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更小，尽管这种关系背后的细胞机制尚不清楚。压力生活事件与抑郁症的风险增加有关，并且暴露于慢性压力下的动物模型先前已被用于研究抑郁症的海马萎缩。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关系程度仍存在争议，特别是因为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积减少的原因将是有价值的。我们建立了一种与人类抑郁症相似的成年雌性食蟹猴抑郁症灵长类动物模型，最近观察到抑郁的猴子的海马前部相对较小。本提案的总体目标是评估抑郁和非抑郁雌性猴子的海马形态、细胞和分子特征，以确定抑郁雌性猴子的小海马是否伴随着神经细胞和突触、棘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，来自于成年雌性猴子的种群，在死前的4年里，我们研究了抑郁症的行为和生理特征。使用来自8只抑郁和8只非抑郁猴子的组织，我们将测定行为抑郁和非抑郁猴子的前后HC前、后HC CA1、CA2、CA3和DG中星形胶质细胞、锥体和颗粒神经元的大小和数量，以及突触、棘和树突完整性标记物的蛋白质和mRNA水平。本研究的结果将为该模型在未来抑郁症的机制研究和干预措施的有效性研究中奠定基础。这项研究特别符合题为“在妇女健康研究中推进新科学”的FOA （PAS-07-381）。提议的研究结果将用于支持竞争性的NIH申请。公共卫生相关性：抑郁症在美国是一个重要的健康问题，尤其是在女性中，因为20%的育龄妇女临床上患有明显的抑郁症。不幸的是，对雌性抑郁症动物模型的研究很少。本文提出的第一个雌性成年抑郁症的灵长类动物模型，与啮齿动物模型相比，与人类神经生物学和抑郁症更相似，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.