Cellular and Molecular Basis of Hippocampal Atrophy in Depressed Female Monkeys

抑郁雌性猴子海马萎缩的细胞和分子基础

• 批准号: 7706199
• 负责人: Carol A. Shively
• 金额: $ 22.2万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7706199
• 关键词: Accounting; Adult; Affect; Age; Animal Model; Animals; Anterior; Astrocytes; Atherosclerosis; Axon; Behavioral; Cessation of life; Characteristics; Chronic stress; Clinical; Collection; Coronary artery; Cytoplasmic Granules; Data; Dendrites; Evaluation; Event; Experimental Models; Face; Female; Freezing; Future; Glucocorticoids; Goals; Grant; Health; Heart Rate; Hippocampus (Brain); Human; Human Characteristics; Individual; Insulin-Like Growth Factor I; Investigation; Life; Macaca fascicularis; Messenger RNA; Modality; Modeling; Molecular; Monkeys; Neurobiology; Neuroglia; Neurons; Neuropil; Physiological; Population; Primates; Process; Proteins; Relative (related person); Research; Risk; Rodent; Rodent Model; Science; Serotonin Receptor 5-HT1A; Stress; Synapses; Testing; Tissues; Treatment Efficacy; United States National Institutes of Health; Woman; Women' s Health; adult neurogenesis; aged; base; biological adaptation to stress; clinically significant; depressed; depression; experience; hippocampal atrophy; male; neurogenesis; neuron loss; neuronal cell body; neurophysiology; novel; numb protein; pre-clinical; public health relevance; receptor binding; relating to nervous system; reproductive; research study

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.

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。压力性生活事件与抑郁症风险增加有关，之前曾使用暴露于慢性压力的动物模型来研究抑郁症时海马体的萎缩。尽管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是女性的两倍，而动物模型大多是雄性啮齿类动物。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。我们在成年雌性食蟹猴中开发了一种灵长类抑郁症模型，该模型与人类抑郁症非常相似，并且最近观察到抑郁症猴子的前海马体相对较小。该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较小的海马是否伴随着神经纤维和突触、棘和树突完整性的减少。我们拥有独特且有价值的固定、冷冻海马体收藏，这些海马体取自成年雌性猴子群体，在死前对抑郁症的行为和生理特征进行了 4 年的研究。使用 8 只抑郁猴和 8 只非抑郁猴的组织，我们将确定星形胶质细胞、锥体神经元和颗粒神经元的大小和数量，以及角部 (CA) CA1、CA2 中突触、棘和树突完整性标记物的蛋白质和 mRNA 水平。行为抑郁和非抑郁猴子的前部和后部 HC 的 CA3 和 DG。这项研究的结果将确立该模型在未来抑郁症机制和抑郁症干预措施有效性研究中的应用。该研究特别响应题为“推进妇女健康研究中的新科学”(PAS-07-381) 的 FOA。拟议研究的结果将用于支持 NIH 的竞争性申请。公共健康相关性：抑郁症在美国是一个严重的健康问题，尤其是对女性而言，因为 20% 的育龄女性患有临床上严重的抑郁症。不幸的是，对雌性抑郁症动物模型进行的研究很少。这里提出的第一个女性成年抑郁症灵长类动物模型的使用，与啮齿类动物模型相比，与人类神经生物学和抑郁症有更大的相似性，将增进我们对抑郁症神经生物学的理解，特别是女性抑郁症的神经生物学。