Prefrontal Cell Pathology Distinguishes Mental Disorders

描述：(申请人提供)已确定的差异和 精神分裂症(SCHZ)与精神分裂症(SCHZ)现象学和治疗的相似性 抑郁症(MDD)。众所周知，抑郁症状会出现 在SCHZ和精神症状中，MDD并不少见。因此，它是 有理由假设不同的大脑区域和/或不同的细胞类型 使用SPECITH神经递质是区分神经病理的关键 这两种疾病都有。神经影像证据显示前额背外侧 SCHZ神经病理中(DIPFC)和眶前叶(ORB)皮质区 和MDD。我们最近对死后组织进行的定量组织病理学研究 揭示dIPFC和ORB区域在 MDD和SCHZ的神经生物学。然而，特定类型的神经元和神经胶质细胞， 这些精神障碍的前额叶病理基础并不是 身份还没确定。该提案的总体目标是区分MDD 和SCFIZ通过使用定量免疫组织化学来识别区域-和 蛋鸡特有的构成脆弱神经元和胶质细胞的生化类型 前额叶功能障碍。具体的假设是：1)被试 MDD的特点是免疫反应神经元数量较少， 在DIPFC和ORB中，胶质细胞和较低水平的营养因子，BDNF和GDNF。 相比之下，患有SCHZ的受试者将表现出与MDD相似的减少，仅在 ORI区域，而在dIPFC中，SCHZ将通过以下方式与MDD区分开来 更多的神经细胞，可能还有神经胶质细胞。2观察到的细胞变化 MDD和SCHZ患者的前额叶区域是由于疾病过程所致 因此，它们不会在大鼠大脑的类似区域中被发现 长期使用抗抑郁剂或抗精神病药物治疗，如果这些 假设得到证实，一种挑衅性的解释将是 DIPFC的解剖-功能改变可能与认知有关 功能障碍。而AS在ORB中的变化可能与抑郁症状有关。 为了检验这些假设，我们将确定易受攻击的细胞类型 免疫组织化学与三维非偏倚相结合的定量方法 体视学。我们将用特定的抗体鉴定前额叶细胞 (含钙结合蛋白抗体的非锥体神经元；锥体 抗神经丝蛋白NF-200的神经元；星形胶质细胞 抗GFAP抗体；抗碱性粒细胞趋化因子受体抗体的小胶质细胞 在患有MDD的受试者中，患有SCHZ的受试者和匹配的受试者的精神状态正常 控制。这项拟议的研究将阐明被破坏的大脑皮层回路 与精神病和抑郁症状有关，可能还涉及皮质部位 抗抑郁和抗精神病药物的作用。

DESCRIPTION: (provided by applicant) There are established differences and similarities in phenomenology and treatment between schizophrenia (SCHZ) and major depressive disorder (MDD). It is well known that depressed symptoms occur in SCHZ and psychotic symptoms are no uncommon for MDD. It is therefore justified to postulate that different brain regions and/or different cell types using specith neurotransmitters are crucial to distinguish the neuropathology of both disorders. Neuroimaging evidence implicates the dorsolateral prefrontal (dIPFC) and orbitofrontal (ORB) cortical areas in the neuropathology of SCHZ and MDD. Our recent quantitative histopathological studies in postmortem tissue reveal the differential involvement of the dIPFC and ORB region in the neurobiology of MDD and SCHZ. However, the specific types of neurons and glia, which underlie the prefrontal pathology of these mental disorders have not been identified yet. The overall objective of this proposal is to distinguish MDD and SCFIZ by using quantitative immunohistochemistry to identify the region-and layer-specific biochemical types o vulnerableneurons and glia constituting dysfunctional prefrontal Circuits. The specific hypotheses are: 1) Subjects with MDD will be characterized by lower numbers of immunoreactive neurons and glia and lower levels of trophic factors, BDNF an GDNF in both dIPFC and ORB. In contrast, subjects with SCHZ will exhibit reductions similar to MDD only in the ORI region, whereas in the dIPFC, SCHZ will be distinguished from MDD by higher neuronal and possibly, glial cell number. 2 Cellular changes observed in prefrontal regions from MDD and SCHZ patients are due to the disease process and therefore they will not be found in analogous regions from rat brains treated chronically with antidepressant or antipsychotic medications If these hypotheses are proven, a provocative interpretation would be that anatomic-functional changes in the dIPFC may b related to cognitive dysfunction. Where as changes in the ORB may be related to depressive symptoms. To test these hypotheses vulnerable cell types will be identified and quantified by the combination of immunohistochemistry and 3-D non-biase stereology. We will identify prefrontal cells with specific antibodies (Nonpyramidal neurons with antibodies to Ca2 binding proteins; Pyramidal neurons with antibodies against neurofilament protein NF-200; Astroglia with an antibody to GFAP; ani-Microglia with antibodies against the bchemokine receptor in subjects with MDD, subjects with SCHZ and in match psychiatrically-normal controls. The proposed study will illuminate disrupted cortical circuits involved in psychotic and depressed symptomatology and possibly cortical Sites of action for antidepressant and antipsychotic medications.