In vivo studies of Neuregulin 1 in addiction pathways

Neuregulin 1 在成瘾途径中的体内研究

• 批准号: 6958241
• 负责人: Lorna W Role
• 金额: $ 12.6万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-05 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6958241
• 关键词: behavior test; behavioral /social science research tag; behavioral genetics; drug addiction; gene deletion mutation; genetically modified animals; genotype; hippocampus; laboratory mouse; microelectrodes; neural plasticity; neuregulins; neurogenetics; neuropsychology; neuroregulation; nicotine; nicotinic receptors; nucleus accumbens; phenotype; schizophrenia; voltage /patch clamp

DESCRIPTION (provided by applicant): The heaviest smoking populations in the US include patients with schizophrenia (SZ). Research indicates that nicotine may constitute an important form of self-medication for such patients, particularly in its effects on the pathognemonic deficits of sensory-gating. Recent studies demonstrate a higher degree of dependence on nicotine in SZ vs. control populations. Genetic variations in the alpha 7 nicotinic acetylcholine receptor (a7*-nAChR) are linked with the sensory gating deficits associated with SZ. Likewise, genetic variants of Neuregulin 1 (Nrg1), a key regulator of (a7*-nAChRs), have recently been associated with heritab e forms of SZ. These observations prompt our proposal of convergent effects on Nrg1 and a7*-expression in the co-morbidity of nicotine abuse and susceptibility to neuropsychiatric disorders such as SZ. CEBRA stage 1 funding is sought to initiate in vivo electrophysiology and behavioral studies in single and compound genetically-modified mice. The genetically altered lines to be examined include the isoform specific: Type Ill-Nrg1 heterozygous mutant (Nrg1) and the a7 nAChR subunit mutant Chrna7(). Proposed studies begin tests of the hypothesized convergence of Nrg1 and a7 regulation as heritable components of susceptibility to nicotine effects, tobacco dependence and facets of SZ phenotypes by comparison of mice prenatal nicotine exposure. Thus, the AIM of this STAGE 1 Application is to initiate tests of whether deficits in Nrg1 (with and without deficits in a7) alter the development, maintenance and/or plasticity of hippocampal-accumbens circuits in vivo. Assessment of genotype dependent changes in synaptic circuits and nicotine-induced excitability in intact systems examine ventral hippocampal-striatal interactions using in vivo intracellular and multi unit recordings. The impact of genetic profile on excitatory-input gating to the ventral striatum and on the effects of nicotine will be assessed in parallel behavioral studies and recordings from adult mice subjected to prenatal and/or acute nicotine exposure.

描述（由申请人提供）：美国最重的吸烟人群包括精神分裂症患者（SZ）。研究表明，尼古丁可能构成对此类患者的一种重要形式的自我治疗形式，尤其是它对感官门控的病理缺陷的影响。最近的研究表明，在SZ与对照人群中，对尼古丁的依赖程度更高。 Alpha 7烟碱乙酰胆碱受体（A7*-NACHR）的遗传变异与与SZ相关的感觉门控缺损有关。同样，神经蛋白1（NRG1）的遗传变异是（A7*-NACHRS）的关键调节剂，最近与Heritab E形式的SZ相关联。这些观察结果促使我们对NRG1和A7*表达的收敛效应提出了建议，这些毒物滥用的合并症以及对SZ等神经精神疾病的敏感性。 CEBRA 1阶段的资金寻求在单个和复合遗传改性的小鼠中启动体内电生理学和行为研究。要检查的遗传变化线包括同工型特异性：ILL-NRG1杂合突变体（NRG1）和A7 NACHR亚基突变体CHRNA7（）。拟议的研究开始测试NRG1和A7调节的假设收敛性，这是对尼古丁作用易感性，烟草依赖性和SZ表型的易感成分，通过比较小鼠产前尼古丁暴露。因此，本阶段1应用的目的是启动测试NRG1中的缺陷（A7中有和没有缺陷）是否会改变体内海马 - acccumbens Circuits的发育，维持和/或可塑性。使用体内的细胞内和多单位记录来评估完整系统中突触回路和尼古丁诱导的兴奋性的依赖性变化。遗传特征对腹侧纹状体的兴奋性输入和尼古丁的影响的影响将在平行行为研究和受到产前和/或急性尼古丁暴露的成年小鼠的记录中进行评估。