SCHIZOPHRENIA LIKE HIPPOCAMPAL NEUROPATHY

由SDA提供的指导和资源将用于 在动物模型中检查前脑神经化学指标， 精神分裂症样海马神经病变 大量研究表明 死后颞叶的形态测量和神经化学异常 精神分裂症患者的脑叶。 然而， 这些与多巴胺能功能障碍相关的异常， 在动物模型中，精神分裂症在很大程度上被忽视了。 解剖和 行为研究间接地暗示了 兴奋性海马传入神经和富含多巴胺的皮质和皮质下神经 地区 在SDA资助期内计划进行的实验 将在老鼠身上测试一系列关于神经化学变化的假设， 在海马扰动后的特定脑结构中。 在 在第一组实验中，将产生分级的海马细胞损失 在成年大鼠脑室内（ICV）注射 兴奋毒素海人酸 在特定的损伤后间隔，环境和 在延髓核中评估阶段性神经递质释放， 纹状体和前额叶皮层 的胞外浓度 多巴胺、谷氨酸和天冬氨酸将在每个脑区定量 使用最先进的微透析技术和高性能液体 色谱联用电化学检测。 定量 放射自显影术也将用于评估海马神经元的作用。 多巴胺受体结合的损伤，包括最近发现的D3 和D4受体。 在三组紧密的 在相关实验中，申请人还打算：1）比较 海马结构其他部位病变的神经化学作用， 海马KA后观察到的海马外扰动效应 病变，2）比较围产期兴奋性毒性的神经化学作用 在成年人海马KA损伤后观察到的影响， 3)观察抗精神病药物对脑缺血再灌注损伤的神经化学作用。 受损的动物 兴奋性氨基酸和多巴胺释放模式 将在这些研究中的动物之间进行比较， 受体结合将在前两组之间进行比较 实验 这些研究应进一步确定 前脑神经化学功能的边缘系统和非边缘系统通路。 更重要的是，这些结果可能会进一步加深我们对 精神分裂症的病理生理学，并导致新的发展 治疗策略

The guidance and resources provided by the SDA will be directed towards examining forebrain neurochemical indices in an animal model of schizophrenia-like hippocampal neuropathy. Numerous studies have revealed morphometric and neurochemical abnormalities post-mortem in the temporal lobe of schizophrenic individuals. However, the potential contribution of these abnormalities to the dopaminergic dysfunction associated with schizophrenia has been largely ignored in animal models. Anatomical and behavioral studies have indirectly implicated a functional link between excitatory hippocampal afferents and dopamine-rich cortical and subcortical areas. The experiments planned for the tenure of the SDA funding period will test a series of hypotheses in the rat regarding neurochemical changes in specific brain structures following hippocampal perturbations. In the primary set of experiments, graded hippocampal cell loss will be produced in adult rats by intracerebroventricular (ICV) injection of the excitotoxin, kainic acid. At specific post-lesion intervals, ambient and phasic neurotransmitter release will be assessed in the nucleus accumbens, corpus striatum, and prefrontal cortex. Extracellular concentrations of dopamine, glutamate and aspartate will be quantified in each brain area using state-of-the-art microdialysis techniques and high-performance liquid chromatography coupled with electrochemical detection. Quantitative autoradiography will also be used to assess the effects of hippocampal lesions on dopamine receptor binding, including the recently discovered D3 and D4 receptors, in specific brain areas. In three sets of closely related experiments, the applicant also intends to: 1) compare the neurochemical effects of lesions elsewhere in the hippocampal formation and extrahippocampal perturbations to effects observed after hippocampal KA lesions, 2) compare the neurochemical effects of perinatal excitotoxic lesions to the effects observed after hippocampal KA lesions in adults, and 3) observe the neurochemical effects of neuroleptics in hippocampally- lesioned animals. Patterns of excitatory amino acid and dopamine release will be compared between animals in each of these studies, and dopamine receptor binding will be compared between groups in the first two experiments. These studies should further define the contributions of limbic and non-limbic pathways to forebrain neurochemical functioning. More importantly, the results may further our understanding of the pathophysiology of schizophrenia and lead to the development of novel therapeutic strategies.