ETIOLOGIC PATHWAYS TO DOPAMINE DYSFUNCTION

多巴胺功能障碍的病因途径

• 批准号: 7643275
• 负责人: STEPHEN RAYPORT
• 金额: $ 21.37万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7643275
• 关键词: Acute; Adolescence; Adolescent; Affect; Amphetamines; Behavior; Behavioral; Brain; Brain imaging; Candidate Disease Gene; Cerebrum; Chemistry; Chromosome Pairing; Clinical Data; Cognitive; Corpus striatum structure; Development; Disruption; Dopamine; Dopamine Agonists; Dopamine Receptor; Etiology; Fiber; Fire - disasters; Functional disorder; Gene Expression; Glutamate Receptor; Glutamates; Goals; Heterozygote; Knock-out; Ligand Binding; Magnetic Resonance Imaging; Methylazoxymethanol Acetate; Microarray Analysis; Microdialysis; Modeling; Morphology; Mus; N-Methyl-D-Aspartate Receptors; NRG1 gene; Neuregulin 1; Neurons; PLAB Protein; Pathogenesis; Pathway interactions; Patients; Phosphate Activated Glutaminase; Physiology; Receptor Activation; Schizophrenia; Structure; Synapses; Synaptic Transmission; Time; Tyrosine 3-Monooxygenase; Weaning; day; dopamine system; dopaminergic neuron; endophenotype; frontal lobe; in vivo; mouse model; nerve supply; novel therapeutics; presynaptic; receptor expression; response; synaptic function; synthetic enzyme

The premise of this Conte Center application is that cortical disruption of glutamatergic synaptic function is the final common pathway in schizophrenia, manifesting in schizophrenia-associated behaviors, a dopamine-imbalance endophenotypes and adolescent-onset aberrations in brain structure/function. The goal of this project is to generate mouse models with a plausible etiology, and to ask whether the models are associated with dopaminergic and glutamatergic abnormalities replicating those seen in patients undergoing brain imaging. The models are an example of timed disruption of cerebral cortical development, administration of the neuronal DNA-methylating agent methylazoxymethanol acetate (MAM) at gestational day 16, a linkage-validated neurodevelopmental model, the NRG1 heterozygote knockdown, and a subtle presynaptic cortical glutamatergic deficit, a restricted knockdown or knockout of the glutamate-synthetic enzyme phosphate-activated glutaminase. These mechanistically distinct mouse models will be studied in concert with the goal of identifying: Aim 1. Dopamine system alterations, looking at the behavioral response to dopaminergic agonists in acute and sensitization paradigms, baseline and amphetamine-stimulated dopamine efflux in the striatum and frontal cortex using in vivo microdialysis, dopamine receptor expression, dopaminergic innervation of stereological quantification of tyrosine hydroxylase-positive fibers, and abnormalities in expression of genes regulated by dopamine in striatum and cortex. Aim 2. Glutamatergic alterations in cortex, looking at frontal-cortical dependent cognitive/behavioral functions, changes in gross morphology and activity using MRI, synapse-associated gene expression using microarray technology, NMDA receptor expression by rt-PCR and by ligand binding, and glutamatergic synaptic transmission and plasticity. Aim 3. glutamate receptor activation or direct stimulation of the frontal cortex affect dopamine neuron firing and dopamine efflux. Aim 4. Development of schizophrenia-associated alterations, looking at young mice prior to weaning and in adolescence, to verify adolescent onset of schizophrenia associated findings. Taken together, the mouse models in this Project together with those in Project by Kandel should identify a possible final common pathway in the pathogenesis of schizophrenia, which can be most effectively analyzed in mice with studies spanning behavior, chemistry, physiology and gene expression. As candidate genes can be validated by correlations with clinical data, new therapeutic directions should become evident.

该孔戴中心应用的前提是，谷氨酸能突触功能的皮质破坏是精神分裂症的最终途径，在精神分裂症相关的行为中表现出来，多巴胺不平衡的内表型和大脑结构/功能中的青少年含量差异。该项目的目的是生成具有合理病因的小鼠模型，并询问模型是否与多巴胺能和谷氨酸能异常相关，以复制在接受脑成像的患者中看到的。 The models are an example of timed disruption of cerebral cortical development, administration of the neuronal DNA-methylating agent methylazoxymethanol acetate (MAM) at gestational day 16, a linkage-validated neurodevelopmental model, the NRG1 heterozygote knockdown, and a subtle presynaptic cortical glutamatergic deficit, a restricted knockdown or knockout of the谷氨酸合成酶磷酸激活的谷氨酰胺酶。这些机械上不同的鼠标模型将与识别目的协同研究：目标1。多巴胺系统的改变，查看对急性和敏化范式中对多巴胺能激动剂的行为反应，基线和苯丙胺刺激的多巴胺外冲上方中使用纹状体和内部colterex中的多种多巴胺剂量的dopivo Microdia，dopamisis sirodiaia dopamisis，dopamine microdiaia dopamisis sirodiace dopamisis sirodiace microdia ississ，酪氨酸羟化酶阳性纤维的立体定量，以及在纹状体和皮质中由多巴胺调节的基因表达异常。 AIM 2。皮质的谷氨酸能改变，着眼于额叶皮质依赖性认知/行为功能，使用MRI的总形态和活性变化，使用Microaray技术，NMDA受体表达，通过RT-PCR和配体结合和谷胱甘肽结合以及谷胱甘肽的突触传播和塑性率。 AIM 3。谷氨酸受体激活或直接刺激额叶皮质会影响多巴胺神经元的触发和多巴胺外排。目标4。与精神分裂症相关的变化的发展，在断奶和青春期之前研究年轻小鼠，以验证精神分裂症相关发现的青少年发作。综上所述，该项目中的小鼠模型以及坎德尔项目中的小鼠模型应确定精神分裂症发病机理中可能的最终共同途径，可以在小鼠中通过跨越行为，化学，生理学和基因表达的研究对小鼠进行最有效的分析。由于可以通过与临床数据的相关性来验证候选基因，因此应明显的新治疗方向。