Hippocampal atrophy in major depression

描述(申请人提供)：海马体的可塑性在学习和记忆，以及对压力和抗抑郁药物的神经生物学反应中发挥作用。19例重度抑郁障碍(MDD)患者的海马神经元和神经胶质细胞密度显著增加，神经元胞体体积缩小。MDD患者的密度变化与自杀或性别无关。据推测，海马神经纤维层的减少是MDD海马区组织病理学的微观基础。AIMS 1-3验证了与正常对照组相比，MDD患者海马神经纤维层减少的假设。AIMS 4-5检验了MDD患者海马区神经生长和突触连接的标志物减少的假设。在目标1中，MDD的体视学实验将估计整个海马区神经元和GILA的细胞总数和密度以及相应的体积。目的2用高尔基银法测定MDD大鼠海马CA1、CA3区锥体神经元的棘密度、树突分支点数目及顶树和基树的总长度。目的3测量MDD大鼠海马区胶质纤维酸性蛋白(GFAP)免疫反应胞体的密度和大小，以及GFAP免疫反应在星形胶质细胞中所占的面积百分比。在目的4中，实验旨在对MDD大鼠海马区突触可塑性标志物[脑源性神经营养因子(BDNF)、生长相关蛋白-43(GAP-43)和多唾液酸化神经细胞黏附分子(PSA-NCAM)]的总免疫反应细胞数和堆积密度进行体视学评估。目的5定量检测MDD大鼠吻侧海马区CA3、CA4区BDNF和GAP-43的mRNA表达。据预测，AIM 4中BDNF和GAP-43蛋白表达的假想下降将继发于海马区相关基因表达的下降。在死后检测到的MDD细胞变化可能是一些在世的MDD受试者检测到的海马萎缩的基础。

DESCRIPTION (provided by applicant): Plasticity in the hippocampus plays a role in learning and memory, and in neurobiological responses to stress and antidepressant drug action. A significant increase in neuron and glial cell density and a decrease in neuronal soma size has been detected in hippocampus of 19 subjects with major depressive disorder (MDD). The changes in density in MDD were independent of suicide or gender. It is hypothesized that a decrease in hippocampal neuropil, in response to diminished markers of neural growth and synaptic connection, resulting in an increase in neuronal and glial density, is the microscopic basis for the histopathology of the hippocampus in MDD. Aims 1-3 examine the hypothesis that in MDD there is a decrease in hippocampal neuropil, as compared to normal controls. Aims 4-5 examine the hypothesis that there will be diminished markers of neural growth and synaptic connection in the hippocampus in MDD. In Aim 1, stereological experiments in MDD will estimate the total cell number and density of neurons and gila and the corresponding volume throughout the entire hippocampus. In Aim 2, the Golgi silver method will be used to measure spine density, number of dendritic branch points and total length of apical and basal dendritic trees of pyramidal neurons in hippocampal CA1 & CA3 subfields in MDD. In Aim 3, the density and size of glial fibrillary acidic protein (GFAP) -immunoreactive cell bodies, and the areal fraction occupied by GFAP-immunoreactivity in astrocytes will be measured in the hippocampus in MDD. In Aim 4, experiments are designed to stereologically estimate the total immunoreactive cell number and packing density of markers of synaptic plasticity [brain derived neurotrophic factor (BDNF), growth associated protein-43 (GAP-43) and polysialylated-nerve cell adhesion molecule (PSA-NCAM)] throughout the hippocampus in MDD. In Aim 5, experiments will be carried out to quantify mRNA for BDNF and GAP-43 in CA3 and CA4 of the rostral hippocampus in MDD. It is predicted that the hypothesized decrease in expression of BDNF and GAP-43 protein in Aim 4 will be secondary to related decreases in gene expression in the hippocampus. Cellular changes detected in MDD postmortem may underlie hippocampal atrophy detected by some in living subjects with MDD.