Cocaine and Brain Development

可卡因与大脑发育

• 批准号: 7287302
• 负责人: PRADEEP G BHIDE
• 金额: $ 33.24万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7287302
• 关键词: Agonist; Attention; Attenuated; Binding Sites; Biological Assay; Brain; CREB1 gene; Cells; Cerebral cortex; Cerebrum; Clinical Research; Cocaine; Cocaine Abuse; Cyclic AMP; DARPP 32; Development; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Economics; Electroporation; Embryo; Equilibrium; Event; Fetal Cocaine Exposure; Goals; Immigration; Impairment; Knockout Mice; Language Development; Learning; Left; Link; Mediating; Messenger RNA; Molecular; Mus; Neurons; Neurotransmitters; Phosphorylation; Pregnant Women; Preparation; Protein Binding; Public Health; Receptor Activation; Receptor Gene; Receptor Signaling; Recommendation; Reporting; Role; Signal Transduction; Slice; Study Section; Suggestion; System; Testing; Thinking; Wild Type Mouse; base; brain behavior; clinically relevant; day; density; fetal; gain of function; gamma-Aminobutyric Acid; insight; loss of function; maternal cocaine abuse; migration; monoamine; novel; protein expression; receptor; receptor binding; research study; response

DESCRIPTION (provided by applicant): The long term goals of the project are to determine if the effects of maternal cocaine abuse on fetal brain development are mediated by impairment of dopamine receptor signaling mechanisms. The specific goal of the current proposal is to examine if cocaine-induced impairment of dopamine receptor signaling contributes to deficits in neuronal migration in mouse embryos. Prenatal cocaine exposure appears to decrease GABA neuron migration from the ganglionic eminence to the cerebral wall in the embryonic mouse brain. Dopamine receptor activation also influences this migration. Prenatal cocaine exposure impairs dopamine receptor signaling. Therefore, we hypothesize that prenatal cocaine exposure interferes with GABA neuron migration from the ganglionic eminence to the cerebral wall by impairing dopamine receptor signaling mechanisms. We propose 3 Specific Aims to test our hypothesis. Specific Aim 1 will examine cocaine-induced changes in dopamine receptor signaling by quantitative analysis of receptor mRNA, protein, binding sites, agonist- induced cyclic AMP synthesis, phosphorylation of CREB and DARPP 32. Specific Aim 2 will determine if the deficits in GABA neuron migration produced by the cocaine exposure can be restored by electroporation of dopamine receptor constructs into neurons of the ganglionic eminence. Specific Aim 3 will use dopamine receptor knockout mice and a combination of loss and gain of function assays to confirm the role of these receptors in neuronal migration. The GABA neurons that migrate from the ganglionic eminence to the cerebral wall establish inhibitory circuits throughout the cerebral cortex. Clinical studies show that prenatal cocaine exposure causes lasting deficits in GABA-mediated functions, such as attention, language development and learning. Imbalance in the dopaminergic system of the developing brain also can cause similar impairments. Therefore, the focus of the proposed experiments on GABA neuron migration, gestational cocaine exposure and dopamine receptor signaling has significant clinical relevance. Cocaine abuse by pregnant women continues to be a major public health and socio-economic concern. Yet cellular and molecular mechanisms of cocaine's action on the developing brain are incompletely understood. The proposed studies promise novel insights into the mechanism of cocaine's action on fetal brain development by examining the link between cocaine, dopamine and development of GABA circuits.

描述（由申请人提供）：该项目的长期目标是确定母亲滥用可卡因对胎儿大脑发育的影响是否是由多巴胺受体信号传导机制受损介导的。当前提案的具体目标是检查可卡因引起的多巴胺受体信号传导损伤是否会导致小鼠胚胎神经元迁移缺陷。产前接触可卡因似乎会减少胚胎小鼠大脑中 GABA 神经元从神经节隆起向脑壁的迁移。多巴胺受体激活也会影响这种迁移。产前接触可卡因会损害多巴胺受体信号传导。因此，我们假设产前接触可卡因会通过损害多巴胺受体信号传导机制来干扰 GABA 神经元从神经节隆起迁移到脑壁。我们提出 3 个具体目标来检验我们的假设。具体目标 1 将通过定量分析受体 mRNA、蛋白质、结合位点、激动剂诱导的环 AMP 合成、CREB ​​和 DARPP 32 的磷酸化来检查可卡因诱导的多巴胺受体信号传导变化。具体目标 2 将确定是否可以通过将多巴胺受体构建体电穿孔到可卡因暴露产生的 GABA 神经元迁移缺陷来恢复 神经节隆起的神经元。 Specific Aim 3 将使用多巴胺受体敲除小鼠以及功能丧失和获得的组合检测来确认这些受体在神经元迁移中的作用。从神经节隆起迁移到脑壁的 GABA 神经元在整个大脑皮层建立抑制回路。临床研究表明，产前接触可卡因会导致 GABA 介导的功能持久缺陷，例如注意力、语言发育和学习。发育中的大脑的多巴胺能系统的不平衡也会导致类似的损伤。因此，所提出的实验重点是 GABA 神经元迁移、妊娠期可卡因暴露和多巴胺受体信号传导，具有重要的临床意义。孕妇滥用可卡因仍然是一个主要的公共卫生和社会经济问题。然而，可卡因对大脑发育的作用的细胞和分子机制尚不完全清楚。拟议的研究通过检查可卡因、多巴胺和 GABA 回路发育之间的联系，有望为可卡因对胎儿大脑发育的作用机制提供新的见解。