Morphology of Hippocampal Neurons in Depression

描述（由申请人提供）：本研究的目的是鉴定重度抑郁症患者海马神经元的树突异常。在实验室动物中，应激和糖皮质激素可导致海马CA 3区锥体细胞萎缩。这些模型长期以来被认为是抑郁症的代表，它们所揭示的树突萎缩是抑郁症患者体内成像所观察到的海马体积缺陷的明显候选者。令人惊讶的是，除了我们早期精神分裂症研究中的少数病例外，重度抑郁症的海马树突形态学尚未得到研究，部分原因无疑是难以获得适当染色的材料。使用一种新的修改Golgi-Cox技术，我们正在积累一个相当大的收集良好的浸渍panccampi良好的特点与DSM IV定义的抑郁症或没有精神疾病的主题。这种修改，我们称之为NeoGolgi，始终产生一个均匀的浸渍部分中的所有区域，允许均匀随机抽样的神经元进行分析。我们建议分析30例重度抑郁症患者和30例年龄和性别相匹配的非精神病患者的大脑中动脉的树突状分支和棘密度。我们将包括齿状回的颗粒细胞和CA 3，CA 1和下托的锥体细胞：海马三突触通路及其主要输出。拟议的研究应该是足够大和全面的，以解决是否有严重的抑郁症海马树突缺陷的问题。此外，由于我们提出的重性抑郁症受试者样本中约有三分之一从未接受过治疗，并在发病后一年内死亡，我们将能够解决观察到的任何缺陷是否是慢性疾病或治疗的结果的问题。我们还建议测量脑源性神经营养因子（BDNF）的海马水平，以确定这些是否与神经元形态学相关，如动物模型所示，以及这种相关性是否受重度抑郁症（与低BDNF水平相关）或抗抑郁治疗的影响，这与更高的水平相关。最后，为了便于探索树突形态和特定的传入连接之间的关系，我们将尝试开发技术，结合联合收割机免疫组织化学和高质量的高尔基体染色。公共卫生相关性重度抑郁症是一种常见的疾病，导致许多残疾和死亡。长期以来，人们一直怀疑重度抑郁症与大脑结构异常有关，包括接收其他神经细胞信息的神经细胞投射萎缩，但这一假设从未得到过验证。如我们所建议的，定位和定位这些异常将告诉我们很多关于这种疾病中大脑的问题以及它是否可以修复。

DESCRIPTION (provided by applicant): The goal of this study is to identify dendritic abnormalities in hippocampal neurons from humans with major depression. In laboratory animals, stress and glucocorticoids have been shown to result in atrophy of pyramidal cells in hippocampal region CA3.These models have long been assumed to represent depression, and the dendritic atrophy that they reveal is an obvious candidate to underlie hippocampal volume deficits observed by in vivo imaging of depressed patients. Surprisingly, except for a few cases included in our earlier studies of schizophrenia, hippocampal dendritic morphology in major depressive disorder has been unexamined, in part, no doubt, because of the difficulty of obtaining appropriately stained material. Using a new modification of the Golgi-Cox technique, we are accumulating a sizable collection of well-impregnated hippocampi from well-characterized subjects with DSM IV defined major depression or without psychiatric illness. This modification, which we call NeoGolgi, consistently yields a uniform impregnation of all regions in the section, permitting uniform random sampling of neurons for analysis. We propose to analyze dendritic arborization and spine density in the hippocampi of 30 subjects with major depressive disorder, and 30 nonpsychiatric subjects matched for age and sex. We will include granular cells from the dentate gyrus and pyramidal cells from CA3, CA1, and subiculum: the intrinsic hippocampal trisynaptic pathway and its major output. The proposed study should be sufficiently large and comprehensive to resolve the question of whether there are significant hippocampal dendritic deficits in major depressive disorder. Furthermore, since approximately one-third of our proposed sample of major depression subjects was never treated and died within one year of the onset of illness, we will be able to address the question of whether any deficits observed are the result of chronic illness or treatment. We also propose to measure hippocampal levels of brain-derived neurotrophic factor (BDNF), in order to determine whether these are correlated with neuronal morphology, as suggested by animal models, and whether such correlations are affected by major depression (associated with low BDNF levels), or with antidepressant treatment, which is associated with higher levels. Finally, in order to facilitate exploration of the relationship between dendritic morphology and specific afferent connections, we will attempt to develop techniques to combine immunohistochemistry and high-quality Golgi staining. PUBLIC HEALTH RELEVANCE Major depressive disorder is a common illness that causes much disability and death. It has long been suspected that major depressive disorder involves structural abnormalities of the brain, including shrinkage of nerve cell projections that receive information from other nerve cells, but this hypothesis has never been tested. Verifying and localizing such abnormalities, as we propose, will tell us much about what is wrong with the brain in this illness and whether it can be repaired.