SCHIZOPHRENIA LIKE HIPPOCAMPAL NEUROPATHY

SDA提供的指导和资源将用于 检测前脑神经化学指标的动物模型 精神分裂样的海马神经病。大量研究表明， 死后颞骨的形态和神经化学异常 精神分裂症患者的脑叶。然而，它的潜在贡献是 这些异常与多巴胺能功能障碍有关 在动物模型中，精神分裂症在很大程度上被忽视。解剖学和 行为研究间接地暗示了 兴奋性海马区传入与富含多巴胺的皮质和皮质下 区域。计划在SDA资助期内进行的实验 将在大鼠身上测试一系列关于神经化学变化的假说 在海马体扰动后的特定大脑结构中。在 初步实验，将产生分级的海马细胞丢失 成年大鼠侧脑室(Icv)注射 刺激性毒素，海藻酸。在特定的损伤后间隔，环境和 伏隔核中的时相神经递质释放将被评估， 纹状体和前额叶皮质。胞外浓度 多巴胺、谷氨酸和天冬氨酸将在每个大脑区域进行量化 使用最先进的微渗析技术和高性能液体 层析与电化学检测联用。量化 放射自显影也将被用来评估海马体的影响 多巴胺受体结合的损伤，包括最近发现的D3 和D4受体，在特定的大脑区域。在三套紧密的 相关实验，申请人还打算：1)比较 海马区其他部位损伤的神经化学效应 海马区外扰动对海马区KA后效应的影响 损害，2)比较围产期兴奋性毒性的神经化学效应 损伤后观察成年大鼠海马KA损伤后的影响，以及 3)观察抗精神病药物对大鼠海马区的神经化学作用。 残废的动物。兴奋性氨基酸和多巴胺的释放模式 将在这些研究中的动物和多巴胺之间进行比较 受体结合将在前两组之间进行比较 实验。这些研究应进一步界定 前脑神经化学功能的边缘和非边缘通路。 更重要的是，这些结果可能会加深我们对 精神分裂症的病理生理学和导致小说的发展 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.