Prefrontal Cell Pathology Distinguishes Mental Disorders

前额叶细胞病理学区分精神障碍

• 批准号: 6400348
• 负责人: GRAZYNA RAJKOWSKA
• 金额: $ 20.04万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-23 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6400348
• 关键词: antidepressants; antipsychotic agents; astrocytes; behavioral /social science research tag; clozapine; desipramine; drug screening /evaluation; glial fibrillary acidic protein; haloperidol; human subject; human therapy evaluation; immunocytochemistry; interneurons; laboratory rat; major depression; mental disorder chemotherapy; microglia; neuroanatomy; neuroimaging; neurotrophic factors; nonhuman therapy evaluation; patient oriented research; postmortem; prefrontal lobe /cortex; schizophrenia; sertraline

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.

描述：（由申请人提供）存在既定差异， 精神分裂症（SCHZ）和 重度抑郁症（MDD）。众所周知，抑郁症的症状 精神病性症状在MDD中并不少见。因此 有理由假设不同的大脑区域和/或不同的细胞类型 特异性神经递质的应用是鉴别神经病理学的关键 这两种疾病。神经影像学证据表明背外侧前额叶 （dIPFC）和眶额（ORB）皮质区在SCHZ神经病理学中的作用 的MDD。我们最近对死后组织的定量组织病理学研究 揭示了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， 这些精神障碍的前额叶病理学基础， 还没确认。本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确定区域和 构成神经元和神经胶质的层特异性生化类型 功能失调的前额叶回路具体假设为：1）主体 MDD的特征是免疫反应神经元数量较少， 胶质细胞和较低水平的营养因子，BDNF和GDNF在dIPFC和ORB。 相比之下，SCHZ受试者仅在以下方面表现出与MDD相似的降低： ORI区域，而在dIPFC中，SCHZ将通过以下方式与MDD区分开 更高的神经元和可能的神经胶质细胞数量。2观察到的细胞变化 MDD和SCHZ患者的前额区是由于疾病过程 因此在大鼠大脑的类似区域中找不到 长期接受抗抑郁或抗精神病药物治疗，如果这些 假设被证明，一个挑衅性的解释是， dIPFC的解剖功能变化可能与认知功能有关。 功能障碍ORB的变化可能与抑郁症状有关。 为了测试这些假设，将识别脆弱的细胞类型， 通过免疫组织化学和3D非偏置酶的组合进行定量 体视学我们会用特定的抗体来识别前额细胞 具有钙结合蛋白抗体的非锥体神经元;锥体神经元 神经元与抗神经丝蛋白NF-200的抗体;星形胶质细胞与抗神经丝蛋白NF-200的抗体。 抗胶质纤维酸性蛋白抗体 在MDD受试者、SCHZ受试者和匹配的精神正常受试者中 对照这项拟议中的研究将阐明被破坏的皮层回路 涉及精神病和抑郁症的神经病学和可能的皮质部位 抗抑郁和抗精神病药物的作用。