NFAT-mediated gene expression and striatal plasticity

描述(申请人提供)：纹状体有助于我们学习感觉运动任务。它还在很大程度上参与了对成瘾药物的渴求、寻求和自我管理。此外，纹状体功能障碍与各种神经疾病有关。所有这些大脑功能长期变化的一个主要组成部分是纹状体基因表达和蛋白质合成的改变。指导这些神经元可塑性变化的转录因子的多样性现在才被认识到。在神经系统之外，NFATc转录因子是免疫反应、血管和心脏发育以及肌肉生长的关键介质。最近，这些转录因子在大脑中被发现，这一假设的核心假设是NFAT依赖的转录是纹状体可塑性的关键介质。具体目标1将表征4，钙/钙调神经磷酸酶敏感的NFATc亚型在纹状体不同神经元亚群中的表达。具体目标2将阐明由多巴胺受体刺激(D1和D2类)触发的细胞内信号通路，这些信号通路导致NFAT依赖的转录发生变化。 具体目标3将确定急性和/或慢性可卡因暴露是否导致依赖NFAT的转录增加，以及抑制NFAT是否会导致可卡因诱导的行为敏感化减弱。总之，利用现代细胞和分子技术，这项研究将揭示哪些NFATc蛋白在纹状体中表达，激活NFAT依赖的转录的刺激，以及NFAT活性的增加是否与暴露于成瘾药物后观察到的神经元变化有关。最终，这个项目将导致更好地理解NFAT依赖的转录在塑造大脑功能的长期变化中所起的作用。

DESCRIPTION (provided by applicant): The striatum contributes to our ability to learn sensorimotor tasks. It is also heavily involved in the wanting, seeking and self-administration of addictive drugs. Additionally, striatal dysfunction has been linked to a variety of neurological disorders. A major component to all these long-term alterations in brain function is modifications in striatal gene expression and protein synthesis. The diversity of transcription factors that direct these changes in neuronal plasticity are just now being appreciated. Outside of the nervous system, NFATc transcription factors are critical mediators of immune responses, vascular and cardiac development, and muscle growth. Recently, these transcription factors were discovered within brain, and it is the central hypothesis of this proposal that NFAT-dependent transcription is a critical mediator of striatal plasticity. Specific Aim 1 will characterize the expression of the 4, calcium/calcineurin-sensitive NFATc isoforms within the different neuronal subpopulations of the striatum. Specific Aim 2 will elucidate the intracellular signaling pathways triggered by dopamine receptor stimulation (D1- and D2-class) that lead to alterations in NFAT-dependent transcription. Specific Aim 3 will determine whether acute and/or chronic cocaine exposure leads to heightened NFAT-dependent transcription, and also whether inhibition of NFAT results in a diminution of cocaine-induced behavioral sensitization. In sum, utilizing modern cellular and molecular techniques, this study will reveal which NFATc proteins are expressed in the striatum, the stimuli that activate of NFAT-dependent transcription, and whether heightened NFAT activity can be linked to neuronal changes observed following exposure to addictive drugs. Ultimately, this project will lead to a better understanding of the role NFAT-dependent transcription plays in shaping long-term changes in brain function.