1，CA 2，CA 3，和DG的前和后HC的行为抑郁症和nondepressed猴子。本研究的结果将建立使用的模型在未来的调查抑郁症的机制和抑郁症的干预措施的有效性。这项研究特别响应了题为“推进妇女健康研究的新科学”的FOA（PAS-07-381）。拟议研究的结果将用于支持竞争性NIH申请。公共卫生相关性：抑郁症在美国是一个严重的健康问题，特别是在女性中，因为20%的育龄妇女患有临床上显著的抑郁症。不幸的是，很少有研究在抑郁症的雌性动物模型中进行。使用第一个灵长类动物模型的成年抑郁症的女性在这里提出的，这有更大的相似性，人类神经生物学和抑郁症比啮齿动物模型，将推进我们的抑郁症的神经生物学的理解，特别是在妇女。

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.