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'Partial' Rodent Model for GABA Defect in Schizophrenia

精神分裂症 GABA 缺陷的“部分”啮齿动物模型

基本信息

批准号：
7162161
负责人：
Sabina Berretta
金额：
$ 20.61万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-13 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7162161
关键词：
Affect Age Akinetic Mutism Amygdaloid structure Animal Model Anterior Autopsy Behavioral Bicuculline Bilateral Biological Assay Brain imaging Brain region Calcium-Binding Proteins Cannulas Carboxy-Lyases Cells Cholecystokinin Chronic Classification Clinical Complex Consensus Continuous Infusion Defect Depth Development Disease Disruption Dissection Dorsal Dose Emotional Emotions Experimental Designs Experimental Models Face Facial Expression Functional disorder Globus Pallidus Glutamate Receptor Glutamates Goals Hallucinations Hippocampus (Brain)Human Impairment In Situ Hybridization Infarction Infusion procedures Interneurons Investigation Lesion Light Link Measures Medial Medial Dorsal Nucleus Messenger RNA Methods Microscopic Modeling N-Methyl-D-Aspartate Receptors N-Methylaspartate NR1 gene Neurons Nucleus Accumbens Outcome Measure Parvalbumins Pathogenesis Peptides Pharmaceutical Preparations Physiological Picrotoxin Placement Play Population Prefrontal Cortex Principal Investigator Process Protein Isoforms Proteins Rattus Reporting Rodent Model Role Schizophrenia Sensory Severities Simulate Site Solid Source Symptoms Temporal Lobe Testing Thalamic structure Thinking Time Ventral Tegmental Area Week Withdrawal Work alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid amino 3 hydroxy 5 methylisoxazole 4 propionate base behavior test calbindin-D28K calretinin cingulate gyrus day density design dopamine system entorhinal cortex experience gamma-Aminobutyric Acid human NR1 protein immunocytochemistry insight mRNA Expression neural circuit neurochemistry neuronal circuitry pars compacta postnatal prepulse inhibition programs receptor receptor expression research study response selective attention social social communication transmission process uptake

项目摘要

DESCRIPTION (provided by applicant): There is growing consensus that multiple limbic regions, including the anterior cingulate gyrus (ACG) and amygdala, are involved in the pathophysiology of schizophrenia. The aim of the proposed investigations is to use a 'partial' rodent model to dissect out, from a complex network of corticolimbic circuitry, one potential source of abnormal input to other limbic brain regions, and to investigate its effects using cytochemical assays and behavioral testing. In particular, these studies are focused on the hypothesis that, in schizophrenia, abnormalities in ACG may, in turn, induce secondary changes in amygdala. ACG and amygdala are massively interconnected and their role in the pathophysiology of schizophrenia is gaining growing support. Solid evidence indicates the presence in ACG of a disruption of GABAergic transmission. In these studies, such a disruption will be mimicked pharmacologically by local chronic infusion of a GABAA receptor antagonist in the ACG of young rats. Neurochemical changes induced in amygdala will be investigated using a time-course experimental design. In particular, densities of neurons expressing ionotropic glutamate receptors and glutamate amino decarboxylase (in situ hybridization and immunocytochemistry) and neuronal subpopulations expressing glutamate, GABA or the calcium binding proteins parvalbumin, calretinin or calbindin D28k (immunocytochemistry) will be measured in each amygdalar subdivision following 1, 2, 4 weeks of chronic, continuous, infusion of a GABAA receptor antagonist in ACG or 3 months after the end of a 4 weeks treatment. These neurochemical changes will be then correlated to measures of startle responsivity in order to assess the validity of this model in reproducing behavioral deficits described in schizophrenia. The combination of these methods will work synergistically to shed light on inter-related changes within distinct neural circuitry and their effect on lasting behavioral abnormalities. The significance of these studies resides in their potential of providing functional links between neurochemical abnormalities in schizophrenia detected in interconnected limbic brain regions.

描述（由申请人提供）：越来越多的共识是，包括前扣带回（ACG）和杏仁核在内的多个边缘系统区域参与精神分裂症的病理生理学。拟议的调查的目的是使用一个“部分”啮齿动物模型解剖出，从一个复杂的网络皮质边缘电路，一个潜在的来源异常输入到其他边缘脑区，并调查其影响使用细胞化学分析和行为测试。特别是，这些研究都集中在假设，在精神分裂症中，ACG异常，反过来，可能会引起杏仁核的继发性变化。ACG和杏仁核是大量相互关联的，它们在精神分裂症的病理生理学中的作用越来越受到支持。确凿的证据表明ACG中存在GABA能传递中断。在这些研究中，将通过在年轻大鼠的ACG中局部慢性输注GABAA受体拮抗剂来模拟这种破坏。杏仁核中诱导的神经化学变化将采用时程实验设计进行研究。特别是，表达离子型谷氨酸受体和谷氨酸氨基脱羧酶的神经元密度（原位杂交和免疫细胞化学）和表达谷氨酸、GABA或钙结合蛋白小清蛋白、钙视网膜蛋白或钙结合蛋白D28k的神经元亚群（免疫细胞化学）将在慢性，连续，在ACG中输注GABAa受体拮抗剂或在4周治疗结束后3个月。然后将这些神经化学变化与惊吓反应的测量相关联，以评估该模型在再现精神分裂症中描述的行为缺陷中的有效性。这些方法的结合将协同工作，阐明不同神经回路内的相互关联的变化及其对持久行为异常的影响。这些研究的意义在于它们提供了在相互连接的边缘脑区域中检测到的精神分裂症神经化学异常之间的功能联系的潜力。