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MODEL OF SCHIZOPHRENIA--ROLE OF CORTICAL DOPAMINE

精神分裂症模型--皮质多巴胺的作用

基本信息

批准号：
6539112
负责人：
JANET M FINLAY
金额：
$ 13.94万
依托单位：
WESTERN WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-01 至 2005-05-31
项目状态：
已结题

项目摘要

Postmortem studies indicate that the dopamine (DA) innervation of prefrontal cortex (PFC) is diminished in schizophrenic subjects. Furthermore, neurodevelopmental disruptions involving mesoprefrontal DA neurons are thought to contribute to the pathophysiology of schizophrenia and could, in part, account for the emergence of symptoms as the individual matures. To determine the potential functional consequences of this structural abnormality, I will examine whether partial loss of DA axons in the prefrontal cortex (PFC) sustained early in development (12 days of age) differentially affect function of PFC in the prepubertal and adult rat. First, we will examine the effect of partial loss of DA axons sustained early in development on local extracellular DA in PFC of the prepubertal and adult rat (Aim 1). Our recent studies indicate that 60% loss of DA axons in PFC sustained immediately prior to puberty (40 days of age), decreased basal and stress- evoked extracellular DA in PFC of the adult rat (68 days of age). Thus, moderate loss of DA fibers as recently observed in PFC of schizophrenic subjects, may be sufficient to impair the function of PFC. I will also examine the effects of partial loss of DA axons in PFC sustained early in development on the ability of the PFC to regulate the neurochemical activity of a subcortical target area, the mesoaccumbens DA projection (Aim 2). Previously, it has been suggested that diminished activity of mesoprefrontal DA neurons augments the activity of subcortical DA neurons and that both events contribute to the pathophysiology of schizophrenia. Our own studies indicate that partial loss of DA axons in PFC sustained immediately prior to puberty, increased stress-evoked DA release in the NAS shell of adult rats. Finally, we will examine the impact of partial loss of DA axons in PFC sustained early in development on behaviors thought to be modulated by mesoprefrontal and mesoaccumbens DA neurons in the prepubertal and adult rat (Aim 3). It has been suggested that dysfunction of mesoprefrontal and mesoaccumbens DA neurons together give rise to some of the behavioral symptoms of schizophrenia. Previously, we reported that partial loss of DA axons in PFC sustained immediately prior to puberty attenuated amphetamine-evoked DA release in the NAS core and amphetamine-induced motor behavior in adult rats. Together, the latter findings suggest that neurochemical interactions between mesocortical and mesoaccumbens DA neurons ultimately play a role in the expression of behavior. The present studies will correlate changes in the activity of mesoprefrontai and mesoaccumbens DA neurons with performance on a delayed response task, motor behavior, and the behavioral response to appetitive and aversive stimuli.

尸检研究表明，精神分裂症患者前额叶皮层（PFC）的多巴胺（DA）神经支配减少。此外，涉及中前额DA神经元的神经发育中断被认为有助于精神分裂症的病理生理学，并且可以部分地解释随着个体成熟而出现的症状。为了确定这种结构异常的潜在功能后果，我将研究是否部分损失的DA轴突在前额叶皮层（PFC）持续早期发展（12天的年龄）差异影响功能的PFC在青春期前和成年大鼠。首先，我们将研究部分损失的DA轴突持续在发展早期对本地细胞外DA在PFC的青春期前和成年大鼠（目的1）。我们最近的研究表明，PFC中60%的DA轴突损失持续到青春期前（40日龄），减少基础和应激诱发的细胞外DA在成年大鼠（68日龄）PFC中。因此，中度损失的DA纤维，最近观察到PFC的精神分裂症患者的科目，可能足以损害PFC的功能。我还将研究部分损失的DA轴突在PFC持续发展的早期PFC的能力，以调节神经化学活性的皮质下靶区，中脑DA投射（目的2）的影响。以前，它已被建议，减少活动的mesoprefrontal DA神经元增强的活动皮层下DA神经元，这两个事件有助于精神分裂症的病理生理。我们自己的研究表明，部分损失的DA轴突在PFC持续青春期前不久，增加应激诱发的DA释放在NAS壳的成年大鼠。最后，我们将研究PFC中DA轴突的部分丧失对发育早期大鼠行为的影响，这些行为被认为是由青春期前和成年大鼠中的中前额叶和中脑DA神经元调制的（目的3）。有人认为，中前额叶和中脑多巴胺能神经元的功能障碍共同引起精神分裂症的一些行为症状。在此之前，我们报道了PFC中DA轴突的部分损失在青春期之前立即持续衰减安非他明诱发的DA释放在NAS核心和安非他明诱导的成年大鼠的运动行为。总之，后者的研究结果表明，mesocortical和mesocorbens DA神经元之间的神经化学相互作用，最终发挥作用的行为表达。目前的研究将相关的mesoprefrontai和mesoprefronbens DA神经元的活动与性能上的延迟反应任务，运动行为，以及对食欲和厌恶刺激的行为反应的变化。