CORTICAL/SUBCORTICAL CIRCUITS IN SCHIZOPRHENIC BRAIN

这是一个研究皮层-皮层下神经化学回路的提议 在精神分裂症的死后大脑中。多巴胺能神经调节异常 神经传递经常与发病机制有关 和/或精神分裂症，因为所有抗精神病药 药物以某种方式影响多巴胺系统。原始 “精神分裂症的多巴胺假说”假设多巴胺能神经元的增加， 在这种疾病的大脑活动，但最近的证据已经导致 这一观点的重新概念化。具体而言，目前的观点是， 大脑皮层中的多巴胺能活动减少， 导致纹状体多巴胺能活性增加。这种相互作用 据推测是通过多巴胺能皮质纹状体 预测。随后的改进表明，皮质纹状体 多巴胺能和纹状体中膜多巴胺能传出会聚于 纹状体，这两个系统之间的动态平衡可能是 精神分裂症的重要性。具体而言，有人建议， 精神分裂症可能与减少或增加的多巴胺能有关。 纹状体中的多巴胺能张力，作为更大的边缘回路的一部分。 令人惊讶的是，迄今为止， 这些原始多巴胺假说的修正版本 精神分裂症在我们建议的工作中，我们将采用检查 编码多巴胺和谷氨酸受体的信使RNA， 死后脑组织，以解决解剖学上的具体表达， 这些受体基因，使用一组特征良好的组织。这些 研究将允许检查这些最近的假设， 参与多巴胺能和多巴胺能调节皮质- 精神分裂症的皮层下回路，即（1）：大脑多巴胺 系统在精神分裂症中受到不同的调节， 纹状体的张力增加，但边缘系统的活动减少 （2）精神分裂症与大脑皮层的调节障碍有关。 反馈回路由皮质纹状体神经元和 中纹状体多巴胺能系统，相互决定的活动， 纹状体丘脑皮质信息处理网络这项工作 代表了对人类大脑进行全面检查的开始， 这些神经化学和神经解剖学的假设 精神分裂症这些研究将使人们更好地了解 这种疾病背后的电路，以及它如何以及在哪里可能被破坏。

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.