EFFECTS OF PARTIAL LOSS OF DOPAMINE INPUTS ON PREFRONTAL CORTICAL FUNCTION

正如中心概述中所总结的，精神分裂症似乎是 与前额叶多巴胺（DA）神经支配减少有关 皮质（PFC）。然而，这种赤字的功能影响，特别是 PFC电路的其他元件， 精神分裂症，还没有得到很好的表征。拟议的实验 将使用大鼠模型和体内神经化学方法来检查四个 与此相关的问题：（1）DA损失的影响是什么 PFC中的轴突在这个区域的细胞外DA上？(2)有何影响 这种γ-氨基丁酸（GABA）中间神经元功能的丧失 在PFC？(3)PFC中DA的丢失是否改变PFC的调节能力 它的一个皮质下靶点中脑多巴胺的活性 投影？(4)PFC中DA轴突的丢失是否持续早期， 发育产生的PFC功能变化不同于 在成年时受损的大鼠中观察到的？神经化学实验描述了 在本项目中，补充项目恩典的研究， Barrionuevo，探索调节电生理的因素， 大鼠和猴PFC活性。此外，拟议的 实验将产生关于神经化学相互作用的信息， 用于指导数据解释的大鼠PFC 在精神分裂症受试者的行为和成像研究中收集 （Projects-Cohen和Project-Sweeney），以及生成假设 关于精神分裂症的神经化学缺陷， 在功能成像研究（项目科恩和斯威尼）测试或 尸检组织分析（路易斯项目）。

As summarized in the Center Overview, schizophrenia appears to be associated with a reduction in the dopamine (DA) innervation of prefrontal cortex (PFC). However, the functional impact of such a deficit especially on other elements of PFC circuitry that are though to be dysfunctional schizophrenia, has not been well characterized. The proposed experiments will use a rat model and in vivo neurochemical methods to examine four questions relevant to this issue: (1) What is the impact of loss of DA axons in PFC on extracellular DA in this region? (2) What is the impact of this loss on the function of gamma-aminobutyric acid (GABA) interneurons in PFC? (3) Does loss of DA in PFC alter the ability of PFC to regulate the activity of one of its subcortical targets, the mesoaccumbens DA projection? (4) Does loss of DA axons in PFC sustained early in development produce changes in PFC function that are different from those seen in rats lesioned as adults? The neurochemical experiments described in the present project complement the studies of Projects Grace and Barrionuevo, which explore factors regulating the electrophysiological activity of PFC in rat and monkey. In addition, results of the proposed experiments will generate information about neurochemical interactions in the PFC of rat that will be used to guide the interpretation of data collected in behavioral and imaging studies in schizophrenic subjects (Projects-Cohen and Project-Sweeney), as well as to generate hypotheses regarding the neurochemical deficits of schizophrenia that may then be tested in functional imaging studies (Projects-Cohen and Sweeney) or be analysis of postmortem tissue (Project-Lewis).