Molecular Responses of Corticostriatal Pyramidal Cells to Antipsychotic Drugs

皮质纹状体锥体细胞对抗精神病药物的分子反应

• 批准号: 8150117
• 负责人: NATHANIEL HEINTZ
• 金额: $ 26万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150117
• 关键词: Affect; Antipsychotic Agents; Basal Ganglia; Biochemical; Cells; Cerebral cortex; Cognitive deficits; Collaborations; Corpus striatum structure; Data; Drug effect disorder; Ganglia; Genetic; Immunohistochemistry; In Situ Hybridization; Mediating; Mental disorders; Messenger RNA; Molecular; Molecular Profiling; Mus; Myxoid cyst; Neurons; Patients; Population; Primates; Public Health; Pyramidal Cells; Rodent; Schizophrenia; Symptoms; Testing; Therapeutic Effect; Transgenic Organisms; adapter protein; atypical antipsychotic; cell type; frontal lobe; inter-alpha-inhibitor; member; novel; novel therapeutics; programs; response; transcription factor

Hypofunction of cortico-basal ganglia circuits has been hypothesized to underlie some of the debilitating cognitive deficits and negative symptoms that are seen in schizophrenic patients. Antipsychotics are thought to mediate some of their therapeutic effects by normalizing this activity. However, the precise cell populations and the molecular changes involved in this response are still not fully understood. In Project 2 of this Conte center application, we hypothesize that cell-type specific changes in neurons projecting from the frontal cortex to the basal ganglia occur in response to typical and atypical antipsychotic drugs. To test this hypothesis, we will make use of a novel mRNA translational profiling approach. In Aim 1 of this project, we will perform these studies on two distinct cortico-striatal cell populations we have targeted genetically. In Aim 2, we will characterize two newly generated mouse lines that may give us translational profiling access to two additional cortico-striatal cell populations. Finally, in Aim 3, in collaboration with the other projects of this center, we will perform a functional analysis of molecules identified in our translational profiling studies of Aims 1 and 2.

假设皮质 - 基质神经节回路的功能不全是在精神分裂症患者中看到的一些使人衰弱的认知缺陷和负面症状的基础。抗精神病药被认为可以通过标准化这种活性来介导其某些治疗作用。但是，该反应中涉及的精确细胞群和分子变化仍未完全了解。在此孔戴中心应用的项目2中，我们假设细胞类型的特异性变化从额叶皮层到基底神经节突出的神经元发生了，这是对典型和非典型的抗精神病药的响应。为了检验这一假设，我们将利用一种新型的mRNA翻译分析方法。在该项目的目标1中，我们将对我们在遗传上靶向的两个不同的皮质纹状体细胞群体进行这些研究。在AIM 2中，我们将表征两条新生成的鼠标线，这可能使我们可以翻译分析访问其他两个皮质纹状体细胞群体。最后，在AIM 3中，与该中心的其他项目合作，我们将对AIM 1和2的翻译研究研究中确定的分子进行功能分析。