Morphology of Hippocampal Neurons in Depression

描述(申请人提供)：这项研究的目标是鉴定患有严重抑郁症的人类海马神经元中的树突异常。在实验动物中，应激和糖皮质激素已被证明导致海马区CA3区锥体细胞萎缩，这些模型长期以来被认为代表抑郁症，它们揭示的树突萎缩是抑郁患者活体成像观察到的海马体积缺陷的明显候选因素。令人惊讶的是，除了我们早期对精神分裂症的研究中包括的几个病例外，严重抑郁障碍的海马树突状细胞形态没有得到研究，部分原因无疑是很难获得适当染色的材料。使用高尔基-考克斯技术的一种新改进，我们正在收集大量受孕良好的海马体，这些受试者来自患有DSM IV定义的重度抑郁症或没有精神疾病的特征良好的受试者。这种修改，我们称之为新高尔基体，一致地产生了切片中所有区域的均匀浸渍，允许对神经元进行均匀随机采样以进行分析。我们建议分析30例重度抑郁症患者和30例年龄和性别匹配的非精神病组患者的海马区树突分枝和棘突密度。我们将包括来自齿状回的颗粒细胞和来自CA3、CA1和下丘的锥体细胞：海马内部三突触通路及其主要输出。拟议的研究应该足够大和全面，以解决在严重抑郁障碍中是否存在显著的海马树突状细胞缺陷的问题。此外，由于我们建议的主要抑郁症受试者样本中约有三分之一从未接受过治疗，并在发病一年内死亡，我们将能够解决观察到的任何缺陷是由慢性病还是治疗造成的问题。我们还建议测量海马区脑源性神经营养因子(BDNF)的水平，以确定这些水平是否与动物模型所建议的神经元形态有关，以及这种相关性是否受到严重抑郁(与低BDNF水平相关)或与抗抑郁治疗(与较高水平相关)的影响。最后，为了便于探索树突状细胞形态和特定传入联系之间的关系，我们将尝试开发结合免疫组织化学和高质量高尔基体染色的技术。与公共卫生相关严重抑郁障碍是一种常见疾病，可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，包括从其他神经细胞接收信息的神经细胞投射缩小，但这一假说从未得到检验。根据我们的建议，验证和定位这种异常将告诉我们许多关于这种疾病中大脑的问题以及它是否可以修复的信息。

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.