CORTICAL/SUBCORTICAL CIRCUITS IN SCHIZOPRHENIC BRAIN

这是一项研究皮质-皮质下神经化学回路的提议。 在精神分裂症的死后大脑中。多巴胺能神经功能失调 神经传递经常与发病机制有关。 和/或精神分裂症的症状学，因为所有的抗精神病药物 药物会以某种方式影响多巴胺系统。原版 “精神分裂症的多巴胺假说”假设多巴胺能 在这种疾病中的大脑活动，但更新的证据导致 对这一观点的重新概念化。具体地说，目前的观点是 大脑皮层中的多巴胺能活动减弱，进而 导致纹状体中的多巴胺能活动增加。这种互动 据推测是通过谷氨酸能皮质纹状体传播的 投射。随后的研究表明，皮质纹状体 谷氨酸能和纹状体中的多巴胺能传出神经汇聚在 纹状体，这两个系统之间的动态平衡可能是 在精神分裂症中的重要性。具体地说，有人建议 精神分裂症可能与谷氨酸能减少或增加有关 纹状体中的多巴胺能音，是较大的边缘环路的一部分。 令人惊讶的是，到目前为止，检查的工作相对较少。 这些对原始多巴胺假说的修改版本 精神分裂症。在我们拟议的工作中，我们将采用审查 编码多巴胺和谷氨酸受体的信使RNA片段 死后脑组织以解决解剖学上的特异性表达 这些受体基因，使用了一组特征良好的组织。这些 研究将允许检验这些最近的假说 大脑皮层的多巴胺能和谷氨酸能调节作用 精神分裂症的皮质下回路，即(1)：大脑中的多巴胺 系统在精神分裂症中有不同的调节，表现为 纹状体的张力增加，但边缘的活动减少 以及(2)精神分裂症与大脑皮质功能失调有关。 皮质纹状体谷氨酸能和脑电反馈回路 相互决定神经元活性的中纹状体多巴胺能系统 纹状体皮质信息处理网络。这部作品 代表着对人脑的全面检查的开始 这些关于神经化学和神经解剖学的假说 精神分裂症。这些研究将使我们更好地了解 这种疾病背后的电路，以及它可能被破坏的方式和地点。

This is a proposal to study cortical-subcortical neurochemical circuitry in postmortem brain in schizophrenia. Dysregulation of dopaminergic neurotransmission has been frequently implicated in the pathogenesis and/or symptomatology of schizophrenia, since all antipsychotic medications affect the dopamine system in some fashion. The original "dopamine hypothesis of schizophrenia" posited an increase in dopaminergic activity in the brain in this illness, but more recent evidence has led to a reconceptualization of this view. Specifically, the current view is that there is diminished dopaminergic activity in the cortex, which in turn leads to increased dopaminergic activity in the striatum. This interaction has been postulated to be transmitted via glutamatergic corticostriatal projections. Subsequent refinement suggests that corticostriatal glutamatergic and mesostriatal dopaminergic efferents converge in the striatum, and the dynamic balance between these two systems may be of importance in schizophrenia. Specifically, it has been suggested that schizophrenia may be associated with diminished glutamatergic or increased dopaminergic tone in the striatum, as part of a larger limbic circuit. Surprisingly, relatively little work has been done to date to examine these modified versions of the original dopamine hypothesis of schizophrenia. In our proposed work, we will employ the examination of messenger RNAs encoding dopamine and glutamate receptors in sectioned postmortem brain tissue to address the anatomically specific expression of these receptor genes, using a well-characterized set of tissue. These studies will allow the examination of these recent hypotheses of the involvement of the dopaminergic and glutamatergic regulation of cortical- subcortical circuits in schizophrenia, namely that (1): the brain dopamine systems are differentially regulated in schizophrenia, manifesting increased tone in the striatum but diminished activity in the limbic cortex; and (2) schizophrenia is associated with dysregulation of a feedback circuit consisting of corticostriatal glutamatergic and mesostriatal dopaminergic systems that mutually determine the activity of a striatothalamocortical information-processing network. This work represents the beginning of a comprehensive examination in human brain of these hypotheses of the neurochemistry and neuroanatomy underlying schizophrenia. These studies will provide a greater understanding of the circuitry underlying this illness, and how and where it may be disrupted.